Multiple Sclerosis

BERLIN—Relapse-induced escalation to a highly effective disease-modifying therapy (DMT) is associated with a reduced risk of relapses, according to comprehensive nationwide data from Danish patients with multiple sclerosis (MS). Escalation is associated with a statistically nonsignificant trend toward reduced time to first one-point worsening of Expanded Disability Status Scale (EDSS) score over the short-to-medium term. “Escalation of therapy to a highly effective DMT when patients experience relapses on a moderately effective DMT is recommended to improve control of relapse activity,” said Thor Ameri Chalmer, MD, a doctoral student at Rigshospitalet in Copenhagen, and colleagues at ECTRIMS 2018.

Patients with relapsing-remitting MS who have relapses often switch to a new DMT. Treatment guidelines recommend switching to a highly effective DMT when a patient experiences clinical disease breakthrough. Nevertheless, patients may switch between moderately effective DMTs because of breakthrough disease or adverse effects. Dr. Chalmer and colleagues compared treatment effectiveness between highly effective DMTs and moderately effective DMTs in patients with relapsing-remitting MS who switch therapy because of relapse activity.

In this registry-based cohort study, the investigators retrieved data from the Danish MS Registry on all adults with relapsing-remitting MS. Eligible participants had an EDSS score below 6, experienced a relapse while treated with a moderately effective DMT, and consequently switched to a highly effective DMT or another moderately effective DMT. The groups were compared from treatment initiation until outcome or censoring. Censoring was defined as postbaseline switch between highly effective DMT and moderately effective DMT, cessation of therapy, relocation, or death, whichever occurred first. The primary outcomes were annualized relapse rate (ARR), relapse rate ratio, time to first relapse, and time to first one-point confirmed EDSS worsening. Dr. Chalmer and colleagues used propensity score matching to balance groups, a Cox proportional hazards model to obtain hazard ratios (HR) when modeling time to first relapse and time to first worsening, and negative binomial regression to obtain ARR and relapse rate ratios.

The matched cohort included 814 patients (407 in each group). The median follow-up time was 3.2 years. The group of patients who switched to a highly effective DMT had a 39% lower hazard rate of reaching first relapse (HR, 0.61). ARRs were 0.21 for patients who switched to a highly effective DMT and 0.34 for patients who switched to a moderately effective DMT. Relapse rate ratio for highly effective DMT compared with moderately effective DMT was 0.62. The group who switched to a highly effective DMT had 13% lower hazard rate of one-point EDSS worsening (HR, 0.87).

BERLIN—Relapse-induced escalation to a highly effective disease-modifying therapy (DMT) is associated with a reduced risk of relapses, according to comprehensive nationwide data from Danish patients with multiple sclerosis (MS). Escalation is associated with a statistically nonsignificant trend toward reduced time to first one-point worsening of Expanded Disability Status Scale (EDSS) score over the short-to-medium term. “Escalation of therapy to a highly effective DMT when patients experience relapses on a moderately effective DMT is recommended to improve control of relapse activity,” said Thor Ameri Chalmer, MD, a doctoral student at Rigshospitalet in Copenhagen, and colleagues at ECTRIMS 2018.

Patients with relapsing-remitting MS who have relapses often switch to a new DMT. Treatment guidelines recommend switching to a highly effective DMT when a patient experiences clinical disease breakthrough. Nevertheless, patients may switch between moderately effective DMTs because of breakthrough disease or adverse effects. Dr. Chalmer and colleagues compared treatment effectiveness between highly effective DMTs and moderately effective DMTs in patients with relapsing-remitting MS who switch therapy because of relapse activity.

In this registry-based cohort study, the investigators retrieved data from the Danish MS Registry on all adults with relapsing-remitting MS. Eligible participants had an EDSS score below 6, experienced a relapse while treated with a moderately effective DMT, and consequently switched to a highly effective DMT or another moderately effective DMT. The groups were compared from treatment initiation until outcome or censoring. Censoring was defined as postbaseline switch between highly effective DMT and moderately effective DMT, cessation of therapy, relocation, or death, whichever occurred first. The primary outcomes were annualized relapse rate (ARR), relapse rate ratio, time to first relapse, and time to first one-point confirmed EDSS worsening. Dr. Chalmer and colleagues used propensity score matching to balance groups, a Cox proportional hazards model to obtain hazard ratios (HR) when modeling time to first relapse and time to first worsening, and negative binomial regression to obtain ARR and relapse rate ratios.

The matched cohort included 814 patients (407 in each group). The median follow-up time was 3.2 years. The group of patients who switched to a highly effective DMT had a 39% lower hazard rate of reaching first relapse (HR, 0.61). ARRs were 0.21 for patients who switched to a highly effective DMT and 0.34 for patients who switched to a moderately effective DMT. Relapse rate ratio for highly effective DMT compared with moderately effective DMT was 0.62. The group who switched to a highly effective DMT had 13% lower hazard rate of one-point EDSS worsening (HR, 0.87).

BERLIN—Relapse-induced escalation to a highly effective disease-modifying therapy (DMT) is associated with a reduced risk of relapses, according to comprehensive nationwide data from Danish patients with multiple sclerosis (MS). Escalation is associated with a statistically nonsignificant trend toward reduced time to first one-point worsening of Expanded Disability Status Scale (EDSS) score over the short-to-medium term. “Escalation of therapy to a highly effective DMT when patients experience relapses on a moderately effective DMT is recommended to improve control of relapse activity,” said Thor Ameri Chalmer, MD, a doctoral student at Rigshospitalet in Copenhagen, and colleagues at ECTRIMS 2018.

Patients with relapsing-remitting MS who have relapses often switch to a new DMT. Treatment guidelines recommend switching to a highly effective DMT when a patient experiences clinical disease breakthrough. Nevertheless, patients may switch between moderately effective DMTs because of breakthrough disease or adverse effects. Dr. Chalmer and colleagues compared treatment effectiveness between highly effective DMTs and moderately effective DMTs in patients with relapsing-remitting MS who switch therapy because of relapse activity.

In this registry-based cohort study, the investigators retrieved data from the Danish MS Registry on all adults with relapsing-remitting MS. Eligible participants had an EDSS score below 6, experienced a relapse while treated with a moderately effective DMT, and consequently switched to a highly effective DMT or another moderately effective DMT. The groups were compared from treatment initiation until outcome or censoring. Censoring was defined as postbaseline switch between highly effective DMT and moderately effective DMT, cessation of therapy, relocation, or death, whichever occurred first. The primary outcomes were annualized relapse rate (ARR), relapse rate ratio, time to first relapse, and time to first one-point confirmed EDSS worsening. Dr. Chalmer and colleagues used propensity score matching to balance groups, a Cox proportional hazards model to obtain hazard ratios (HR) when modeling time to first relapse and time to first worsening, and negative binomial regression to obtain ARR and relapse rate ratios.

The matched cohort included 814 patients (407 in each group). The median follow-up time was 3.2 years. The group of patients who switched to a highly effective DMT had a 39% lower hazard rate of reaching first relapse (HR, 0.61). ARRs were 0.21 for patients who switched to a highly effective DMT and 0.34 for patients who switched to a moderately effective DMT. Relapse rate ratio for highly effective DMT compared with moderately effective DMT was 0.62. The group who switched to a highly effective DMT had 13% lower hazard rate of one-point EDSS worsening (HR, 0.87).

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Smoking and low vitamin D levels are key modifiable prognostic factors that show a significant interaction with risk of Expanded Disability Status Scale (EDSS) progression in patients with clinically isolated syndrome (CIS), according to a study presented at ECTRIMS 2018. This finding suggests potential preventive strategies for avoiding disability, said Susana Otero-Romero, MD, PhD, an epidemiologist at the Multiple Sclerosis Center of Catalonia (CEMCAT) at University Hospital Vall d’Hebron in Barcelona, and her research colleagues.

A dynamic model for predicting long-term prognosis incorporating age, sex, topography of CIS, oligoclonal bands, and number of T2 lesions was designed by Dr. Otero-Romero and colleagues. They then sought to include modifiable environmental factors such as vitamin D and cotinine serum levels (as a surrogate for smoking status) to their modeling strategy for predicting long-term prognosis.

From 1995 to 2016, the researchers prospectively recruited 1,088 patients with CIS for clinical assessment and brain MRI follow-up. Baseline hazard for EDSS 3.0 was calculated after fitting several parametric models (Weibull, generalized gamma) for a linear combination of baseline domains, including: age, sex, topography, oligoclonal bands, and baseline T2 lesions. A recursive partitioning regression tree (RPART) method was used to stratify patients in risk groups according to their predicted median time to EDSS 3.0. This prognostic model was further updated by adding vitamin D deficiency (n = 472; cutoff, 8 ng/mL), smoking (n = 435; cotinine cutoff, 14 ng/mL), and their interactions with risk groups. Harrell C statistic was used to evaluate the performance of these models.

The predictive model is based on 1,062 patients with more than one year of follow-up. After fitting several models, a final Weibull (proportional hazard) model was selected. RPART allowed patients to be stratified in three groups: low risk (n = 442; hazard ratio [HR], 1.0 reference), medium risk (n = 561; HR, 3.0), and high risk (n = 51; HR, 9.6) with a Harrell C of 0.65. An interaction was observed for vitamin D deficiency and risk group. Vitamin D deficiency increased the risk for EDSS progression. Patients with vitamin D deficiency with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. In patients with high risk at baseline, the impact of vitamin D deficiency was minor. Overall Harrell C increased from 0.65 to 0.69.

A similar interaction was observed for smoking and risk group. High cotinine levels increased the risk for EDSS progression. Patients with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. For the high-risk group, adding smoking status raised hazard ratios from 13.8 to 64.2. Harrell C improved from 0.68 to 0.73.

This study was financed with grants from the Spanish Ministry of Economy and Competitiveness, the Fondo de Investigación Sanitaria, and the Instituto de Salud Carlos III. It also was supported by a grant from Genzyme.

BERLIN—Smoking and low vitamin D levels are key modifiable prognostic factors that show a significant interaction with risk of Expanded Disability Status Scale (EDSS) progression in patients with clinically isolated syndrome (CIS), according to a study presented at ECTRIMS 2018. This finding suggests potential preventive strategies for avoiding disability, said Susana Otero-Romero, MD, PhD, an epidemiologist at the Multiple Sclerosis Center of Catalonia (CEMCAT) at University Hospital Vall d’Hebron in Barcelona, and her research colleagues.

A dynamic model for predicting long-term prognosis incorporating age, sex, topography of CIS, oligoclonal bands, and number of T2 lesions was designed by Dr. Otero-Romero and colleagues. They then sought to include modifiable environmental factors such as vitamin D and cotinine serum levels (as a surrogate for smoking status) to their modeling strategy for predicting long-term prognosis.

From 1995 to 2016, the researchers prospectively recruited 1,088 patients with CIS for clinical assessment and brain MRI follow-up. Baseline hazard for EDSS 3.0 was calculated after fitting several parametric models (Weibull, generalized gamma) for a linear combination of baseline domains, including: age, sex, topography, oligoclonal bands, and baseline T2 lesions. A recursive partitioning regression tree (RPART) method was used to stratify patients in risk groups according to their predicted median time to EDSS 3.0. This prognostic model was further updated by adding vitamin D deficiency (n = 472; cutoff, 8 ng/mL), smoking (n = 435; cotinine cutoff, 14 ng/mL), and their interactions with risk groups. Harrell C statistic was used to evaluate the performance of these models.

The predictive model is based on 1,062 patients with more than one year of follow-up. After fitting several models, a final Weibull (proportional hazard) model was selected. RPART allowed patients to be stratified in three groups: low risk (n = 442; hazard ratio [HR], 1.0 reference), medium risk (n = 561; HR, 3.0), and high risk (n = 51; HR, 9.6) with a Harrell C of 0.65. An interaction was observed for vitamin D deficiency and risk group. Vitamin D deficiency increased the risk for EDSS progression. Patients with vitamin D deficiency with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. In patients with high risk at baseline, the impact of vitamin D deficiency was minor. Overall Harrell C increased from 0.65 to 0.69.

A similar interaction was observed for smoking and risk group. High cotinine levels increased the risk for EDSS progression. Patients with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. For the high-risk group, adding smoking status raised hazard ratios from 13.8 to 64.2. Harrell C improved from 0.68 to 0.73.

This study was financed with grants from the Spanish Ministry of Economy and Competitiveness, the Fondo de Investigación Sanitaria, and the Instituto de Salud Carlos III. It also was supported by a grant from Genzyme.

BERLIN—Smoking and low vitamin D levels are key modifiable prognostic factors that show a significant interaction with risk of Expanded Disability Status Scale (EDSS) progression in patients with clinically isolated syndrome (CIS), according to a study presented at ECTRIMS 2018. This finding suggests potential preventive strategies for avoiding disability, said Susana Otero-Romero, MD, PhD, an epidemiologist at the Multiple Sclerosis Center of Catalonia (CEMCAT) at University Hospital Vall d’Hebron in Barcelona, and her research colleagues.

A dynamic model for predicting long-term prognosis incorporating age, sex, topography of CIS, oligoclonal bands, and number of T2 lesions was designed by Dr. Otero-Romero and colleagues. They then sought to include modifiable environmental factors such as vitamin D and cotinine serum levels (as a surrogate for smoking status) to their modeling strategy for predicting long-term prognosis.

From 1995 to 2016, the researchers prospectively recruited 1,088 patients with CIS for clinical assessment and brain MRI follow-up. Baseline hazard for EDSS 3.0 was calculated after fitting several parametric models (Weibull, generalized gamma) for a linear combination of baseline domains, including: age, sex, topography, oligoclonal bands, and baseline T2 lesions. A recursive partitioning regression tree (RPART) method was used to stratify patients in risk groups according to their predicted median time to EDSS 3.0. This prognostic model was further updated by adding vitamin D deficiency (n = 472; cutoff, 8 ng/mL), smoking (n = 435; cotinine cutoff, 14 ng/mL), and their interactions with risk groups. Harrell C statistic was used to evaluate the performance of these models.

The predictive model is based on 1,062 patients with more than one year of follow-up. After fitting several models, a final Weibull (proportional hazard) model was selected. RPART allowed patients to be stratified in three groups: low risk (n = 442; hazard ratio [HR], 1.0 reference), medium risk (n = 561; HR, 3.0), and high risk (n = 51; HR, 9.6) with a Harrell C of 0.65. An interaction was observed for vitamin D deficiency and risk group. Vitamin D deficiency increased the risk for EDSS progression. Patients with vitamin D deficiency with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. In patients with high risk at baseline, the impact of vitamin D deficiency was minor. Overall Harrell C increased from 0.65 to 0.69.

A similar interaction was observed for smoking and risk group. High cotinine levels increased the risk for EDSS progression. Patients with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. For the high-risk group, adding smoking status raised hazard ratios from 13.8 to 64.2. Harrell C improved from 0.68 to 0.73.

This study was financed with grants from the Spanish Ministry of Economy and Competitiveness, the Fondo de Investigación Sanitaria, and the Instituto de Salud Carlos III. It also was supported by a grant from Genzyme.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—The risk of cancer, and breast cancer in particular, was not elevated above background levels in a large cohort of patients with multiple sclerosis (MS) taking disease-modifying therapies, according to research presented at ECTRIMS 2018.

Those findings from the Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.

After statistical adjustment and use of rituximab as the standard, the hazard ratio (HR) for any malignancy with fingolimod was 1.74 (95% confidence interval [CI], 0.92–3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53–2.10), said Peter Alping, a PhD student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm.

Surveillance for Risk of Malignancy

Limited data exist for real-world MS cohorts exposed to novel disease-modifying therapies, said Mr. Alping. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens and patient characteristics differ in patients with MS, he noted. However, surveillance for risk of malignancy is important “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers,” he said.

The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping. There were four breast cancers in the ocrelizumab population, which would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers in the placebo group. “To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.

To answer the question, he and his colleagues at the Karolinska Institute sought to compare the risk of cancer in patients with MS who were treated with rituximab, fingolimod, and natalizumab.

They conducted a nationwide cohort study using the Swedish MS registry. The researchers examined treatment episodes between 2011 and 2016. In Sweden, the MS registry is linked to the overall patient registry, as well as to registries for cancer and prescription drug use. In addition, patient data are linked to national census data.

Mr. Alping and his colleagues identified the first instance of use for an MS patient of rituximab, natalizumab, or fingolimod between 2011 and 2016. Then they matched patient records from the general population by age, sex, and geographic location to enroll matched controls at the same time point as the MS match entered the study.

Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.

The statistical analysis used an ever-treated approach and did not attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, history of cancer, and MS disease characteristics.

Comparing Incidence Rates

At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. Less than one-third of the patients (26.3%–31.6%) were male, and the mean age was 35–43. Most patients (66%–86%) had received one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20–2.88. Less than 2% of patients (0.9%–1.7%) had a history of cancer.

Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.

Breast cancer rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.

Using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted HR for any malignancy under the various treatment conditions.

Among women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06–12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.

Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.

No Increased Risk When Compared With the General Population

“For malignant cancer of any type, we found no increased risk for rituximab, compared with fingolimod and natalizumab,” Mr. Alping said, noting the wide confidence intervals in the adjusted data. The incidence of breast cancer in women who have taken rituximab is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab,” he said. “The overall cancer risk and risk of breast cancer might not be major concerns in the short term when treating MS patients with rituximab, relative to other disease-modifying therapies,” Mr. Alping concluded.

The study was partially funded by the Patient-Centered Outcomes Research Institute.

—Kari Oakes

BERLIN—The risk of cancer, and breast cancer in particular, was not elevated above background levels in a large cohort of patients with multiple sclerosis (MS) taking disease-modifying therapies, according to research presented at ECTRIMS 2018.

Those findings from the Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.

After statistical adjustment and use of rituximab as the standard, the hazard ratio (HR) for any malignancy with fingolimod was 1.74 (95% confidence interval [CI], 0.92–3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53–2.10), said Peter Alping, a PhD student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm.

Surveillance for Risk of Malignancy

Limited data exist for real-world MS cohorts exposed to novel disease-modifying therapies, said Mr. Alping. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens and patient characteristics differ in patients with MS, he noted. However, surveillance for risk of malignancy is important “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers,” he said.

The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping. There were four breast cancers in the ocrelizumab population, which would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers in the placebo group. “To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.

To answer the question, he and his colleagues at the Karolinska Institute sought to compare the risk of cancer in patients with MS who were treated with rituximab, fingolimod, and natalizumab.

They conducted a nationwide cohort study using the Swedish MS registry. The researchers examined treatment episodes between 2011 and 2016. In Sweden, the MS registry is linked to the overall patient registry, as well as to registries for cancer and prescription drug use. In addition, patient data are linked to national census data.

Mr. Alping and his colleagues identified the first instance of use for an MS patient of rituximab, natalizumab, or fingolimod between 2011 and 2016. Then they matched patient records from the general population by age, sex, and geographic location to enroll matched controls at the same time point as the MS match entered the study.

Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.

The statistical analysis used an ever-treated approach and did not attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, history of cancer, and MS disease characteristics.

Comparing Incidence Rates

At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. Less than one-third of the patients (26.3%–31.6%) were male, and the mean age was 35–43. Most patients (66%–86%) had received one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20–2.88. Less than 2% of patients (0.9%–1.7%) had a history of cancer.

Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.

Breast cancer rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.

Using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted HR for any malignancy under the various treatment conditions.

Among women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06–12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.

Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.

No Increased Risk When Compared With the General Population

“For malignant cancer of any type, we found no increased risk for rituximab, compared with fingolimod and natalizumab,” Mr. Alping said, noting the wide confidence intervals in the adjusted data. The incidence of breast cancer in women who have taken rituximab is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab,” he said. “The overall cancer risk and risk of breast cancer might not be major concerns in the short term when treating MS patients with rituximab, relative to other disease-modifying therapies,” Mr. Alping concluded.

The study was partially funded by the Patient-Centered Outcomes Research Institute.

—Kari Oakes

BERLIN—The risk of cancer, and breast cancer in particular, was not elevated above background levels in a large cohort of patients with multiple sclerosis (MS) taking disease-modifying therapies, according to research presented at ECTRIMS 2018.

Those findings from the Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.

After statistical adjustment and use of rituximab as the standard, the hazard ratio (HR) for any malignancy with fingolimod was 1.74 (95% confidence interval [CI], 0.92–3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53–2.10), said Peter Alping, a PhD student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm.

Surveillance for Risk of Malignancy

Limited data exist for real-world MS cohorts exposed to novel disease-modifying therapies, said Mr. Alping. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens and patient characteristics differ in patients with MS, he noted. However, surveillance for risk of malignancy is important “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers,” he said.

The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping. There were four breast cancers in the ocrelizumab population, which would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers in the placebo group. “To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.

To answer the question, he and his colleagues at the Karolinska Institute sought to compare the risk of cancer in patients with MS who were treated with rituximab, fingolimod, and natalizumab.

They conducted a nationwide cohort study using the Swedish MS registry. The researchers examined treatment episodes between 2011 and 2016. In Sweden, the MS registry is linked to the overall patient registry, as well as to registries for cancer and prescription drug use. In addition, patient data are linked to national census data.

Mr. Alping and his colleagues identified the first instance of use for an MS patient of rituximab, natalizumab, or fingolimod between 2011 and 2016. Then they matched patient records from the general population by age, sex, and geographic location to enroll matched controls at the same time point as the MS match entered the study.

Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.

The statistical analysis used an ever-treated approach and did not attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, history of cancer, and MS disease characteristics.

Comparing Incidence Rates

At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. Less than one-third of the patients (26.3%–31.6%) were male, and the mean age was 35–43. Most patients (66%–86%) had received one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20–2.88. Less than 2% of patients (0.9%–1.7%) had a history of cancer.

Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.

Breast cancer rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.

Using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted HR for any malignancy under the various treatment conditions.

Among women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06–12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.

Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.

No Increased Risk When Compared With the General Population

“For malignant cancer of any type, we found no increased risk for rituximab, compared with fingolimod and natalizumab,” Mr. Alping said, noting the wide confidence intervals in the adjusted data. The incidence of breast cancer in women who have taken rituximab is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab,” he said. “The overall cancer risk and risk of breast cancer might not be major concerns in the short term when treating MS patients with rituximab, relative to other disease-modifying therapies,” Mr. Alping concluded.

The study was partially funded by the Patient-Centered Outcomes Research Institute.

—Kari Oakes

BERLIN—Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis (MS), according to the results of a large Swedish registry-based study.

Depression increased the risk of having a sustained Expanded Dis­ability Status Scale (EDSS) score of 3.0 by 54%. Depression increased the risk of having a sustained EDSS score of 4.0 by 87%. Depression also doubled the risk of having an EDSS of 6.0.

SSRI treatment also increased the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% increased risk of having a sustained EDSS of 4.0, and a 2.2-fold increased risk of a sustained EDSS of 6.0.

Prevalent Comorbidities

“We know that mood disorders are highly prevalent in people with MS,” said Stefanie Binzer, MD, at ECTRIMS 2018.

Mood disorders are associated with reduced quality of life, said Dr. Binzer, of the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is a major risk factor for suicidality in patients with MS. However, prior studies have not established the effect of having a comorbid mood disorder on disability levels of patients with MS.

Dr. Binzer and her coinvestigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% of the patients with MS (n = 502) had an International Classification of Diseases, 10th revision (ICD-10) code for depression. Of these patients, 261 had received a diagnosis of depression before their diagnosis of MS.

Of 3,817 pa­tients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.

Patients with MS who had an ICD code for depression or who had received SSRIs “had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she said.

“The difference between the groups [with and without depression] seemed to increase with EDSS,” Dr. Binzer said.

Patients with depression tended to be more likely to convert to secondary progressive MS, with a hazard ratio (HR) of 1.38.

Disability at Younger Ages

A sensitivity analysis found that among those who had depression before their first MS symptom, “the median age when they reached EDSS 3.0 and 4.0 was reduced by three and seven years, respectively,” Dr. Binzer said.

In addition, 1.5% (n = 200) of 13,125 patients with MS diagnosed between 1973 and 2014 were identified with bipolar disorder. It significantly increased the risk of reaching an EDSS score of 4.0 by 58%, but not did not affect the risk of reaching EDSS 3.0 (HR = 1.34) or 6.0 (HR = 1.16).

The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk, and those with bipolar disorder a 31% increased risk, of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS, respectively.

“We do not know the mechanisms that underlie these associations,” Dr. Binzer said. “Irrespective of the underlying mechanisms, [the study] clearly shows that it is imperative that we recognize early mood disorders in MS patients and manage them effectively to provide better care and hopefully reduce MS disability worsening.”

The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.

—Sara Freeman

BERLIN—Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis (MS), according to the results of a large Swedish registry-based study.

Depression increased the risk of having a sustained Expanded Dis­ability Status Scale (EDSS) score of 3.0 by 54%. Depression increased the risk of having a sustained EDSS score of 4.0 by 87%. Depression also doubled the risk of having an EDSS of 6.0.

SSRI treatment also increased the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% increased risk of having a sustained EDSS of 4.0, and a 2.2-fold increased risk of a sustained EDSS of 6.0.

Prevalent Comorbidities

“We know that mood disorders are highly prevalent in people with MS,” said Stefanie Binzer, MD, at ECTRIMS 2018.

Mood disorders are associated with reduced quality of life, said Dr. Binzer, of the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is a major risk factor for suicidality in patients with MS. However, prior studies have not established the effect of having a comorbid mood disorder on disability levels of patients with MS.

Dr. Binzer and her coinvestigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% of the patients with MS (n = 502) had an International Classification of Diseases, 10th revision (ICD-10) code for depression. Of these patients, 261 had received a diagnosis of depression before their diagnosis of MS.

Of 3,817 pa­tients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.

Patients with MS who had an ICD code for depression or who had received SSRIs “had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she said.

“The difference between the groups [with and without depression] seemed to increase with EDSS,” Dr. Binzer said.

Patients with depression tended to be more likely to convert to secondary progressive MS, with a hazard ratio (HR) of 1.38.

Disability at Younger Ages

A sensitivity analysis found that among those who had depression before their first MS symptom, “the median age when they reached EDSS 3.0 and 4.0 was reduced by three and seven years, respectively,” Dr. Binzer said.

In addition, 1.5% (n = 200) of 13,125 patients with MS diagnosed between 1973 and 2014 were identified with bipolar disorder. It significantly increased the risk of reaching an EDSS score of 4.0 by 58%, but not did not affect the risk of reaching EDSS 3.0 (HR = 1.34) or 6.0 (HR = 1.16).

The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk, and those with bipolar disorder a 31% increased risk, of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS, respectively.

“We do not know the mechanisms that underlie these associations,” Dr. Binzer said. “Irrespective of the underlying mechanisms, [the study] clearly shows that it is imperative that we recognize early mood disorders in MS patients and manage them effectively to provide better care and hopefully reduce MS disability worsening.”

The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.

—Sara Freeman

BERLIN—Depression and bipolar disorder are major risk factors for worsening disability in people with multiple sclerosis (MS), according to the results of a large Swedish registry-based study.

Depression increased the risk of having a sustained Expanded Dis­ability Status Scale (EDSS) score of 3.0 by 54%. Depression increased the risk of having a sustained EDSS score of 4.0 by 87%. Depression also doubled the risk of having an EDSS of 6.0.

SSRI treatment also increased the risk of greater disability, with patients exposed to SSRIs having a 40% increased risk of a sustained EDSS of 3.0, a 97% increased risk of having a sustained EDSS of 4.0, and a 2.2-fold increased risk of a sustained EDSS of 6.0.

Prevalent Comorbidities

“We know that mood disorders are highly prevalent in people with MS,” said Stefanie Binzer, MD, at ECTRIMS 2018.

Mood disorders are associated with reduced quality of life, said Dr. Binzer, of the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm. Furthermore, depression is a major risk factor for suicidality in patients with MS. However, prior studies have not established the effect of having a comorbid mood disorder on disability levels of patients with MS.

Dr. Binzer and her coinvestigators analyzed data from 5,875 patients in the Swedish MS registry between 2001 and 2014. By matching these patients to records in the Swedish National Patient Registry and the Swedish National Prescribed Drug Registry, they found that 8.5% of the patients with MS (n = 502) had an International Classification of Diseases, 10th revision (ICD-10) code for depression. Of these patients, 261 had received a diagnosis of depression before their diagnosis of MS.

Of 3,817 pa­tients with MS onset between 2005 and 2014, 27.4% (n = 1,048) had collected at least one prescription for an SSRI.

Patients with MS who had an ICD code for depression or who had received SSRIs “had a significantly increased risk of reaching EDSS 3.0,” Dr. Binzer reported. The age at which patients reached these milestones were younger in both groups when compared with MS patients without depression, she said.

“The difference between the groups [with and without depression] seemed to increase with EDSS,” Dr. Binzer said.

Patients with depression tended to be more likely to convert to secondary progressive MS, with a hazard ratio (HR) of 1.38.

Disability at Younger Ages

A sensitivity analysis found that among those who had depression before their first MS symptom, “the median age when they reached EDSS 3.0 and 4.0 was reduced by three and seven years, respectively,” Dr. Binzer said.

In addition, 1.5% (n = 200) of 13,125 patients with MS diagnosed between 1973 and 2014 were identified with bipolar disorder. It significantly increased the risk of reaching an EDSS score of 4.0 by 58%, but not did not affect the risk of reaching EDSS 3.0 (HR = 1.34) or 6.0 (HR = 1.16).

The investigators’ analysis of the results stratified by sex, conducted because men tend to fare worse than women with MS and progress faster, showed that for depression and bipolar disorder, men were at significantly higher risk of reaching sustained disability milestones. Indeed, compared with women, men with depression had a 61% increased risk, and those with bipolar disorder a 31% increased risk, of reaching an EDSS score of 6.0. They also had 51% and 32% increased risks of conversion to secondary progressive MS, respectively.

“We do not know the mechanisms that underlie these associations,” Dr. Binzer said. “Irrespective of the underlying mechanisms, [the study] clearly shows that it is imperative that we recognize early mood disorders in MS patients and manage them effectively to provide better care and hopefully reduce MS disability worsening.”

The research was funded by the Swedish Research Council and the Swedish Brain Foundation. Dr. Binzer has received speaker fees and travel grants from Biogen.

—Sara Freeman

BERLIN—Gray matter–white matter (GM/WM) contrast ratio on T1 magnetization prepared rapid gradient echo (MPRAGE) is sensitive to multiple sclerosis (MS), but not to migraine pathology, according to research presented at ECTRIMS 2018. The diagnostic and prognostic value of this MRI marker could be subjects for future investigations, said the study authors.

Researchers have suggested that MRI brain T1 GM/WM contrast may be a marker of neurodegeneration in Alzheimer’s disease. Whether this contrast has diagnostic value in MS remains unknown, however. Tina Mitrovic, a research assistant at the University of Basel in Switzerland, and colleagues conducted a study to compare the T1 GM/WM contrast in patients with MS, migraineurs, and healthy controls. They also investigated whether the contrast was associated with disability outcomes in MS.

BERLIN—Gray matter–white matter (GM/WM) contrast ratio on T1 magnetization prepared rapid gradient echo (MPRAGE) is sensitive to multiple sclerosis (MS), but not to migraine pathology, according to research presented at ECTRIMS 2018. The diagnostic and prognostic value of this MRI marker could be subjects for future investigations, said the study authors.

Researchers have suggested that MRI brain T1 GM/WM contrast may be a marker of neurodegeneration in Alzheimer’s disease. Whether this contrast has diagnostic value in MS remains unknown, however. Tina Mitrovic, a research assistant at the University of Basel in Switzerland, and colleagues conducted a study to compare the T1 GM/WM contrast in patients with MS, migraineurs, and healthy controls. They also investigated whether the contrast was associated with disability outcomes in MS.

BERLIN—Gray matter–white matter (GM/WM) contrast ratio on T1 magnetization prepared rapid gradient echo (MPRAGE) is sensitive to multiple sclerosis (MS), but not to migraine pathology, according to research presented at ECTRIMS 2018. The diagnostic and prognostic value of this MRI marker could be subjects for future investigations, said the study authors.

Researchers have suggested that MRI brain T1 GM/WM contrast may be a marker of neurodegeneration in Alzheimer’s disease. Whether this contrast has diagnostic value in MS remains unknown, however. Tina Mitrovic, a research assistant at the University of Basel in Switzerland, and colleagues conducted a study to compare the T1 GM/WM contrast in patients with MS, migraineurs, and healthy controls. They also investigated whether the contrast was associated with disability outcomes in MS.

BERLIN—Research supports the previously observed association of periventricular lesions with cortical thinning in relapsing-remitting multiple sclerosis (MS) and extends this association to clinically isolated syndrome (CIS) and primary progressive MS, according to results presented at ECTRIMS 2018. “Beyond supporting the role of CSF-related factors for disease-related damage, a periventricular lesion MS phenotype associated with reduced cortical thickness might have the potential to be explored regarding response to different disease-modifying treatments,” said Lukas Pirpamer, a doctoral student at Graz University of Technology in Austria.

Neurologists previously had hypothesized that subpial cortical pathology in MS partly results from CSF factors. In an earlier single-center study, Mr. Pirpamer and colleagues investigated whether tissue changes in intracerebral areas close to CSF were related to cortical pathology. They found that the percentage of periventricular lesion occupancy was correlated with cortical thinning in relapsing-remitting MS, but not in CIS. To corroborate these findings and examine other forms of MS, Mr. Pirpamer and colleagues conducted a multicenter study of the MRI in MS (MAGNIMS) study group, which included patients with primary progressive MS and those with secondary progressive MS.

BERLIN—Research supports the previously observed association of periventricular lesions with cortical thinning in relapsing-remitting multiple sclerosis (MS) and extends this association to clinically isolated syndrome (CIS) and primary progressive MS, according to results presented at ECTRIMS 2018. “Beyond supporting the role of CSF-related factors for disease-related damage, a periventricular lesion MS phenotype associated with reduced cortical thickness might have the potential to be explored regarding response to different disease-modifying treatments,” said Lukas Pirpamer, a doctoral student at Graz University of Technology in Austria.

Neurologists previously had hypothesized that subpial cortical pathology in MS partly results from CSF factors. In an earlier single-center study, Mr. Pirpamer and colleagues investigated whether tissue changes in intracerebral areas close to CSF were related to cortical pathology. They found that the percentage of periventricular lesion occupancy was correlated with cortical thinning in relapsing-remitting MS, but not in CIS. To corroborate these findings and examine other forms of MS, Mr. Pirpamer and colleagues conducted a multicenter study of the MRI in MS (MAGNIMS) study group, which included patients with primary progressive MS and those with secondary progressive MS.

BERLIN—Research supports the previously observed association of periventricular lesions with cortical thinning in relapsing-remitting multiple sclerosis (MS) and extends this association to clinically isolated syndrome (CIS) and primary progressive MS, according to results presented at ECTRIMS 2018. “Beyond supporting the role of CSF-related factors for disease-related damage, a periventricular lesion MS phenotype associated with reduced cortical thickness might have the potential to be explored regarding response to different disease-modifying treatments,” said Lukas Pirpamer, a doctoral student at Graz University of Technology in Austria.

Neurologists previously had hypothesized that subpial cortical pathology in MS partly results from CSF factors. In an earlier single-center study, Mr. Pirpamer and colleagues investigated whether tissue changes in intracerebral areas close to CSF were related to cortical pathology. They found that the percentage of periventricular lesion occupancy was correlated with cortical thinning in relapsing-remitting MS, but not in CIS. To corroborate these findings and examine other forms of MS, Mr. Pirpamer and colleagues conducted a multicenter study of the MRI in MS (MAGNIMS) study group, which included patients with primary progressive MS and those with secondary progressive MS.