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Criterion Based on the Central Vein Sign Distinguishes Between MS and Mimics
Key clinical point: Applying a criterion of three lesions with the central vein sign distinguishes between multiple sclerosis and its mimics.
Major finding: The criterion has a sensitivity and specificity of 61.9% and 89.0%, respectively.
Study details: A multicenter study of 606 participants with clinically isolated syndrome, multiple sclerosis, and multiple sclerosis mimics.
Disclosures: Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
Citation: Sinnecker T et al. AAN 2019, Abstract S6.002.
Key clinical point: Applying a criterion of three lesions with the central vein sign distinguishes between multiple sclerosis and its mimics.
Major finding: The criterion has a sensitivity and specificity of 61.9% and 89.0%, respectively.
Study details: A multicenter study of 606 participants with clinically isolated syndrome, multiple sclerosis, and multiple sclerosis mimics.
Disclosures: Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
Citation: Sinnecker T et al. AAN 2019, Abstract S6.002.
Key clinical point: Applying a criterion of three lesions with the central vein sign distinguishes between multiple sclerosis and its mimics.
Major finding: The criterion has a sensitivity and specificity of 61.9% and 89.0%, respectively.
Study details: A multicenter study of 606 participants with clinically isolated syndrome, multiple sclerosis, and multiple sclerosis mimics.
Disclosures: Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
Citation: Sinnecker T et al. AAN 2019, Abstract S6.002.
Multiple Sclerosis May Not Flare Up After Pregnancy
Key clinical point: Women with MS may be able to have children, breastfeed, and resume treatment without experiencing an increased risk of relapse during the postpartum period.
Major finding: Patients’ annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum.
Study details: An analysis of prospectively collected data from 466 pregnancies among 375 women with MS between 2008 and 2016.
Disclosures: The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
Citation: Langer-Gould A et al. AAN 2019, Abstract S6.007.
Key clinical point: Women with MS may be able to have children, breastfeed, and resume treatment without experiencing an increased risk of relapse during the postpartum period.
Major finding: Patients’ annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum.
Study details: An analysis of prospectively collected data from 466 pregnancies among 375 women with MS between 2008 and 2016.
Disclosures: The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
Citation: Langer-Gould A et al. AAN 2019, Abstract S6.007.
Key clinical point: Women with MS may be able to have children, breastfeed, and resume treatment without experiencing an increased risk of relapse during the postpartum period.
Major finding: Patients’ annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum.
Study details: An analysis of prospectively collected data from 466 pregnancies among 375 women with MS between 2008 and 2016.
Disclosures: The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
Citation: Langer-Gould A et al. AAN 2019, Abstract S6.007.
Evobrutinib demonstrates efficacy, safety in relapsing MS
PHILADELPHIA – Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.
Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.
“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.
This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.
In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.
Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.
The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.
There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.
There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.
Most treatment-emergent adverse events were mild or moderate, according to the investigators.
Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.
Results of the study were published concurrently in the New England Journal of Medicine.
Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.
SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.
PHILADELPHIA – Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.
Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.
“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.
This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.
In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.
Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.
The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.
There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.
There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.
Most treatment-emergent adverse events were mild or moderate, according to the investigators.
Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.
Results of the study were published concurrently in the New England Journal of Medicine.
Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.
SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.
PHILADELPHIA – Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.
Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.
“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.
This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.
In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.
Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.
The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.
There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.
There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.
Most treatment-emergent adverse events were mild or moderate, according to the investigators.
Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.
Results of the study were published concurrently in the New England Journal of Medicine.
Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.
SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.
FROM AAN 2019
Fingolimod reduced disease activity more than glatiramer acetate in RRMS: ASSESS study results
PHILADELPHIA – reported at the annual meeting of the American Academy of Neurology. The optimal efficacious dose of fingolimod was 0.5 mg once daily, according to the results of the ASSESS study, which also evaluated a 0.25-mg daily dose of fingolimod versus a 20-mg daily dose of glatiramer acetate.
Adverse events seen with fingolimod were consistent with the established safety profile of the immunomodulatory drug, according to investigator Bruce Cree, MD, PhD, of the UCSF Weill Institute for Neurosciences, department of neurology, University of California, San Francisco.
“I believe this is the first study to go head to head versus glatiramer acetate to show superiority,” Dr. Cree said in a podium presentation of the results.
While fingolimod 0.5 mg has shown superior efficacy over placebo and interferon beta-1a in previous phase 3 trials, head-to-head comparisons versus disease-modifying therapies can help inform treatment decisions in clinical practice, Dr. Cree and coinvestigators noted in the abstract that describes their results.
The randomized, three-armed, phase 3b ASSESS study included 12 months of dose-blinded treatment and 3 months of follow-up. Investigators enrolled 1,054 patients with relapsing-remitting MS, of whom about 74% were women and the average age was 40 years, Dr. Cree said in his presentation.
Annualized relapse rate, the primary endpoint of the study, was 0.153 for the fingolimod 0.5-mg arm, versus 0.258 for the glatiramer acetate 20-mg arm, for a 40.7% relative reduction (P = .013), Dr. Cree reported. By contrast, he said, the annualized relapse rate within the fingolimod 0.25-mg arm was 0.221, which was not statistically different versus glatiramer acetate.
The fingolimod 0.5-mg arm was also superior to glatiramer acetate on a number of radiographic endpoints at month 12, including new or newly enlarged T2 lesion count, change in T2 lesion volume, gadolinium-positive T1 lesion count, and gadolinium-positive T1 lesion volume, Dr. Cree said.
Adverse events and serious adverse events were “much as expected” in all three study groups, Dr. Cree said.
The observed safety with fingolimod was consistent with previously available data on fingolimod 0.5 mg, and the safety profile of the lower 0.25-mg dose seemed to be comparable with the 0.5-mg dose, according to his presentation.
Adverse events with fingolimod were “largely laboratory abnormalities,” that occurred more frequently in the fingolimod arms, he said. Although there was an apparent dose-dependent effect between the 0.25-mg and 0.5-mg doses, the overall proportion of patients experiencing low white blood cell counts or elevations in liver enzymes was low, he added.
Bradycardia was “infrequent” in both fingolimod groups in first-dose observations, though it did again occur with a dose-dependent effect, Dr. Cree said.
He reported bradycardia in two patients (0.5%) in the fingolimod 0.25-mg group and four (1.2%) in the fingolimod 0.5-mg group, while the number of patients requiring overnight hospitalizations was one (0.3%) and five (1.5%) in the 0.25- and 0.5-mg groups, respectively.
Hepatic enzyme abnormalities were the leading reason for discontinuation of fingolimod, while in contrast, drug hypersensitivity and injection site reactions led to discontinuations in the glatiramer acetate arm, he added.
Novartis sponsored the study. Dr. Cree provided disclosures related to Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis.
SOURCE: Cree B et al. AAN 2019, Abstract 56.009.
PHILADELPHIA – reported at the annual meeting of the American Academy of Neurology. The optimal efficacious dose of fingolimod was 0.5 mg once daily, according to the results of the ASSESS study, which also evaluated a 0.25-mg daily dose of fingolimod versus a 20-mg daily dose of glatiramer acetate.
Adverse events seen with fingolimod were consistent with the established safety profile of the immunomodulatory drug, according to investigator Bruce Cree, MD, PhD, of the UCSF Weill Institute for Neurosciences, department of neurology, University of California, San Francisco.
“I believe this is the first study to go head to head versus glatiramer acetate to show superiority,” Dr. Cree said in a podium presentation of the results.
While fingolimod 0.5 mg has shown superior efficacy over placebo and interferon beta-1a in previous phase 3 trials, head-to-head comparisons versus disease-modifying therapies can help inform treatment decisions in clinical practice, Dr. Cree and coinvestigators noted in the abstract that describes their results.
The randomized, three-armed, phase 3b ASSESS study included 12 months of dose-blinded treatment and 3 months of follow-up. Investigators enrolled 1,054 patients with relapsing-remitting MS, of whom about 74% were women and the average age was 40 years, Dr. Cree said in his presentation.
Annualized relapse rate, the primary endpoint of the study, was 0.153 for the fingolimod 0.5-mg arm, versus 0.258 for the glatiramer acetate 20-mg arm, for a 40.7% relative reduction (P = .013), Dr. Cree reported. By contrast, he said, the annualized relapse rate within the fingolimod 0.25-mg arm was 0.221, which was not statistically different versus glatiramer acetate.
The fingolimod 0.5-mg arm was also superior to glatiramer acetate on a number of radiographic endpoints at month 12, including new or newly enlarged T2 lesion count, change in T2 lesion volume, gadolinium-positive T1 lesion count, and gadolinium-positive T1 lesion volume, Dr. Cree said.
Adverse events and serious adverse events were “much as expected” in all three study groups, Dr. Cree said.
The observed safety with fingolimod was consistent with previously available data on fingolimod 0.5 mg, and the safety profile of the lower 0.25-mg dose seemed to be comparable with the 0.5-mg dose, according to his presentation.
Adverse events with fingolimod were “largely laboratory abnormalities,” that occurred more frequently in the fingolimod arms, he said. Although there was an apparent dose-dependent effect between the 0.25-mg and 0.5-mg doses, the overall proportion of patients experiencing low white blood cell counts or elevations in liver enzymes was low, he added.
Bradycardia was “infrequent” in both fingolimod groups in first-dose observations, though it did again occur with a dose-dependent effect, Dr. Cree said.
He reported bradycardia in two patients (0.5%) in the fingolimod 0.25-mg group and four (1.2%) in the fingolimod 0.5-mg group, while the number of patients requiring overnight hospitalizations was one (0.3%) and five (1.5%) in the 0.25- and 0.5-mg groups, respectively.
Hepatic enzyme abnormalities were the leading reason for discontinuation of fingolimod, while in contrast, drug hypersensitivity and injection site reactions led to discontinuations in the glatiramer acetate arm, he added.
Novartis sponsored the study. Dr. Cree provided disclosures related to Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis.
SOURCE: Cree B et al. AAN 2019, Abstract 56.009.
PHILADELPHIA – reported at the annual meeting of the American Academy of Neurology. The optimal efficacious dose of fingolimod was 0.5 mg once daily, according to the results of the ASSESS study, which also evaluated a 0.25-mg daily dose of fingolimod versus a 20-mg daily dose of glatiramer acetate.
Adverse events seen with fingolimod were consistent with the established safety profile of the immunomodulatory drug, according to investigator Bruce Cree, MD, PhD, of the UCSF Weill Institute for Neurosciences, department of neurology, University of California, San Francisco.
“I believe this is the first study to go head to head versus glatiramer acetate to show superiority,” Dr. Cree said in a podium presentation of the results.
While fingolimod 0.5 mg has shown superior efficacy over placebo and interferon beta-1a in previous phase 3 trials, head-to-head comparisons versus disease-modifying therapies can help inform treatment decisions in clinical practice, Dr. Cree and coinvestigators noted in the abstract that describes their results.
The randomized, three-armed, phase 3b ASSESS study included 12 months of dose-blinded treatment and 3 months of follow-up. Investigators enrolled 1,054 patients with relapsing-remitting MS, of whom about 74% were women and the average age was 40 years, Dr. Cree said in his presentation.
Annualized relapse rate, the primary endpoint of the study, was 0.153 for the fingolimod 0.5-mg arm, versus 0.258 for the glatiramer acetate 20-mg arm, for a 40.7% relative reduction (P = .013), Dr. Cree reported. By contrast, he said, the annualized relapse rate within the fingolimod 0.25-mg arm was 0.221, which was not statistically different versus glatiramer acetate.
The fingolimod 0.5-mg arm was also superior to glatiramer acetate on a number of radiographic endpoints at month 12, including new or newly enlarged T2 lesion count, change in T2 lesion volume, gadolinium-positive T1 lesion count, and gadolinium-positive T1 lesion volume, Dr. Cree said.
Adverse events and serious adverse events were “much as expected” in all three study groups, Dr. Cree said.
The observed safety with fingolimod was consistent with previously available data on fingolimod 0.5 mg, and the safety profile of the lower 0.25-mg dose seemed to be comparable with the 0.5-mg dose, according to his presentation.
Adverse events with fingolimod were “largely laboratory abnormalities,” that occurred more frequently in the fingolimod arms, he said. Although there was an apparent dose-dependent effect between the 0.25-mg and 0.5-mg doses, the overall proportion of patients experiencing low white blood cell counts or elevations in liver enzymes was low, he added.
Bradycardia was “infrequent” in both fingolimod groups in first-dose observations, though it did again occur with a dose-dependent effect, Dr. Cree said.
He reported bradycardia in two patients (0.5%) in the fingolimod 0.25-mg group and four (1.2%) in the fingolimod 0.5-mg group, while the number of patients requiring overnight hospitalizations was one (0.3%) and five (1.5%) in the 0.25- and 0.5-mg groups, respectively.
Hepatic enzyme abnormalities were the leading reason for discontinuation of fingolimod, while in contrast, drug hypersensitivity and injection site reactions led to discontinuations in the glatiramer acetate arm, he added.
Novartis sponsored the study. Dr. Cree provided disclosures related to Abbvie, Akili, Biogen, EMD Serono, GeNeuro and Novartis.
SOURCE: Cree B et al. AAN 2019, Abstract 56.009.
REPORTING FROM AAN 2019
Sugary drink intake may be associated with MS severity
PHILADELPHIA – presented at the annual meeting of the American Academy of Neurology. Overall diet quality, however, is not associated with disability, the study showed.
The results do not establish that sugary drinks cause disability, and the potential association needs to be confirmed in larger, longitudinal studies, the researchers said. Nevertheless, “we do know that sodas have no nutritional value, and people with MS may want to consider reducing or eliminating them from their diet,” study lead author Elisa Meier-Gerdingh, MD, of St. Josef Hospital in Bochum, Germany, said in a written statement.
Diet may influence metabolic comorbidities, immune function, oxidative stress, and gut microbiota in patients with MS, but data about diet’s effects on MS progression are limited, the researchers said.
To examine dietary intake and disability in patients with MS, Dr. Meier-Gerdingh and her colleagues conducted a cross-sectional study of 135 participants with MS who were treated at a large referral center in Germany. Participants had a mean age of 44.6 years and mean body mass index of 24.5. Mean disease duration was 13.8 years, and 73% were women. Participants completed a 102-item food frequency questionnaire, which the investigators used to calculate each participant’s Dietary Approaches to Stop Hypertension (DASH) score. The score is a composite measure of dietary quality that favorably scores intake of fruits, vegetables, nuts and legumes, whole grains, and dairy and unfavorably scores intake of sodium, sugar-sweetened beverages, and red and processed meats.
“We chose to study the DASH diet because adherence to the DASH diet is associated with lower risk of other chronic diseases like high blood pressure, diabetes, and cardiovascular diseases,” Dr. Meier-Gerdingh said.
The researchers considered severe disability to be an Expanded Disability Status Scale (EDSS) score of 6 or greater. They assessed the association between overall DASH scores and disability status using logistic regression models that adjusted for age, sex, body mass index, smoking, and symptom duration. They also assessed the association between disability and each nutritional component of the DASH score.
In all, 30 participants had severe disability. “Overall DASH scores were not associated with disability status,” Dr. Meier-Gerdingh and her colleagues said. When they looked at individual DASH score components, patients with higher intakes of sugar-sweetened beverages had a higher risk of severe disability (P for trend = .01). Participants in the highest quartile consumed about 290 calories of sugar-sweetened beverages per day on average, compared with 7 calories per day for patients in the lowest quartile. The top quartile had an average EDSS of 4.1, and the bottom quartile had an average EDSS of 3.4. Other DASH score components were not associated with disability status.
Dr. Meier-Gerdingh had no disclosures. Her coauthors reported research support and personal compensation from pharmaceutical companies.
SOURCE: Meier-Gerdingh E et al. AAN 2019, Abstract P4.2-063.
PHILADELPHIA – presented at the annual meeting of the American Academy of Neurology. Overall diet quality, however, is not associated with disability, the study showed.
The results do not establish that sugary drinks cause disability, and the potential association needs to be confirmed in larger, longitudinal studies, the researchers said. Nevertheless, “we do know that sodas have no nutritional value, and people with MS may want to consider reducing or eliminating them from their diet,” study lead author Elisa Meier-Gerdingh, MD, of St. Josef Hospital in Bochum, Germany, said in a written statement.
Diet may influence metabolic comorbidities, immune function, oxidative stress, and gut microbiota in patients with MS, but data about diet’s effects on MS progression are limited, the researchers said.
To examine dietary intake and disability in patients with MS, Dr. Meier-Gerdingh and her colleagues conducted a cross-sectional study of 135 participants with MS who were treated at a large referral center in Germany. Participants had a mean age of 44.6 years and mean body mass index of 24.5. Mean disease duration was 13.8 years, and 73% were women. Participants completed a 102-item food frequency questionnaire, which the investigators used to calculate each participant’s Dietary Approaches to Stop Hypertension (DASH) score. The score is a composite measure of dietary quality that favorably scores intake of fruits, vegetables, nuts and legumes, whole grains, and dairy and unfavorably scores intake of sodium, sugar-sweetened beverages, and red and processed meats.
“We chose to study the DASH diet because adherence to the DASH diet is associated with lower risk of other chronic diseases like high blood pressure, diabetes, and cardiovascular diseases,” Dr. Meier-Gerdingh said.
The researchers considered severe disability to be an Expanded Disability Status Scale (EDSS) score of 6 or greater. They assessed the association between overall DASH scores and disability status using logistic regression models that adjusted for age, sex, body mass index, smoking, and symptom duration. They also assessed the association between disability and each nutritional component of the DASH score.
In all, 30 participants had severe disability. “Overall DASH scores were not associated with disability status,” Dr. Meier-Gerdingh and her colleagues said. When they looked at individual DASH score components, patients with higher intakes of sugar-sweetened beverages had a higher risk of severe disability (P for trend = .01). Participants in the highest quartile consumed about 290 calories of sugar-sweetened beverages per day on average, compared with 7 calories per day for patients in the lowest quartile. The top quartile had an average EDSS of 4.1, and the bottom quartile had an average EDSS of 3.4. Other DASH score components were not associated with disability status.
Dr. Meier-Gerdingh had no disclosures. Her coauthors reported research support and personal compensation from pharmaceutical companies.
SOURCE: Meier-Gerdingh E et al. AAN 2019, Abstract P4.2-063.
PHILADELPHIA – presented at the annual meeting of the American Academy of Neurology. Overall diet quality, however, is not associated with disability, the study showed.
The results do not establish that sugary drinks cause disability, and the potential association needs to be confirmed in larger, longitudinal studies, the researchers said. Nevertheless, “we do know that sodas have no nutritional value, and people with MS may want to consider reducing or eliminating them from their diet,” study lead author Elisa Meier-Gerdingh, MD, of St. Josef Hospital in Bochum, Germany, said in a written statement.
Diet may influence metabolic comorbidities, immune function, oxidative stress, and gut microbiota in patients with MS, but data about diet’s effects on MS progression are limited, the researchers said.
To examine dietary intake and disability in patients with MS, Dr. Meier-Gerdingh and her colleagues conducted a cross-sectional study of 135 participants with MS who were treated at a large referral center in Germany. Participants had a mean age of 44.6 years and mean body mass index of 24.5. Mean disease duration was 13.8 years, and 73% were women. Participants completed a 102-item food frequency questionnaire, which the investigators used to calculate each participant’s Dietary Approaches to Stop Hypertension (DASH) score. The score is a composite measure of dietary quality that favorably scores intake of fruits, vegetables, nuts and legumes, whole grains, and dairy and unfavorably scores intake of sodium, sugar-sweetened beverages, and red and processed meats.
“We chose to study the DASH diet because adherence to the DASH diet is associated with lower risk of other chronic diseases like high blood pressure, diabetes, and cardiovascular diseases,” Dr. Meier-Gerdingh said.
The researchers considered severe disability to be an Expanded Disability Status Scale (EDSS) score of 6 or greater. They assessed the association between overall DASH scores and disability status using logistic regression models that adjusted for age, sex, body mass index, smoking, and symptom duration. They also assessed the association between disability and each nutritional component of the DASH score.
In all, 30 participants had severe disability. “Overall DASH scores were not associated with disability status,” Dr. Meier-Gerdingh and her colleagues said. When they looked at individual DASH score components, patients with higher intakes of sugar-sweetened beverages had a higher risk of severe disability (P for trend = .01). Participants in the highest quartile consumed about 290 calories of sugar-sweetened beverages per day on average, compared with 7 calories per day for patients in the lowest quartile. The top quartile had an average EDSS of 4.1, and the bottom quartile had an average EDSS of 3.4. Other DASH score components were not associated with disability status.
Dr. Meier-Gerdingh had no disclosures. Her coauthors reported research support and personal compensation from pharmaceutical companies.
SOURCE: Meier-Gerdingh E et al. AAN 2019, Abstract P4.2-063.
REPORTING FROM AAN 2019
BTK inhibitor reduces MS enhancing lesions
. However, there was no difference between the 25-mg once daily, 75-mg once daily, 75-mg twice daily, and placebo-treated groups in Expanded Disability Status Scale scores, according to a double-blind, randomized, phase 2 trial published in the New England Journal of Medicine (2019 May 10. doi: 10.1056/NEJMoa1901981).
We first reported on the results of this trial when they were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Find our coverage at the link below.
. However, there was no difference between the 25-mg once daily, 75-mg once daily, 75-mg twice daily, and placebo-treated groups in Expanded Disability Status Scale scores, according to a double-blind, randomized, phase 2 trial published in the New England Journal of Medicine (2019 May 10. doi: 10.1056/NEJMoa1901981).
We first reported on the results of this trial when they were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Find our coverage at the link below.
. However, there was no difference between the 25-mg once daily, 75-mg once daily, 75-mg twice daily, and placebo-treated groups in Expanded Disability Status Scale scores, according to a double-blind, randomized, phase 2 trial published in the New England Journal of Medicine (2019 May 10. doi: 10.1056/NEJMoa1901981).
We first reported on the results of this trial when they were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Find our coverage at the link below.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Interview with Stephen Krieger, MD, on the topographical model of multiple sclerosis
We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.
What is the concept behind the topographical model of multiple sclerosis (MS)?
DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.
We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.
The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.
As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.
This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.
In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.
We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.
In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?
DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.
The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.
One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.
To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore, those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.
This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.
How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?
DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.
Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.
Is there any other recent research that supports these concepts?
DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.
A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.
In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.
We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.
What is the concept behind the topographical model of multiple sclerosis (MS)?
DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.
We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.
The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.
As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.
This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.
In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.
We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.
In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?
DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.
The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.
One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.
To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore, those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.
This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.
How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?
DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.
Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.
Is there any other recent research that supports these concepts?
DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.
A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.
In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.
We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.
What is the concept behind the topographical model of multiple sclerosis (MS)?
DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.
We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.
The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.
As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.
This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.
In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms. What the topographical model displays is that patients with MS lose reserve as time passes.
We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.
In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?
DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.
The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.
One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.
To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore, those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.
This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.
How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?
DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.
Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.
Is there any other recent research that supports these concepts?
DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.
A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.
In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.
Changes in brain networks may predict MS worsening
PHILADELPHIA – (MS), according to a study described at the annual meeting of the American Academy of Neurology.
Neurologists do not have reliable biomarkers to predict disease evolution in the medium or long term for patients with MS. The ability to predict disease evolution accurately could aid in the choice of treatment.
Maria Assunta Rocca, MD, head of the Neuroimaging of CNS White Matter Unit, Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale, San Raffaele, Milan, Italy, and colleagues sought to evaluate structural and functional network MRI measures as predictors of clinical deterioration over 6.5 years. They obtained conventional, 3D, T1-weighted, diffusion-weighted MRI, and resting-state functional MRI images at baseline from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic examination at baseline and after a median follow-up period of 6.5 years. At follow-up, the researchers classified patients as clinically stable or worsened, according to their change in Expanded Disability Status Scale (EDSS) score. They also evaluated conversion to secondary progressive MS among patients with relapsing remitting MS at baseline.
To identify the main large-scale resting state functional connectivity networks, Dr. Rocca and colleagues applied spatial independent component analysis to resting state functional MRI data. They applied the same technique to gray matter probability maps and fractional anisotropy maps to identify the corresponding structural gray matter and white matter networks.
At follow-up, 105 patients with MS (45%) had significant EDSS worsening. Of 157 patients with relapsing remitting MS, 26 (16%) converted to secondary progressive MS. The multivariable model, after adjustment for follow-up duration, identified baseline EDSS score (odds ratio, 1.59), normalized gray matter volume (OR, 0.99), and abnormally high baseline resting state functional connectivity of the left precentral gyrus in the sensorimotor network (OR, 1.67) as predictors of EDSS worsening. These variables remained significant after the researchers adjusted for treatment effect. Independent variables associated with conversion to secondary progressive MS included baseline EDSS score (OR, 2.8) and atrophy of gray matter networks associated with sensory (OR, 0.5) and motor (OR, 0.4) functions.
Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche..
SOURCE: Filippi M et al. AAN 2019, Abstract S49.004.
PHILADELPHIA – (MS), according to a study described at the annual meeting of the American Academy of Neurology.
Neurologists do not have reliable biomarkers to predict disease evolution in the medium or long term for patients with MS. The ability to predict disease evolution accurately could aid in the choice of treatment.
Maria Assunta Rocca, MD, head of the Neuroimaging of CNS White Matter Unit, Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale, San Raffaele, Milan, Italy, and colleagues sought to evaluate structural and functional network MRI measures as predictors of clinical deterioration over 6.5 years. They obtained conventional, 3D, T1-weighted, diffusion-weighted MRI, and resting-state functional MRI images at baseline from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic examination at baseline and after a median follow-up period of 6.5 years. At follow-up, the researchers classified patients as clinically stable or worsened, according to their change in Expanded Disability Status Scale (EDSS) score. They also evaluated conversion to secondary progressive MS among patients with relapsing remitting MS at baseline.
To identify the main large-scale resting state functional connectivity networks, Dr. Rocca and colleagues applied spatial independent component analysis to resting state functional MRI data. They applied the same technique to gray matter probability maps and fractional anisotropy maps to identify the corresponding structural gray matter and white matter networks.
At follow-up, 105 patients with MS (45%) had significant EDSS worsening. Of 157 patients with relapsing remitting MS, 26 (16%) converted to secondary progressive MS. The multivariable model, after adjustment for follow-up duration, identified baseline EDSS score (odds ratio, 1.59), normalized gray matter volume (OR, 0.99), and abnormally high baseline resting state functional connectivity of the left precentral gyrus in the sensorimotor network (OR, 1.67) as predictors of EDSS worsening. These variables remained significant after the researchers adjusted for treatment effect. Independent variables associated with conversion to secondary progressive MS included baseline EDSS score (OR, 2.8) and atrophy of gray matter networks associated with sensory (OR, 0.5) and motor (OR, 0.4) functions.
Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche..
SOURCE: Filippi M et al. AAN 2019, Abstract S49.004.
PHILADELPHIA – (MS), according to a study described at the annual meeting of the American Academy of Neurology.
Neurologists do not have reliable biomarkers to predict disease evolution in the medium or long term for patients with MS. The ability to predict disease evolution accurately could aid in the choice of treatment.
Maria Assunta Rocca, MD, head of the Neuroimaging of CNS White Matter Unit, Department of Neurology, Institute of Experimental Neurology, Scientific Institute Ospedale, San Raffaele, Milan, Italy, and colleagues sought to evaluate structural and functional network MRI measures as predictors of clinical deterioration over 6.5 years. They obtained conventional, 3D, T1-weighted, diffusion-weighted MRI, and resting-state functional MRI images at baseline from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic examination at baseline and after a median follow-up period of 6.5 years. At follow-up, the researchers classified patients as clinically stable or worsened, according to their change in Expanded Disability Status Scale (EDSS) score. They also evaluated conversion to secondary progressive MS among patients with relapsing remitting MS at baseline.
To identify the main large-scale resting state functional connectivity networks, Dr. Rocca and colleagues applied spatial independent component analysis to resting state functional MRI data. They applied the same technique to gray matter probability maps and fractional anisotropy maps to identify the corresponding structural gray matter and white matter networks.
At follow-up, 105 patients with MS (45%) had significant EDSS worsening. Of 157 patients with relapsing remitting MS, 26 (16%) converted to secondary progressive MS. The multivariable model, after adjustment for follow-up duration, identified baseline EDSS score (odds ratio, 1.59), normalized gray matter volume (OR, 0.99), and abnormally high baseline resting state functional connectivity of the left precentral gyrus in the sensorimotor network (OR, 1.67) as predictors of EDSS worsening. These variables remained significant after the researchers adjusted for treatment effect. Independent variables associated with conversion to secondary progressive MS included baseline EDSS score (OR, 2.8) and atrophy of gray matter networks associated with sensory (OR, 0.5) and motor (OR, 0.4) functions.
Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche..
SOURCE: Filippi M et al. AAN 2019, Abstract S49.004.
REPORTING FROM AAN 2019
Key clinical point: Structural and functional network MRI measures predict long-term worsening in multiple sclerosis.
Major finding: The odds ratio of worsening for patients with abnormally high baseline resting state functional connectivity is 1.67.
Study details: A prospective imaging study of 233 patients with multiple sclerosis and 77 healthy controls.
Disclosures: Dr. Rocca received personal compensation from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. Coauthors reported research support from Biogen, Merck Serono, Novartis, Teva, and Roche.
Source: Filippi M et al. AAN 2019, Abstract S49.004.
Ibudilast’s efficacy differs in primary and secondary progressive MS
PHILADELPHIA – researchers reported at the annual meeting of the American Academy of Neurology.
The difference may be related to faster atrophy rates among patients with primary progressive MS who received placebo, compared with those with secondary progressive MS who received placebo.
The finding was surprising, said Andrew Goodman, MD, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.). “Going into the trial, it was my bias and expectation that both primary and secondary progressive MS would behave more similarly than different.”
The trial, SPRINT-MS, included more than 250 patients with progressive MS at 28 sites. Patients were aged 18-65 years and were followed for 96 weeks. Patients had primary progressive MS (n = 134) or secondary progressive MS (n = 121) and were randomized 1:1 to ibudilast or placebo.
Ibudilast is an orally administered small molecule that has been used in Japan for approximately 30 years for asthma and other indications, Dr. Goodman said. Preclinical models suggested that the drug may have neuroprotective effects.
The trial’s primary result – a 48% slowing in the rate of whole brain atrophy as measured by brain parenchymal fraction with ibudilast – was reported last year (N Engl J Med. 2018 Aug 30;379[9]:846-55).
The present study examined whether the treatment effect of ibudilast was similar by progressive disease type using a linear mixed model analytic approach.
The group with primary progressive MS included a smaller percentage of women. Patients with secondary progressive MS had longer disease duration and more brain atrophy at baseline.
“The overall benefit which we previously reported appears to be driven by subjects with primary progressive rather than secondary progressive MS,” Dr. Goodman said. Accounting for baseline covariates did not affect this result.
Among patients who received placebo, brain atrophy in those with secondary progressive MS was 57% slower than in those with primary progressive MS. The rate of atrophy for untreated patients with primary progressive MS “was roughly twice as fast as that in the secondary progressive MS group, which we think may explain in part the differential in efficacy,” Dr. Goodman said. “These findings may impact future trial design for progressive MS.”
The SPRINT-MS trial was funded by the National Institute of Neurological Disorders and Stroke. The National Multiple Sclerosis Society and MediciNova also supported the study. Dr. Goodman reported receiving research support from pharmaceutical companies, as well as personal compensation from companies for consulting, serving on a scientific advisory board, and speaking.
SOURCE: Goodman A et al. AAN 2019, Abstract S12.007.
PHILADELPHIA – researchers reported at the annual meeting of the American Academy of Neurology.
The difference may be related to faster atrophy rates among patients with primary progressive MS who received placebo, compared with those with secondary progressive MS who received placebo.
The finding was surprising, said Andrew Goodman, MD, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.). “Going into the trial, it was my bias and expectation that both primary and secondary progressive MS would behave more similarly than different.”
The trial, SPRINT-MS, included more than 250 patients with progressive MS at 28 sites. Patients were aged 18-65 years and were followed for 96 weeks. Patients had primary progressive MS (n = 134) or secondary progressive MS (n = 121) and were randomized 1:1 to ibudilast or placebo.
Ibudilast is an orally administered small molecule that has been used in Japan for approximately 30 years for asthma and other indications, Dr. Goodman said. Preclinical models suggested that the drug may have neuroprotective effects.
The trial’s primary result – a 48% slowing in the rate of whole brain atrophy as measured by brain parenchymal fraction with ibudilast – was reported last year (N Engl J Med. 2018 Aug 30;379[9]:846-55).
The present study examined whether the treatment effect of ibudilast was similar by progressive disease type using a linear mixed model analytic approach.
The group with primary progressive MS included a smaller percentage of women. Patients with secondary progressive MS had longer disease duration and more brain atrophy at baseline.
“The overall benefit which we previously reported appears to be driven by subjects with primary progressive rather than secondary progressive MS,” Dr. Goodman said. Accounting for baseline covariates did not affect this result.
Among patients who received placebo, brain atrophy in those with secondary progressive MS was 57% slower than in those with primary progressive MS. The rate of atrophy for untreated patients with primary progressive MS “was roughly twice as fast as that in the secondary progressive MS group, which we think may explain in part the differential in efficacy,” Dr. Goodman said. “These findings may impact future trial design for progressive MS.”
The SPRINT-MS trial was funded by the National Institute of Neurological Disorders and Stroke. The National Multiple Sclerosis Society and MediciNova also supported the study. Dr. Goodman reported receiving research support from pharmaceutical companies, as well as personal compensation from companies for consulting, serving on a scientific advisory board, and speaking.
SOURCE: Goodman A et al. AAN 2019, Abstract S12.007.
PHILADELPHIA – researchers reported at the annual meeting of the American Academy of Neurology.
The difference may be related to faster atrophy rates among patients with primary progressive MS who received placebo, compared with those with secondary progressive MS who received placebo.
The finding was surprising, said Andrew Goodman, MD, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.). “Going into the trial, it was my bias and expectation that both primary and secondary progressive MS would behave more similarly than different.”
The trial, SPRINT-MS, included more than 250 patients with progressive MS at 28 sites. Patients were aged 18-65 years and were followed for 96 weeks. Patients had primary progressive MS (n = 134) or secondary progressive MS (n = 121) and were randomized 1:1 to ibudilast or placebo.
Ibudilast is an orally administered small molecule that has been used in Japan for approximately 30 years for asthma and other indications, Dr. Goodman said. Preclinical models suggested that the drug may have neuroprotective effects.
The trial’s primary result – a 48% slowing in the rate of whole brain atrophy as measured by brain parenchymal fraction with ibudilast – was reported last year (N Engl J Med. 2018 Aug 30;379[9]:846-55).
The present study examined whether the treatment effect of ibudilast was similar by progressive disease type using a linear mixed model analytic approach.
The group with primary progressive MS included a smaller percentage of women. Patients with secondary progressive MS had longer disease duration and more brain atrophy at baseline.
“The overall benefit which we previously reported appears to be driven by subjects with primary progressive rather than secondary progressive MS,” Dr. Goodman said. Accounting for baseline covariates did not affect this result.
Among patients who received placebo, brain atrophy in those with secondary progressive MS was 57% slower than in those with primary progressive MS. The rate of atrophy for untreated patients with primary progressive MS “was roughly twice as fast as that in the secondary progressive MS group, which we think may explain in part the differential in efficacy,” Dr. Goodman said. “These findings may impact future trial design for progressive MS.”
The SPRINT-MS trial was funded by the National Institute of Neurological Disorders and Stroke. The National Multiple Sclerosis Society and MediciNova also supported the study. Dr. Goodman reported receiving research support from pharmaceutical companies, as well as personal compensation from companies for consulting, serving on a scientific advisory board, and speaking.
SOURCE: Goodman A et al. AAN 2019, Abstract S12.007.
REPORTING FROM AAN 2019
The art of selecting an MS therapy
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
EXPERT ANALYSIS FROM ACTRIMS