Multiple Sclerosis

BERLIN—Applying the 2017 McDonald criteria to children is feasible and allows an earlier diagnosis of multiple sclerosis (MS), according to data described at ECTRIMS 2018. The presence of oligoclonal bands and negativity of myelin oligodendrocyte glycoprotein (MOG)-IgG are informative biomarkers when evaluating the risk of MS in children with a first demyelinating event, said the authors.

Few researchers have examined the application of the revised 2017 McDonald criteria to children. In addition, the role of biomarkers in confirming or ruling out a diagnosis of MS is uncertain. Georgina Arrambide, MD, PhD, a neurologist at Vall d’Hebron University Hospital in Barcelona, and colleagues conducted a prospective cohort study to compare the application of the 2017 and 2010 McDonald criteria in children with a first demyelinating event and to evaluate the contribution of biomarkers (ie, oligoclonal bands, aquaporin 4 [AQP4], and MOG-IgG) in predicting their clinical course.

BERLIN—Applying the 2017 McDonald criteria to children is feasible and allows an earlier diagnosis of multiple sclerosis (MS), according to data described at ECTRIMS 2018. The presence of oligoclonal bands and negativity of myelin oligodendrocyte glycoprotein (MOG)-IgG are informative biomarkers when evaluating the risk of MS in children with a first demyelinating event, said the authors.

Few researchers have examined the application of the revised 2017 McDonald criteria to children. In addition, the role of biomarkers in confirming or ruling out a diagnosis of MS is uncertain. Georgina Arrambide, MD, PhD, a neurologist at Vall d’Hebron University Hospital in Barcelona, and colleagues conducted a prospective cohort study to compare the application of the 2017 and 2010 McDonald criteria in children with a first demyelinating event and to evaluate the contribution of biomarkers (ie, oligoclonal bands, aquaporin 4 [AQP4], and MOG-IgG) in predicting their clinical course.

BERLIN—Applying the 2017 McDonald criteria to children is feasible and allows an earlier diagnosis of multiple sclerosis (MS), according to data described at ECTRIMS 2018. The presence of oligoclonal bands and negativity of myelin oligodendrocyte glycoprotein (MOG)-IgG are informative biomarkers when evaluating the risk of MS in children with a first demyelinating event, said the authors.

Few researchers have examined the application of the revised 2017 McDonald criteria to children. In addition, the role of biomarkers in confirming or ruling out a diagnosis of MS is uncertain. Georgina Arrambide, MD, PhD, a neurologist at Vall d’Hebron University Hospital in Barcelona, and colleagues conducted a prospective cohort study to compare the application of the 2017 and 2010 McDonald criteria in children with a first demyelinating event and to evaluate the contribution of biomarkers (ie, oligoclonal bands, aquaporin 4 [AQP4], and MOG-IgG) in predicting their clinical course.

BERLIN – A delay in undertaking plasma exchange may predict a poorer outcome after a first attack of neuromyelitis optica spectrum disorder, while antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to predict a more positive outcome.

Michele G. Sullivan/MDedge News

“We saw that for each day of delay in plasma exchange, the Expanded Disability Status Scale [EDSS] at 6 months increased by about 0.028 points, indicating a worse prognosis,” Maxime Guillaume, MD, said at the annual congress of the European Committee for Treatment and Research in Multiples Sclerosis.

However, said Dr. Guillaume, a resident at Rouen University Hospital, France, steroids are still a reasonable first-line therapy as long as they are discontinued quickly if they don’t appear to be helping. Plasma exchange is most effective if administered less than 2 weeks after symptom onset.

His study examined 6-month outcomes among 214 attacks in 188 patients; some patients had several first attacks in different areas. Response was defined in two ways. First, patients were clinically classified as having a good response, a bad response, or no response to treatment. The second definition was based on the EDSS. Good response was an EDSS decrease of at least 2 points for an initial score of 3 or higher, or a decrease of 1 point if the initial score was less than 3. Poor response was an EDSS that decreased without reaching these thresholds.

The cohort was largely female, with a mean age of 38 years. Most (55%) were positive for antibodies against aquaporin-4. Anti-MOG antibodies were present in 30%. A total of 7.5% were negative for both antibodies, and the remainder had an undetermined serotype.

The clinical presentations varied. Most frequently, patients presented with myelitis only (44%). This was followed by optic neuritis only (34%), both myelitis and optic neuritis (8%), and myelitis plus brainstem involvement (5%). Other clinical manifestations were acute demyelinating encephalomyelitis, and encephalitis alone.

The most common treatment was methylprednisolone (73%), followed by plasma exchange (25%), which occurred at a median of 9 days after symptom onset.

Outcomes varied according to the definition of response. By clinical characteristics, there was a complete response in 41, a partial response in 122, and no response in 51. By change in EDSS, 136 had a good response and 27 a partial response; 51 were still considered nonresponders.

Dr. Guillaume conducted a multivariate analysis to determine predictive factors. In both definitions, anti-MOG antibodies nearly quadrupled the chance of a good treatment response, and delaying plasma exchange was associated with a significantly increased chance of a poor response. When judged by the clinical response definition, multiple lines of treatment also were associated with a poor response. This, he said, was another reflection of plasma exchange delay.

Dr. Guillaume had no financial disclosures.

msullivan@mdedge.com

SOURCE: Guillaume M. et al. ECTRIMS 2018, Abstract 211.

BERLIN – A delay in undertaking plasma exchange may predict a poorer outcome after a first attack of neuromyelitis optica spectrum disorder, while antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to predict a more positive outcome.

Michele G. Sullivan/MDedge News

“We saw that for each day of delay in plasma exchange, the Expanded Disability Status Scale [EDSS] at 6 months increased by about 0.028 points, indicating a worse prognosis,” Maxime Guillaume, MD, said at the annual congress of the European Committee for Treatment and Research in Multiples Sclerosis.

However, said Dr. Guillaume, a resident at Rouen University Hospital, France, steroids are still a reasonable first-line therapy as long as they are discontinued quickly if they don’t appear to be helping. Plasma exchange is most effective if administered less than 2 weeks after symptom onset.

His study examined 6-month outcomes among 214 attacks in 188 patients; some patients had several first attacks in different areas. Response was defined in two ways. First, patients were clinically classified as having a good response, a bad response, or no response to treatment. The second definition was based on the EDSS. Good response was an EDSS decrease of at least 2 points for an initial score of 3 or higher, or a decrease of 1 point if the initial score was less than 3. Poor response was an EDSS that decreased without reaching these thresholds.

The cohort was largely female, with a mean age of 38 years. Most (55%) were positive for antibodies against aquaporin-4. Anti-MOG antibodies were present in 30%. A total of 7.5% were negative for both antibodies, and the remainder had an undetermined serotype.

The clinical presentations varied. Most frequently, patients presented with myelitis only (44%). This was followed by optic neuritis only (34%), both myelitis and optic neuritis (8%), and myelitis plus brainstem involvement (5%). Other clinical manifestations were acute demyelinating encephalomyelitis, and encephalitis alone.

The most common treatment was methylprednisolone (73%), followed by plasma exchange (25%), which occurred at a median of 9 days after symptom onset.

Outcomes varied according to the definition of response. By clinical characteristics, there was a complete response in 41, a partial response in 122, and no response in 51. By change in EDSS, 136 had a good response and 27 a partial response; 51 were still considered nonresponders.

Dr. Guillaume conducted a multivariate analysis to determine predictive factors. In both definitions, anti-MOG antibodies nearly quadrupled the chance of a good treatment response, and delaying plasma exchange was associated with a significantly increased chance of a poor response. When judged by the clinical response definition, multiple lines of treatment also were associated with a poor response. This, he said, was another reflection of plasma exchange delay.

Dr. Guillaume had no financial disclosures.

msullivan@mdedge.com

SOURCE: Guillaume M. et al. ECTRIMS 2018, Abstract 211.

BERLIN – A delay in undertaking plasma exchange may predict a poorer outcome after a first attack of neuromyelitis optica spectrum disorder, while antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to predict a more positive outcome.

Michele G. Sullivan/MDedge News

“We saw that for each day of delay in plasma exchange, the Expanded Disability Status Scale [EDSS] at 6 months increased by about 0.028 points, indicating a worse prognosis,” Maxime Guillaume, MD, said at the annual congress of the European Committee for Treatment and Research in Multiples Sclerosis.

However, said Dr. Guillaume, a resident at Rouen University Hospital, France, steroids are still a reasonable first-line therapy as long as they are discontinued quickly if they don’t appear to be helping. Plasma exchange is most effective if administered less than 2 weeks after symptom onset.

His study examined 6-month outcomes among 214 attacks in 188 patients; some patients had several first attacks in different areas. Response was defined in two ways. First, patients were clinically classified as having a good response, a bad response, or no response to treatment. The second definition was based on the EDSS. Good response was an EDSS decrease of at least 2 points for an initial score of 3 or higher, or a decrease of 1 point if the initial score was less than 3. Poor response was an EDSS that decreased without reaching these thresholds.

The cohort was largely female, with a mean age of 38 years. Most (55%) were positive for antibodies against aquaporin-4. Anti-MOG antibodies were present in 30%. A total of 7.5% were negative for both antibodies, and the remainder had an undetermined serotype.

The clinical presentations varied. Most frequently, patients presented with myelitis only (44%). This was followed by optic neuritis only (34%), both myelitis and optic neuritis (8%), and myelitis plus brainstem involvement (5%). Other clinical manifestations were acute demyelinating encephalomyelitis, and encephalitis alone.

The most common treatment was methylprednisolone (73%), followed by plasma exchange (25%), which occurred at a median of 9 days after symptom onset.

Outcomes varied according to the definition of response. By clinical characteristics, there was a complete response in 41, a partial response in 122, and no response in 51. By change in EDSS, 136 had a good response and 27 a partial response; 51 were still considered nonresponders.

Dr. Guillaume conducted a multivariate analysis to determine predictive factors. In both definitions, anti-MOG antibodies nearly quadrupled the chance of a good treatment response, and delaying plasma exchange was associated with a significantly increased chance of a poor response. When judged by the clinical response definition, multiple lines of treatment also were associated with a poor response. This, he said, was another reflection of plasma exchange delay.

Dr. Guillaume had no financial disclosures.

msullivan@mdedge.com

SOURCE: Guillaume M. et al. ECTRIMS 2018, Abstract 211.

BERLIN – Escalating treatment to a “highly effective” disease-modifying treatment (DMT) results in fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) than does switching to another “moderately effective” therapy, according to data from a Danish cohort study.

Sara Freeman/MDedge News

The annualized relapse rate (ARR) was 0.23 for patients who switched to a highly effective DMT, defined as either natalizumab (Tysabri) or fingolimod (Gilenya), whereas the ARR was 0.35 in those who were switched to a moderately effective DMT, defined as an interferon-beta, glatiramer acetate (Copaxone), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera).

This resulted in a relapse-rate ratio of 0.67 (95% confidence interval [CI], 0.55-0.83) comparing high to moderate DMT, or a 33% lower relapse rate in the high DMT group, Thor Ameri Chalmer, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Dr. Chalmer, who works at the Danish Multiple Sclerosis Center at Rigshospitalet, the University of Copenhagen, reported that the time to first relapse and the likelihood for having recurrent relapses were all lowered by escalating treatment rather than switching treatment. Indeed, there was a 38% increase in the time to first relapse (hazard ratio [HR] = 0.62; 95% CI, 0.50-0.76) and a 31% reduction in recurrent relapses (HR = 0.69; 95% CI, 0.57-0.83).

However, there were “no clear differences” in the time to 3-month confirmed Expanded Disability Status Scale (EDSS) worsening and improvement, Dr. Chalmer said. The HR for time to first worsening in the 3-month confirmed EDSS was 0.86, and for recurrent worsening it was 0.86, but the 95% CI in both cases crossed over from 1.0 (0.65-1.14 and 0.71-1.05, respectively). There was no difference in the time to first improvement (HR = 1.23; 95% CI, 0.95-1.60).

“The aim of this study was to use data from the [Danish] MS Registry, find the patients who started on what we define as moderately effective DMT for the first time, and on this treatment experienced a disease breakthrough and then either switched to another moderately effective DMT or escalated to a highly effective DMT,” Dr. Chalmer explained.

Disease breakthrough was defined as at least one relapse occurring within 12 months of the treatment switch, or the treating neurologist defined the reason for switching as disease breakthrough. Dr. Chalmer acknowledged that this was one of the limitations of the observational study as patients could have been misclassified and switched treatment for another reason. The severity of the relapse was not recorded.

Data on more than 5,000 patients enrolled in the Danish Multiple Sclerosis Registry (DMSR) were considered, with a final propensity-match population of 788 included in the analysis; half had received highly effective DMT and half moderately effective DMT.

The DMSR contains data on virtually all patients with MS treated in Denmark, Dr. Chalmer observed; treatment with DMT is free of charge and it can be prescribed only in public MS clinics, he explained. Furthermore, all MS clinics are required to register information about treatment response at each clinical visit.

The mean age of patients in the study was 39 years, around 70% were female, and average disease duration was 5 years.

“I don’t see in your study what is really new,” Gilles Edan, MD, observed during a discussion. “We know that using more active, more efficient drugs gives more control on relapse.”

Dr. Edan, professor and head of the neurosciences department of University Hospital Pontchaillou, Rennes (France), added that these data “confirmed what has already been observed in the clinical trials.”

It is important to consider the safety and efficacy concerns on an individual level, Dr. Edan argued, questioning whether the more highly active drugs should be systematically used first-line rather than second-line in all patients with MS. He also noted that of course patients would need to be treated for very long periods.

Dr. Chalmer responded: “I agree some of the randomized trials have touched upon on this as well, but I think it’s really important to not just rely on one or two trials but to keep on doing the trials over and over again so that we show that we have the right results.”

Dr. Chalmer added that the present study looked only at efficacy and that the median follow-up time was 3.2 years. “Safety is important of course, but it was not the aim of this study.” Perhaps longer follow-up might have detected more differences in the EDSS outcomes, he added.

The study was funded by the Danish Multiple Sclerosis Society, the Foundation for Research in Neurology, Ejnar Jonassen, and Gangstedfonden. Dr. Chalmer disclosed he had received support for congress participation from Merck, Biogen, and Roche.

SOURCE: Chalmer T et al. Mult Scler. 2018;24(S2):99. Abstract 263.

BERLIN – Escalating treatment to a “highly effective” disease-modifying treatment (DMT) results in fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) than does switching to another “moderately effective” therapy, according to data from a Danish cohort study.

Sara Freeman/MDedge News

The annualized relapse rate (ARR) was 0.23 for patients who switched to a highly effective DMT, defined as either natalizumab (Tysabri) or fingolimod (Gilenya), whereas the ARR was 0.35 in those who were switched to a moderately effective DMT, defined as an interferon-beta, glatiramer acetate (Copaxone), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera).

This resulted in a relapse-rate ratio of 0.67 (95% confidence interval [CI], 0.55-0.83) comparing high to moderate DMT, or a 33% lower relapse rate in the high DMT group, Thor Ameri Chalmer, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Dr. Chalmer, who works at the Danish Multiple Sclerosis Center at Rigshospitalet, the University of Copenhagen, reported that the time to first relapse and the likelihood for having recurrent relapses were all lowered by escalating treatment rather than switching treatment. Indeed, there was a 38% increase in the time to first relapse (hazard ratio [HR] = 0.62; 95% CI, 0.50-0.76) and a 31% reduction in recurrent relapses (HR = 0.69; 95% CI, 0.57-0.83).

However, there were “no clear differences” in the time to 3-month confirmed Expanded Disability Status Scale (EDSS) worsening and improvement, Dr. Chalmer said. The HR for time to first worsening in the 3-month confirmed EDSS was 0.86, and for recurrent worsening it was 0.86, but the 95% CI in both cases crossed over from 1.0 (0.65-1.14 and 0.71-1.05, respectively). There was no difference in the time to first improvement (HR = 1.23; 95% CI, 0.95-1.60).

“The aim of this study was to use data from the [Danish] MS Registry, find the patients who started on what we define as moderately effective DMT for the first time, and on this treatment experienced a disease breakthrough and then either switched to another moderately effective DMT or escalated to a highly effective DMT,” Dr. Chalmer explained.

Disease breakthrough was defined as at least one relapse occurring within 12 months of the treatment switch, or the treating neurologist defined the reason for switching as disease breakthrough. Dr. Chalmer acknowledged that this was one of the limitations of the observational study as patients could have been misclassified and switched treatment for another reason. The severity of the relapse was not recorded.

Data on more than 5,000 patients enrolled in the Danish Multiple Sclerosis Registry (DMSR) were considered, with a final propensity-match population of 788 included in the analysis; half had received highly effective DMT and half moderately effective DMT.

The DMSR contains data on virtually all patients with MS treated in Denmark, Dr. Chalmer observed; treatment with DMT is free of charge and it can be prescribed only in public MS clinics, he explained. Furthermore, all MS clinics are required to register information about treatment response at each clinical visit.

The mean age of patients in the study was 39 years, around 70% were female, and average disease duration was 5 years.

“I don’t see in your study what is really new,” Gilles Edan, MD, observed during a discussion. “We know that using more active, more efficient drugs gives more control on relapse.”

Dr. Edan, professor and head of the neurosciences department of University Hospital Pontchaillou, Rennes (France), added that these data “confirmed what has already been observed in the clinical trials.”

It is important to consider the safety and efficacy concerns on an individual level, Dr. Edan argued, questioning whether the more highly active drugs should be systematically used first-line rather than second-line in all patients with MS. He also noted that of course patients would need to be treated for very long periods.

Dr. Chalmer responded: “I agree some of the randomized trials have touched upon on this as well, but I think it’s really important to not just rely on one or two trials but to keep on doing the trials over and over again so that we show that we have the right results.”

Dr. Chalmer added that the present study looked only at efficacy and that the median follow-up time was 3.2 years. “Safety is important of course, but it was not the aim of this study.” Perhaps longer follow-up might have detected more differences in the EDSS outcomes, he added.

The study was funded by the Danish Multiple Sclerosis Society, the Foundation for Research in Neurology, Ejnar Jonassen, and Gangstedfonden. Dr. Chalmer disclosed he had received support for congress participation from Merck, Biogen, and Roche.

SOURCE: Chalmer T et al. Mult Scler. 2018;24(S2):99. Abstract 263.

BERLIN – Escalating treatment to a “highly effective” disease-modifying treatment (DMT) results in fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) than does switching to another “moderately effective” therapy, according to data from a Danish cohort study.

Sara Freeman/MDedge News

The annualized relapse rate (ARR) was 0.23 for patients who switched to a highly effective DMT, defined as either natalizumab (Tysabri) or fingolimod (Gilenya), whereas the ARR was 0.35 in those who were switched to a moderately effective DMT, defined as an interferon-beta, glatiramer acetate (Copaxone), teriflunomide (Aubagio), or dimethyl fumarate (Tecfidera).

This resulted in a relapse-rate ratio of 0.67 (95% confidence interval [CI], 0.55-0.83) comparing high to moderate DMT, or a 33% lower relapse rate in the high DMT group, Thor Ameri Chalmer, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Dr. Chalmer, who works at the Danish Multiple Sclerosis Center at Rigshospitalet, the University of Copenhagen, reported that the time to first relapse and the likelihood for having recurrent relapses were all lowered by escalating treatment rather than switching treatment. Indeed, there was a 38% increase in the time to first relapse (hazard ratio [HR] = 0.62; 95% CI, 0.50-0.76) and a 31% reduction in recurrent relapses (HR = 0.69; 95% CI, 0.57-0.83).

However, there were “no clear differences” in the time to 3-month confirmed Expanded Disability Status Scale (EDSS) worsening and improvement, Dr. Chalmer said. The HR for time to first worsening in the 3-month confirmed EDSS was 0.86, and for recurrent worsening it was 0.86, but the 95% CI in both cases crossed over from 1.0 (0.65-1.14 and 0.71-1.05, respectively). There was no difference in the time to first improvement (HR = 1.23; 95% CI, 0.95-1.60).

“The aim of this study was to use data from the [Danish] MS Registry, find the patients who started on what we define as moderately effective DMT for the first time, and on this treatment experienced a disease breakthrough and then either switched to another moderately effective DMT or escalated to a highly effective DMT,” Dr. Chalmer explained.

Disease breakthrough was defined as at least one relapse occurring within 12 months of the treatment switch, or the treating neurologist defined the reason for switching as disease breakthrough. Dr. Chalmer acknowledged that this was one of the limitations of the observational study as patients could have been misclassified and switched treatment for another reason. The severity of the relapse was not recorded.

Data on more than 5,000 patients enrolled in the Danish Multiple Sclerosis Registry (DMSR) were considered, with a final propensity-match population of 788 included in the analysis; half had received highly effective DMT and half moderately effective DMT.

The DMSR contains data on virtually all patients with MS treated in Denmark, Dr. Chalmer observed; treatment with DMT is free of charge and it can be prescribed only in public MS clinics, he explained. Furthermore, all MS clinics are required to register information about treatment response at each clinical visit.

The mean age of patients in the study was 39 years, around 70% were female, and average disease duration was 5 years.

“I don’t see in your study what is really new,” Gilles Edan, MD, observed during a discussion. “We know that using more active, more efficient drugs gives more control on relapse.”

Dr. Edan, professor and head of the neurosciences department of University Hospital Pontchaillou, Rennes (France), added that these data “confirmed what has already been observed in the clinical trials.”

It is important to consider the safety and efficacy concerns on an individual level, Dr. Edan argued, questioning whether the more highly active drugs should be systematically used first-line rather than second-line in all patients with MS. He also noted that of course patients would need to be treated for very long periods.

Dr. Chalmer responded: “I agree some of the randomized trials have touched upon on this as well, but I think it’s really important to not just rely on one or two trials but to keep on doing the trials over and over again so that we show that we have the right results.”

Dr. Chalmer added that the present study looked only at efficacy and that the median follow-up time was 3.2 years. “Safety is important of course, but it was not the aim of this study.” Perhaps longer follow-up might have detected more differences in the EDSS outcomes, he added.

The study was funded by the Danish Multiple Sclerosis Society, the Foundation for Research in Neurology, Ejnar Jonassen, and Gangstedfonden. Dr. Chalmer disclosed he had received support for congress participation from Merck, Biogen, and Roche.

SOURCE: Chalmer T et al. Mult Scler. 2018;24(S2):99. Abstract 263.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

dbrunk@mdedge.com

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

dbrunk@mdedge.com

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

dbrunk@mdedge.com

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

msullivan@mdedge.com

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

msullivan@mdedge.com

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

msullivan@mdedge.com

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).

However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.

Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.

The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.

Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.

Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.

Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.

These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.

The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.

ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.

He has been a paid consultant for Merck Serono, which is developing evobrutinib.

msullivan@mdedge.com

SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.

BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).

However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.

Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.

The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.

Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.

Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.

Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.

These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.

The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.

ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.

He has been a paid consultant for Merck Serono, which is developing evobrutinib.

msullivan@mdedge.com

SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.

BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).

However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.

Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.

The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.

Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.

Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.

Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.

These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.

The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.

ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.

He has been a paid consultant for Merck Serono, which is developing evobrutinib.

msullivan@mdedge.com

SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.

BERLIN—MD1003, a high-dose pharmaceutical grade biotin, is effective in the treatment of patients with progressive multiple sclerosis (MS), according to a report presented at ECTRIMS 2018. “This real-world study supports the growing body of evidence that MD1003 is an effective and safe treatment for progressive MS,” said lead author Jonathan Ciron, MD, of the Department of Neurology, CHU Toulouse, France, and colleagues.

In the 2016 MS-SPI study, MD1003 treatment was shown to be effective and well tolerated in patients with progressive MS. Notably, MD1003 reversed MS-related disease disability in 13% of patients with progressive MS. Based on these findings, MD1003 is currently being prescribed to patients with progressive MS in France under an expanded access program.

In the present study, Dr. Ciron and colleagues sought to determine the benefits, in terms of effectiveness and safety, of MD1003 in patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) in a clinical center.

MD1003 300 mg/day (100 mg tid) was prescribed to patients with PPMS or SPMS receiving care at a single center in France (CHU Toulouse) starting in January 2016. The following measures of effectiveness and safety were administered: Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25W), nine-hole peg test (9-HPT), number of relapses, and gadolinium-enhancing lesions on T1-weighted images.

As of May 2018, a total of 220 patients received MD1003. The research team presented the results of the first 91 patients to complete one year of follow-up. At baseline, mean age was 59.5, 61.5% were female, 70.3% had SPMS, mean EDSS was 5.9, mean T25W was 50.7 seconds, 9-HPT in the dominant hand was 35.1 seconds, and the mean number of previous relapses was 5.1. After one year of treatment with MD1003, 19 (23%; n = 83 with data) patients experienced improvement in EDSS and 15 (23%; n = 66 with data) patients experienced 20% or greater improvement in T25W. Active disease, a clinically-defined relapse, or a gadolinium-enhancing T1 lesion was observed in nine (11%; n = 79 with data) patients. MD1003 was also well tolerated, the researchers noted.

BERLIN—MD1003, a high-dose pharmaceutical grade biotin, is effective in the treatment of patients with progressive multiple sclerosis (MS), according to a report presented at ECTRIMS 2018. “This real-world study supports the growing body of evidence that MD1003 is an effective and safe treatment for progressive MS,” said lead author Jonathan Ciron, MD, of the Department of Neurology, CHU Toulouse, France, and colleagues.

In the 2016 MS-SPI study, MD1003 treatment was shown to be effective and well tolerated in patients with progressive MS. Notably, MD1003 reversed MS-related disease disability in 13% of patients with progressive MS. Based on these findings, MD1003 is currently being prescribed to patients with progressive MS in France under an expanded access program.

In the present study, Dr. Ciron and colleagues sought to determine the benefits, in terms of effectiveness and safety, of MD1003 in patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) in a clinical center.

MD1003 300 mg/day (100 mg tid) was prescribed to patients with PPMS or SPMS receiving care at a single center in France (CHU Toulouse) starting in January 2016. The following measures of effectiveness and safety were administered: Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25W), nine-hole peg test (9-HPT), number of relapses, and gadolinium-enhancing lesions on T1-weighted images.

As of May 2018, a total of 220 patients received MD1003. The research team presented the results of the first 91 patients to complete one year of follow-up. At baseline, mean age was 59.5, 61.5% were female, 70.3% had SPMS, mean EDSS was 5.9, mean T25W was 50.7 seconds, 9-HPT in the dominant hand was 35.1 seconds, and the mean number of previous relapses was 5.1. After one year of treatment with MD1003, 19 (23%; n = 83 with data) patients experienced improvement in EDSS and 15 (23%; n = 66 with data) patients experienced 20% or greater improvement in T25W. Active disease, a clinically-defined relapse, or a gadolinium-enhancing T1 lesion was observed in nine (11%; n = 79 with data) patients. MD1003 was also well tolerated, the researchers noted.

BERLIN—MD1003, a high-dose pharmaceutical grade biotin, is effective in the treatment of patients with progressive multiple sclerosis (MS), according to a report presented at ECTRIMS 2018. “This real-world study supports the growing body of evidence that MD1003 is an effective and safe treatment for progressive MS,” said lead author Jonathan Ciron, MD, of the Department of Neurology, CHU Toulouse, France, and colleagues.

In the 2016 MS-SPI study, MD1003 treatment was shown to be effective and well tolerated in patients with progressive MS. Notably, MD1003 reversed MS-related disease disability in 13% of patients with progressive MS. Based on these findings, MD1003 is currently being prescribed to patients with progressive MS in France under an expanded access program.

In the present study, Dr. Ciron and colleagues sought to determine the benefits, in terms of effectiveness and safety, of MD1003 in patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) in a clinical center.

MD1003 300 mg/day (100 mg tid) was prescribed to patients with PPMS or SPMS receiving care at a single center in France (CHU Toulouse) starting in January 2016. The following measures of effectiveness and safety were administered: Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25W), nine-hole peg test (9-HPT), number of relapses, and gadolinium-enhancing lesions on T1-weighted images.

As of May 2018, a total of 220 patients received MD1003. The research team presented the results of the first 91 patients to complete one year of follow-up. At baseline, mean age was 59.5, 61.5% were female, 70.3% had SPMS, mean EDSS was 5.9, mean T25W was 50.7 seconds, 9-HPT in the dominant hand was 35.1 seconds, and the mean number of previous relapses was 5.1. After one year of treatment with MD1003, 19 (23%; n = 83 with data) patients experienced improvement in EDSS and 15 (23%; n = 66 with data) patients experienced 20% or greater improvement in T25W. Active disease, a clinically-defined relapse, or a gadolinium-enhancing T1 lesion was observed in nine (11%; n = 79 with data) patients. MD1003 was also well tolerated, the researchers noted.

BERLIN—Cognitive impairment in patients with multiple sclerosis (MS) varies in presence and degree in a manner that is neither identified nor quantified by the Symbol Digit Modalities Test (SDMT), according to a study presented at ECTRIMS 2018. “A unidimensional score or measure is insufficient to adequately identify and appreciate the richness and variation of the combinations and degrees of cognitive impairment that occur in patients with MS and impact the appearance of meaningful cognitive-related disability,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York, and colleagues. “Better screening tools are required for evaluation of cognitive impairment in patients with MS.”

Cognitive impairment is common in people with MS. This impairment impacts economically important milestones and patient quality of life. Clinician and patient perceptions of the presence and degree of cognitive impairment are insufficiently sensitive measures, according to Dr. Gudesblatt. An increasing number of cognitive domains impaired greater than 1 standard deviation below age- and education-matched persons with MS has been shown to progressively impact self-reported driving, employment, and fall risk in patients with an EDSS score less than 6. Important cognitive disability in patients with MS can be unrelated to visible physical disability. Variability in the location and degree of MS plaque burden may differentially affect cognitive and physical ability, and many other factors may influence cognitive impairment in patients with MS. Routine cognitive screening in MS care is uncommon, Dr. Gudesblatt said. The SDMT, although frequently recommended, provides a single screening score that does not provide information about individual cognitive domains or the presence and degree of impairment across multiple cognitive domains or the accumulation of cognitive impairment.

Dr. Gudesblatt and colleagues conducted a retrospective review of consecutive patients with MS referred for screening with a multidomain computerized screening cognitive assessment battery (CAB) in the course of routine care who also underwent testing with the oral version of the SDMT on the same day. Their study included 113 patients with MS. The cohort had a mean age of 48.9, and 85% were female.

Within this patient sample, the SDMT defined cognitive function as follows: 68% normal classification, 14% low, 5% moderately low, and 12% very low. In this same patient group, the multidomain screening CAB identified the following domains of cognitive impairment greater than 1 standard deviation below normal values: memory (32%), executive function (25%), attention (28%), information processing speed (30%), visuospatial processing (20%), verbal function (23%), motor skills (20%), and a global summary screening score (24%). The multidimensional screening CAB in this same patient population further identified the number of cognitive domains impaired: zero domains, 36%; one domain, 24%; two domains, 11.5%; and three or more domains, 28%.

BERLIN—Cognitive impairment in patients with multiple sclerosis (MS) varies in presence and degree in a manner that is neither identified nor quantified by the Symbol Digit Modalities Test (SDMT), according to a study presented at ECTRIMS 2018. “A unidimensional score or measure is insufficient to adequately identify and appreciate the richness and variation of the combinations and degrees of cognitive impairment that occur in patients with MS and impact the appearance of meaningful cognitive-related disability,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York, and colleagues. “Better screening tools are required for evaluation of cognitive impairment in patients with MS.”

Cognitive impairment is common in people with MS. This impairment impacts economically important milestones and patient quality of life. Clinician and patient perceptions of the presence and degree of cognitive impairment are insufficiently sensitive measures, according to Dr. Gudesblatt. An increasing number of cognitive domains impaired greater than 1 standard deviation below age- and education-matched persons with MS has been shown to progressively impact self-reported driving, employment, and fall risk in patients with an EDSS score less than 6. Important cognitive disability in patients with MS can be unrelated to visible physical disability. Variability in the location and degree of MS plaque burden may differentially affect cognitive and physical ability, and many other factors may influence cognitive impairment in patients with MS. Routine cognitive screening in MS care is uncommon, Dr. Gudesblatt said. The SDMT, although frequently recommended, provides a single screening score that does not provide information about individual cognitive domains or the presence and degree of impairment across multiple cognitive domains or the accumulation of cognitive impairment.

Dr. Gudesblatt and colleagues conducted a retrospective review of consecutive patients with MS referred for screening with a multidomain computerized screening cognitive assessment battery (CAB) in the course of routine care who also underwent testing with the oral version of the SDMT on the same day. Their study included 113 patients with MS. The cohort had a mean age of 48.9, and 85% were female.

Within this patient sample, the SDMT defined cognitive function as follows: 68% normal classification, 14% low, 5% moderately low, and 12% very low. In this same patient group, the multidomain screening CAB identified the following domains of cognitive impairment greater than 1 standard deviation below normal values: memory (32%), executive function (25%), attention (28%), information processing speed (30%), visuospatial processing (20%), verbal function (23%), motor skills (20%), and a global summary screening score (24%). The multidimensional screening CAB in this same patient population further identified the number of cognitive domains impaired: zero domains, 36%; one domain, 24%; two domains, 11.5%; and three or more domains, 28%.

BERLIN—Cognitive impairment in patients with multiple sclerosis (MS) varies in presence and degree in a manner that is neither identified nor quantified by the Symbol Digit Modalities Test (SDMT), according to a study presented at ECTRIMS 2018. “A unidimensional score or measure is insufficient to adequately identify and appreciate the richness and variation of the combinations and degrees of cognitive impairment that occur in patients with MS and impact the appearance of meaningful cognitive-related disability,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York, and colleagues. “Better screening tools are required for evaluation of cognitive impairment in patients with MS.”

Cognitive impairment is common in people with MS. This impairment impacts economically important milestones and patient quality of life. Clinician and patient perceptions of the presence and degree of cognitive impairment are insufficiently sensitive measures, according to Dr. Gudesblatt. An increasing number of cognitive domains impaired greater than 1 standard deviation below age- and education-matched persons with MS has been shown to progressively impact self-reported driving, employment, and fall risk in patients with an EDSS score less than 6. Important cognitive disability in patients with MS can be unrelated to visible physical disability. Variability in the location and degree of MS plaque burden may differentially affect cognitive and physical ability, and many other factors may influence cognitive impairment in patients with MS. Routine cognitive screening in MS care is uncommon, Dr. Gudesblatt said. The SDMT, although frequently recommended, provides a single screening score that does not provide information about individual cognitive domains or the presence and degree of impairment across multiple cognitive domains or the accumulation of cognitive impairment.

Dr. Gudesblatt and colleagues conducted a retrospective review of consecutive patients with MS referred for screening with a multidomain computerized screening cognitive assessment battery (CAB) in the course of routine care who also underwent testing with the oral version of the SDMT on the same day. Their study included 113 patients with MS. The cohort had a mean age of 48.9, and 85% were female.

Within this patient sample, the SDMT defined cognitive function as follows: 68% normal classification, 14% low, 5% moderately low, and 12% very low. In this same patient group, the multidomain screening CAB identified the following domains of cognitive impairment greater than 1 standard deviation below normal values: memory (32%), executive function (25%), attention (28%), information processing speed (30%), visuospatial processing (20%), verbal function (23%), motor skills (20%), and a global summary screening score (24%). The multidimensional screening CAB in this same patient population further identified the number of cognitive domains impaired: zero domains, 36%; one domain, 24%; two domains, 11.5%; and three or more domains, 28%.

BERLIN – Higher vitamin D levels at multiple sclerosis onset were predictive of higher cognitive function 11 years on, and heavy smokers took a “clinically significant” cognitive hit, according to a recent study.

“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.

“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.

According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.

Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.

Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.

The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.

“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.

In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.

In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.

“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.

Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.

Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.

“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”

Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”

Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).

“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.

For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.

Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.

Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.

koakes@mdedge.com

SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.

*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11. 

BERLIN – Higher vitamin D levels at multiple sclerosis onset were predictive of higher cognitive function 11 years on, and heavy smokers took a “clinically significant” cognitive hit, according to a recent study.

“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.

“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.

According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.

Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.

Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.

The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.

“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.

In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.

In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.

“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.

Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.

Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.

“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”

Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”

Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).

“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.

For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.

Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.

Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.

koakes@mdedge.com

SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.

*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11. 

BERLIN – Higher vitamin D levels at multiple sclerosis onset were predictive of higher cognitive function 11 years on, and heavy smokers took a “clinically significant” cognitive hit, according to a recent study.

“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.

“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.

According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.

Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.

Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.

The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.

“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.

In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.

In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.

“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.

Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.

Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.

“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”

Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”

Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).

“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.

For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.

Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.

Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.

koakes@mdedge.com

SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.

*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11. 

BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.

Michelle Sullivan/Mdedge News

Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.

msullivan@mdedge.com

SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323

BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.

Michelle Sullivan/Mdedge News

Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.

msullivan@mdedge.com

SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323

BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.

Michelle Sullivan/Mdedge News

Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.

msullivan@mdedge.com

SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323