Multiple Sclerosis Hub

For patients with multiple sclerosis (MS), having no evidence of disease activity (NEDA) at two years has a positive predictive value of 78.3% for absence of progression at seven years, according to research published in the February issue of JAMA Neurology.

Although 46% of patients in the study had achieved NEDA at one year, 7.9% of patients maintained NEDA after seven years. These findings result from a longitudinal study of 215 patients with clinically isolated syndrome or relapsing-remitting MS.

Dalia L. Rotstein, MD, Assistant Professor of Neurology at the University of Toronto, and her colleagues analyzed data for members of the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital (CLIMB) cohort who had a minimum of seven years of prospective MRI and clinical follow-up data.

The concept of NEDA is common in the treatment of diseases such as cancer and rheumatoid arthritis, but is considered a secondary outcome measure in MS. NEDA is defined as the absence of new or enlarging T2 lesions or T1 gadolinium-enhancing lesions on MRI and the absence of sustained Expanded Disability Status Scale score progression or clinical relapse.

During the study period, clinical and MRI indicators of disease progress were dissociated, said the investigators. The percentage of patients who had no evidence of disease progression on one measure but not on another ranged from 42.9% at year 2 to 30.6% at year 7. No MRI disease activity occurred in 23.5% of patients at year 1 and in 14.8% of patients at year 7, but the percentage of participants who had NEDA was about 15% at both time points.

“Although NEDA has the potential to become not only a key outcome measure of disease-modifying therapy, but also a treat-to-target goal, it will require a comprehensive approach that integrates advances in MRI technology, linkage of blood and CSF biomarkers, and a high degree of cooperation among investigators,” said the authors.

The study did not explore the effects of different treatment approaches, but NEDA is a necessary, albeit ambitious, benchmark that likely will become an important goal in MS care, said Jaime Imitola, MD, Assistant Professor of Neurology and Neuroscience, and Michael K. Racke, MD, Professor and Chair of the Department of Neurology, both at Ohio State University in Columbus, in an accompanying editorial.

Although the study suggests that NEDA is difficult to maintain over the long term, the outcome has prognostic value at two years. “Neurologists must start discussing the goal of disease-activity-free status with their patients to take NEDA from the uniform environment of clinical trials to actual clinical practice,” said Drs. Imitola and Racke.

—Bianca Nogrady

For patients with multiple sclerosis (MS), having no evidence of disease activity (NEDA) at two years has a positive predictive value of 78.3% for absence of progression at seven years, according to research published in the February issue of JAMA Neurology.

Although 46% of patients in the study had achieved NEDA at one year, 7.9% of patients maintained NEDA after seven years. These findings result from a longitudinal study of 215 patients with clinically isolated syndrome or relapsing-remitting MS.

Dalia L. Rotstein, MD, Assistant Professor of Neurology at the University of Toronto, and her colleagues analyzed data for members of the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital (CLIMB) cohort who had a minimum of seven years of prospective MRI and clinical follow-up data.

The concept of NEDA is common in the treatment of diseases such as cancer and rheumatoid arthritis, but is considered a secondary outcome measure in MS. NEDA is defined as the absence of new or enlarging T2 lesions or T1 gadolinium-enhancing lesions on MRI and the absence of sustained Expanded Disability Status Scale score progression or clinical relapse.

During the study period, clinical and MRI indicators of disease progress were dissociated, said the investigators. The percentage of patients who had no evidence of disease progression on one measure but not on another ranged from 42.9% at year 2 to 30.6% at year 7. No MRI disease activity occurred in 23.5% of patients at year 1 and in 14.8% of patients at year 7, but the percentage of participants who had NEDA was about 15% at both time points.

“Although NEDA has the potential to become not only a key outcome measure of disease-modifying therapy, but also a treat-to-target goal, it will require a comprehensive approach that integrates advances in MRI technology, linkage of blood and CSF biomarkers, and a high degree of cooperation among investigators,” said the authors.

The study did not explore the effects of different treatment approaches, but NEDA is a necessary, albeit ambitious, benchmark that likely will become an important goal in MS care, said Jaime Imitola, MD, Assistant Professor of Neurology and Neuroscience, and Michael K. Racke, MD, Professor and Chair of the Department of Neurology, both at Ohio State University in Columbus, in an accompanying editorial.

Although the study suggests that NEDA is difficult to maintain over the long term, the outcome has prognostic value at two years. “Neurologists must start discussing the goal of disease-activity-free status with their patients to take NEDA from the uniform environment of clinical trials to actual clinical practice,” said Drs. Imitola and Racke.

—Bianca Nogrady

For patients with multiple sclerosis (MS), having no evidence of disease activity (NEDA) at two years has a positive predictive value of 78.3% for absence of progression at seven years, according to research published in the February issue of JAMA Neurology.

Although 46% of patients in the study had achieved NEDA at one year, 7.9% of patients maintained NEDA after seven years. These findings result from a longitudinal study of 215 patients with clinically isolated syndrome or relapsing-remitting MS.

Dalia L. Rotstein, MD, Assistant Professor of Neurology at the University of Toronto, and her colleagues analyzed data for members of the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital (CLIMB) cohort who had a minimum of seven years of prospective MRI and clinical follow-up data.

The concept of NEDA is common in the treatment of diseases such as cancer and rheumatoid arthritis, but is considered a secondary outcome measure in MS. NEDA is defined as the absence of new or enlarging T2 lesions or T1 gadolinium-enhancing lesions on MRI and the absence of sustained Expanded Disability Status Scale score progression or clinical relapse.

During the study period, clinical and MRI indicators of disease progress were dissociated, said the investigators. The percentage of patients who had no evidence of disease progression on one measure but not on another ranged from 42.9% at year 2 to 30.6% at year 7. No MRI disease activity occurred in 23.5% of patients at year 1 and in 14.8% of patients at year 7, but the percentage of participants who had NEDA was about 15% at both time points.

“Although NEDA has the potential to become not only a key outcome measure of disease-modifying therapy, but also a treat-to-target goal, it will require a comprehensive approach that integrates advances in MRI technology, linkage of blood and CSF biomarkers, and a high degree of cooperation among investigators,” said the authors.

The study did not explore the effects of different treatment approaches, but NEDA is a necessary, albeit ambitious, benchmark that likely will become an important goal in MS care, said Jaime Imitola, MD, Assistant Professor of Neurology and Neuroscience, and Michael K. Racke, MD, Professor and Chair of the Department of Neurology, both at Ohio State University in Columbus, in an accompanying editorial.

Although the study suggests that NEDA is difficult to maintain over the long term, the outcome has prognostic value at two years. “Neurologists must start discussing the goal of disease-activity-free status with their patients to take NEDA from the uniform environment of clinical trials to actual clinical practice,” said Drs. Imitola and Racke.

—Bianca Nogrady

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) is significantly superior to mitoxantrone in reducing MRI activity in patients with severe multiple sclerosis (MS), according to a study published online ahead of print February 11 in Neurology.

The study involved 21 people whose MS-related disability had increased during the previous year despite treatment with first-line MS drugs. Participants’ average age was 36, and their average disability level required them to use a cane or crutch to walk.

Giovanni L. Mancardi, MD, Director of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health at the University of Genoa, and colleagues conducted a multicenter, phase II trial. They enrolled patients with secondary progressive or relapsing-remitting MS who had a documented increase in the year prior to enrollment on the Expanded Disability Status Scale (EDSS) score and one or more gadolinium-enhancing areas.

The primary end point was the cumulative number of new T2 lesions in the four years following randomization. Secondary end points were the cumulative number of gadolinium-enhancing lesions, relapse rate, and disability progression. A total of 21 patients were randomized. Following immunosupression, 12 patients received mitoxantrone (20 mg every month for six months) and nine patients underwent AHSCT. Seventeen patients had postbaseline evaluable MRI scans.

Intense immunosuppression followed by AHSCT reduced by 79% the number of new T2 lesions, compared with mitoxantrone treatment (2.5 new T2 lesions vs eight new T2 lesions, respectively). AHSCT also reduced gadolinium-enhancing lesions. None of the people who received AHSCT had a new gadolinium-enhancing lesion during the study, while 56% of those taking mitoxantrone had at least one new lesion. Annualized relapse rate was also reduced, but no difference was seen in the progression of disability.

AHSCT “appears to reset the immune system,” said Dr. Mancardi, lead author of the study. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” Dr. Mancardi said.

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) is significantly superior to mitoxantrone in reducing MRI activity in patients with severe multiple sclerosis (MS), according to a study published online ahead of print February 11 in Neurology.

The study involved 21 people whose MS-related disability had increased during the previous year despite treatment with first-line MS drugs. Participants’ average age was 36, and their average disability level required them to use a cane or crutch to walk.

Giovanni L. Mancardi, MD, Director of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health at the University of Genoa, and colleagues conducted a multicenter, phase II trial. They enrolled patients with secondary progressive or relapsing-remitting MS who had a documented increase in the year prior to enrollment on the Expanded Disability Status Scale (EDSS) score and one or more gadolinium-enhancing areas.

The primary end point was the cumulative number of new T2 lesions in the four years following randomization. Secondary end points were the cumulative number of gadolinium-enhancing lesions, relapse rate, and disability progression. A total of 21 patients were randomized. Following immunosupression, 12 patients received mitoxantrone (20 mg every month for six months) and nine patients underwent AHSCT. Seventeen patients had postbaseline evaluable MRI scans.

Intense immunosuppression followed by AHSCT reduced by 79% the number of new T2 lesions, compared with mitoxantrone treatment (2.5 new T2 lesions vs eight new T2 lesions, respectively). AHSCT also reduced gadolinium-enhancing lesions. None of the people who received AHSCT had a new gadolinium-enhancing lesion during the study, while 56% of those taking mitoxantrone had at least one new lesion. Annualized relapse rate was also reduced, but no difference was seen in the progression of disability.

AHSCT “appears to reset the immune system,” said Dr. Mancardi, lead author of the study. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” Dr. Mancardi said.

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) is significantly superior to mitoxantrone in reducing MRI activity in patients with severe multiple sclerosis (MS), according to a study published online ahead of print February 11 in Neurology.

The study involved 21 people whose MS-related disability had increased during the previous year despite treatment with first-line MS drugs. Participants’ average age was 36, and their average disability level required them to use a cane or crutch to walk.

Giovanni L. Mancardi, MD, Director of the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health at the University of Genoa, and colleagues conducted a multicenter, phase II trial. They enrolled patients with secondary progressive or relapsing-remitting MS who had a documented increase in the year prior to enrollment on the Expanded Disability Status Scale (EDSS) score and one or more gadolinium-enhancing areas.

The primary end point was the cumulative number of new T2 lesions in the four years following randomization. Secondary end points were the cumulative number of gadolinium-enhancing lesions, relapse rate, and disability progression. A total of 21 patients were randomized. Following immunosupression, 12 patients received mitoxantrone (20 mg every month for six months) and nine patients underwent AHSCT. Seventeen patients had postbaseline evaluable MRI scans.

Intense immunosuppression followed by AHSCT reduced by 79% the number of new T2 lesions, compared with mitoxantrone treatment (2.5 new T2 lesions vs eight new T2 lesions, respectively). AHSCT also reduced gadolinium-enhancing lesions. None of the people who received AHSCT had a new gadolinium-enhancing lesion during the study, while 56% of those taking mitoxantrone had at least one new lesion. Annualized relapse rate was also reduced, but no difference was seen in the progression of disability.

AHSCT “appears to reset the immune system,” said Dr. Mancardi, lead author of the study. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” Dr. Mancardi said.

CHICAGO—Approximately 60% of patients with multiple sclerosis (MS) and uveitis receive diagnoses of both diseases within a five-year period, according to a large retrospective study presented at the 118th Annual Meeting of the American Academy of Ophthalmology. Although the association between the eye condition and MS has long been known, this study is the first to provide a detailed description of the relative onset of uveitis and that of MS, as well as to calculate the likelihood of an MS diagnosis among patients with uveitis.

Uveitis can be a sign of MS, and between 1% and 10% of people with MS have uveitis. To achieve a better understanding of the association between the two diseases, researchers from Casey Eye Institute at the Oregon Health and Science University in Portland and investigators from the University of Heidelberg in Germany searched a Casey Eye Institute database of approximately 3,000 patients with uveitis and a University of Heidelberg database of 5,319 patients with uveitis who presented between 1985 and 2013. The researchers identified 24 patients from the Casey Eye Institute and 89 patients from the University of Heidelberg who fulfilled the diagnostic criteria for uveitis and MS. Thus, 113 individuals were included in the study.

Compared with the prevalence of MS in American and European populations, MS is 18 times and 21 times more common in American and European populations with uveitis, respectively, according to the researchers. They found that MS was diagnosed before uveitis in 28 (29%) patients, simultaneously in 15 (15%) patients, and after uveitis diagnosis in 54 (56%) patients.

“With a population size four times larger than [that of] any study to date on this topic, our study provides a wealth of clinical information to allow clinicians to make more accurate diagnoses, while giving patients a better understanding of their prognosis,” said Wyatt Messenger, MD, a research fellow at the University of Utah in Salt Lake City and former lead researcher from the Casey Eye Institute. “Knowing more about the onset may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system.”

In addition, this study is the first to estimate the relative frequency of anatomical subtypes of uveitis in patients with MS. Traditionally, patients with MS are thought to present most often with intermediate uveitis, which also is referred to as pars planitis. Although 80% of cases in this study had intermediate uveitis at the time of MS diagnosis, the researchers found that nearly one in six participants presented with anterior uveitis. The investigators also observed that visual acuity is generally stable in this population; the majority of patients improved during follow-up.

A major limitation of the study is the lack of availability of brain MRI for all of the patients, according to the researchers. The study also lacks detailed neurologic studies, which would have allowed investigators to correlate the patients’ uveitis with their neurologic disease.

CHICAGO—Approximately 60% of patients with multiple sclerosis (MS) and uveitis receive diagnoses of both diseases within a five-year period, according to a large retrospective study presented at the 118th Annual Meeting of the American Academy of Ophthalmology. Although the association between the eye condition and MS has long been known, this study is the first to provide a detailed description of the relative onset of uveitis and that of MS, as well as to calculate the likelihood of an MS diagnosis among patients with uveitis.

Uveitis can be a sign of MS, and between 1% and 10% of people with MS have uveitis. To achieve a better understanding of the association between the two diseases, researchers from Casey Eye Institute at the Oregon Health and Science University in Portland and investigators from the University of Heidelberg in Germany searched a Casey Eye Institute database of approximately 3,000 patients with uveitis and a University of Heidelberg database of 5,319 patients with uveitis who presented between 1985 and 2013. The researchers identified 24 patients from the Casey Eye Institute and 89 patients from the University of Heidelberg who fulfilled the diagnostic criteria for uveitis and MS. Thus, 113 individuals were included in the study.

Compared with the prevalence of MS in American and European populations, MS is 18 times and 21 times more common in American and European populations with uveitis, respectively, according to the researchers. They found that MS was diagnosed before uveitis in 28 (29%) patients, simultaneously in 15 (15%) patients, and after uveitis diagnosis in 54 (56%) patients.

“With a population size four times larger than [that of] any study to date on this topic, our study provides a wealth of clinical information to allow clinicians to make more accurate diagnoses, while giving patients a better understanding of their prognosis,” said Wyatt Messenger, MD, a research fellow at the University of Utah in Salt Lake City and former lead researcher from the Casey Eye Institute. “Knowing more about the onset may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system.”

In addition, this study is the first to estimate the relative frequency of anatomical subtypes of uveitis in patients with MS. Traditionally, patients with MS are thought to present most often with intermediate uveitis, which also is referred to as pars planitis. Although 80% of cases in this study had intermediate uveitis at the time of MS diagnosis, the researchers found that nearly one in six participants presented with anterior uveitis. The investigators also observed that visual acuity is generally stable in this population; the majority of patients improved during follow-up.

A major limitation of the study is the lack of availability of brain MRI for all of the patients, according to the researchers. The study also lacks detailed neurologic studies, which would have allowed investigators to correlate the patients’ uveitis with their neurologic disease.

CHICAGO—Approximately 60% of patients with multiple sclerosis (MS) and uveitis receive diagnoses of both diseases within a five-year period, according to a large retrospective study presented at the 118th Annual Meeting of the American Academy of Ophthalmology. Although the association between the eye condition and MS has long been known, this study is the first to provide a detailed description of the relative onset of uveitis and that of MS, as well as to calculate the likelihood of an MS diagnosis among patients with uveitis.

Uveitis can be a sign of MS, and between 1% and 10% of people with MS have uveitis. To achieve a better understanding of the association between the two diseases, researchers from Casey Eye Institute at the Oregon Health and Science University in Portland and investigators from the University of Heidelberg in Germany searched a Casey Eye Institute database of approximately 3,000 patients with uveitis and a University of Heidelberg database of 5,319 patients with uveitis who presented between 1985 and 2013. The researchers identified 24 patients from the Casey Eye Institute and 89 patients from the University of Heidelberg who fulfilled the diagnostic criteria for uveitis and MS. Thus, 113 individuals were included in the study.

Compared with the prevalence of MS in American and European populations, MS is 18 times and 21 times more common in American and European populations with uveitis, respectively, according to the researchers. They found that MS was diagnosed before uveitis in 28 (29%) patients, simultaneously in 15 (15%) patients, and after uveitis diagnosis in 54 (56%) patients.

“With a population size four times larger than [that of] any study to date on this topic, our study provides a wealth of clinical information to allow clinicians to make more accurate diagnoses, while giving patients a better understanding of their prognosis,” said Wyatt Messenger, MD, a research fellow at the University of Utah in Salt Lake City and former lead researcher from the Casey Eye Institute. “Knowing more about the onset may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system.”

In addition, this study is the first to estimate the relative frequency of anatomical subtypes of uveitis in patients with MS. Traditionally, patients with MS are thought to present most often with intermediate uveitis, which also is referred to as pars planitis. Although 80% of cases in this study had intermediate uveitis at the time of MS diagnosis, the researchers found that nearly one in six participants presented with anterior uveitis. The investigators also observed that visual acuity is generally stable in this population; the majority of patients improved during follow-up.

A major limitation of the study is the lack of availability of brain MRI for all of the patients, according to the researchers. The study also lacks detailed neurologic studies, which would have allowed investigators to correlate the patients’ uveitis with their neurologic disease.

BOSTON—The concentration of GABA in the sensorimotor cortex and in the hippocampus is decreased significantly in patients with secondary progressive multiple sclerosis (MS), compared with healthy individuals, according to research described at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The decreased concentration in the sensorimotor cortex is associated with impaired motor performance.

The reduced GABA levels likely reflect pathologic changes that result from neuronal loss and may indicate a decrease in synaptic density, said Niamh Cawley, MRCPI, Clinical Research Associate at University College London.

Clinical and Cognitive Assessments
For their investigation, Dr. Cawley and colleagues enrolled patients with secondary progressive MS and an Expanded Disability Status Scale (EDSS) score of between 4 and 6.5. Patients taking medications that alter the GABAnergic system were excluded from the study. The researchers recruited healthy controls as a comparison group.

The investigators performed cognitive assessments that examined attention and information processing speed, executive function, working memory, and visual and verbal memory. Clinical assessments included EDSS, the Nine-Hole Peg Test, the Timed Walk Test, grip strength of the right upper limb, muscle strength of the right upper and lower limbs, and vibration sensation of the right upper and lower limbs. Brain images were obtained with a 3-T scanner.

The researchers used a general linear model to compare differences in metabolite concentration between patients and controls, while adjusting for age, gender, and gray matter fraction within the spectroscopic voxel. A linear regression model enabled Dr. Cawley’s group to examine the relationships between cognitive and clinical scores and GABA concentrations. Data were adjusted for age, gender, gray matter fraction, and gray matter lesions within the spectroscopic voxel.

GABA Was Decreased in Two Brain Regions
Data were analyzed for 30 patients and 17 controls. Patients’ median EDSS score was 6. Patients performed significantly worse than controls on grip strength, muscle strength, the Nine-Hole Peg Test, and vibration sensation. Patients also performed significantly worse on digit span and immediate and delayed verbal recall.

The investigators found a significant decrease in the concentration of GABA in the sensorimotor cortex and in the hippocampus in patients, compared with controls. They did not observe a significant difference in the concentration of GABA in the prefrontal cortex. Data analysis revealed a significant positive correlation between the concentration of GABA in the sensorimotor cortex and scores on the Nine-Hole Peg Test, as well as grip strength and muscle strength. No significant correlation was seen between the concentration of GABA in the prefrontal cortex or the hippocampus and any cognitive assessments.

Although the current results are consistent with a previous post mortem investigation that demonstrated reduced presynaptic and postsynaptic GABA neurotransmission in patients with progressive MS, the findings diverge from those of Bhattacharyya et al, who found an inverse correlation between scores obtained on the Nine-Hole Peg Test and concentration of GABA in the sensorimotor cortex among patients with relapsing-remitting MS. “Our findings in patients with progressive disease are likely to reflect the loss of the compensatory mechanisms associated with plasticity due to this neuronal loss,” said Dr. Cawley. She plans to follow the patients over time to monitor GABA changes in the three brain regions, as well as to examine the association between GABA levels and functional changes.

—Erik Greb

BOSTON—The concentration of GABA in the sensorimotor cortex and in the hippocampus is decreased significantly in patients with secondary progressive multiple sclerosis (MS), compared with healthy individuals, according to research described at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The decreased concentration in the sensorimotor cortex is associated with impaired motor performance.

The reduced GABA levels likely reflect pathologic changes that result from neuronal loss and may indicate a decrease in synaptic density, said Niamh Cawley, MRCPI, Clinical Research Associate at University College London.

Clinical and Cognitive Assessments
For their investigation, Dr. Cawley and colleagues enrolled patients with secondary progressive MS and an Expanded Disability Status Scale (EDSS) score of between 4 and 6.5. Patients taking medications that alter the GABAnergic system were excluded from the study. The researchers recruited healthy controls as a comparison group.

The investigators performed cognitive assessments that examined attention and information processing speed, executive function, working memory, and visual and verbal memory. Clinical assessments included EDSS, the Nine-Hole Peg Test, the Timed Walk Test, grip strength of the right upper limb, muscle strength of the right upper and lower limbs, and vibration sensation of the right upper and lower limbs. Brain images were obtained with a 3-T scanner.

The researchers used a general linear model to compare differences in metabolite concentration between patients and controls, while adjusting for age, gender, and gray matter fraction within the spectroscopic voxel. A linear regression model enabled Dr. Cawley’s group to examine the relationships between cognitive and clinical scores and GABA concentrations. Data were adjusted for age, gender, gray matter fraction, and gray matter lesions within the spectroscopic voxel.

GABA Was Decreased in Two Brain Regions
Data were analyzed for 30 patients and 17 controls. Patients’ median EDSS score was 6. Patients performed significantly worse than controls on grip strength, muscle strength, the Nine-Hole Peg Test, and vibration sensation. Patients also performed significantly worse on digit span and immediate and delayed verbal recall.

The investigators found a significant decrease in the concentration of GABA in the sensorimotor cortex and in the hippocampus in patients, compared with controls. They did not observe a significant difference in the concentration of GABA in the prefrontal cortex. Data analysis revealed a significant positive correlation between the concentration of GABA in the sensorimotor cortex and scores on the Nine-Hole Peg Test, as well as grip strength and muscle strength. No significant correlation was seen between the concentration of GABA in the prefrontal cortex or the hippocampus and any cognitive assessments.

Although the current results are consistent with a previous post mortem investigation that demonstrated reduced presynaptic and postsynaptic GABA neurotransmission in patients with progressive MS, the findings diverge from those of Bhattacharyya et al, who found an inverse correlation between scores obtained on the Nine-Hole Peg Test and concentration of GABA in the sensorimotor cortex among patients with relapsing-remitting MS. “Our findings in patients with progressive disease are likely to reflect the loss of the compensatory mechanisms associated with plasticity due to this neuronal loss,” said Dr. Cawley. She plans to follow the patients over time to monitor GABA changes in the three brain regions, as well as to examine the association between GABA levels and functional changes.

—Erik Greb

BOSTON—The concentration of GABA in the sensorimotor cortex and in the hippocampus is decreased significantly in patients with secondary progressive multiple sclerosis (MS), compared with healthy individuals, according to research described at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The decreased concentration in the sensorimotor cortex is associated with impaired motor performance.

The reduced GABA levels likely reflect pathologic changes that result from neuronal loss and may indicate a decrease in synaptic density, said Niamh Cawley, MRCPI, Clinical Research Associate at University College London.

Clinical and Cognitive Assessments
For their investigation, Dr. Cawley and colleagues enrolled patients with secondary progressive MS and an Expanded Disability Status Scale (EDSS) score of between 4 and 6.5. Patients taking medications that alter the GABAnergic system were excluded from the study. The researchers recruited healthy controls as a comparison group.

The investigators performed cognitive assessments that examined attention and information processing speed, executive function, working memory, and visual and verbal memory. Clinical assessments included EDSS, the Nine-Hole Peg Test, the Timed Walk Test, grip strength of the right upper limb, muscle strength of the right upper and lower limbs, and vibration sensation of the right upper and lower limbs. Brain images were obtained with a 3-T scanner.

The researchers used a general linear model to compare differences in metabolite concentration between patients and controls, while adjusting for age, gender, and gray matter fraction within the spectroscopic voxel. A linear regression model enabled Dr. Cawley’s group to examine the relationships between cognitive and clinical scores and GABA concentrations. Data were adjusted for age, gender, gray matter fraction, and gray matter lesions within the spectroscopic voxel.

GABA Was Decreased in Two Brain Regions
Data were analyzed for 30 patients and 17 controls. Patients’ median EDSS score was 6. Patients performed significantly worse than controls on grip strength, muscle strength, the Nine-Hole Peg Test, and vibration sensation. Patients also performed significantly worse on digit span and immediate and delayed verbal recall.

The investigators found a significant decrease in the concentration of GABA in the sensorimotor cortex and in the hippocampus in patients, compared with controls. They did not observe a significant difference in the concentration of GABA in the prefrontal cortex. Data analysis revealed a significant positive correlation between the concentration of GABA in the sensorimotor cortex and scores on the Nine-Hole Peg Test, as well as grip strength and muscle strength. No significant correlation was seen between the concentration of GABA in the prefrontal cortex or the hippocampus and any cognitive assessments.

Although the current results are consistent with a previous post mortem investigation that demonstrated reduced presynaptic and postsynaptic GABA neurotransmission in patients with progressive MS, the findings diverge from those of Bhattacharyya et al, who found an inverse correlation between scores obtained on the Nine-Hole Peg Test and concentration of GABA in the sensorimotor cortex among patients with relapsing-remitting MS. “Our findings in patients with progressive disease are likely to reflect the loss of the compensatory mechanisms associated with plasticity due to this neuronal loss,” said Dr. Cawley. She plans to follow the patients over time to monitor GABA changes in the three brain regions, as well as to examine the association between GABA levels and functional changes.

—Erik Greb

BOSTON—Neuropsychiatric disorders, particularly depression and anxiety, are more common among people with multiple sclerosis (MS) than among the general population, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Many of these disorders are treatable, and patients may respond well to medication.

“When you’ve got a disease without cure affecting young and middle-aged people, good symptom management becomes important,” said Anthony Feinstein, MBBCh, PhD, Associate Scientist at Sunnybrook Health Sciences Center in Toronto. Available therapies for neuropsychiatric disorders often can improve quality of life for patients with MS, “so the diagnosis should not be missed,” he added.

Major Depression
One in two patients with MS will develop major depression during his or her lifetime. Changes in appetite, insomnia, fatigue, and diminished ability to concentrate are hallmarks of depression, but MS also may cause these symptoms. Self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale can help neurologists determine whether a patient’s symptoms result from depression. The dexamethasone suppression test also may help confirm a diagnosis of depression. If a patient’s cortisol level remains high after a single dose of dexamethasone, then he or she may have depression.

For patients with MS and depression, a neurologist may first prescribe monotherapy with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine. If treatment fails, the neurologist may switch to another SSRI or a serotonin–norepinephrine reuptake inhibitor such as venlafaxine or mirtazapine. These agents sometimes cause sexual difficulties, but bupropion or mirtazepine can treat depression effectively without causing this side effect, said Dr. Feinstein. If the patient does not respond to monotherapy, combination therapy may be appropriate. Combination therapy could include an antidepressant plus methylphenidate or lithium carbonate.

If combination therapy is not effective and the patient is severely depressed and suicidal, electroconvulsive therapy (ECT) may be an option. The guidelines for this therapy are strict, and it is “a safe treatment for patients with MS,” said Dr. Feinstein. ECT carries a small risk of MS relapse, so a neurologist should determine whether the patient has active disease. “We give our patients a gadolinium-enhanced MRI before we consider ECT,” said Dr. Feinstein. “If there’s no contrast enhancement and no active disease, we think that ECT is quite safe, and the response rate is excellent.”

Patients who do not want to take medication may benefit from cognitive behavioral therapy (CBT). Evidence suggests that CBT, which Cochrane Review endorses, is as effective for depression as SSRIs. CBT can be administered to individuals, to groups, or by telephone. A variant of CBT called mindfulness-based therapy also has been effective in patients with MS and depression. The advantage of CBT is its lack of side effects, but not every neurologist has access to a cognitive behavioral therapist, said Dr. Feinstein.

Interest in exercise as a treatment for depression has been rising, but no study of exercise has yet had depression relief as its primary end point. Studies in which depression relief was a secondary end point suggest that exercise is beneficial, but until there’s a randomized controlled study of exercise with depression relief as a primary end point, “the jury’s going to be out on this,” said Dr. Feinstein.

Anxiety
Anxiety is more common than depression in patients with MS, and the two disorders often are comorbid. Like depression, anxiety has symptoms that may be ascribed mistakenly to MS. The Hospital Anxiety Depression Scale can help neurologists determine whether a patient with MS has anxiety.

Few researchers have studied the treatment of anxiety in patients with MS, and none have examined pharmacologic therapies. Current data do suggest that CBT is effective, however. Stress inoculation therapy, a form of CBT, is intended to reduce negative thoughts and minimize stress. This therapy “is potentially effective in reducing anxiety,” said Dr. Feinstein. Randomized controlled trials indicate that CBT helps to reduce the anxiety that results from a diagnosis of MS. Needle phobia, which affects compliance with treatment, also can respond well to CBT.

Pseudobulbar Affect and Other Disorders
Approximately 10% of patients with MS have pseudobulbar affect, which responds well to medication. Low-dose amitriptyline, SSRIs, levodopa, and amantadine treat this condition effectively. In addition, the FDA recently approved dextromethorphan–quinidine for the treatment of pseudobulbar affect, and a 2006 study published in Annals of Neurology showed that the combination was effective for patients with pseudobulbar affect and MS. “When you treat this particular syndrome, you’re going to get a response in about 48 to 72 hours,” said Dr. Feinstein. “If you treat someone with major depression with medication, the response time is usually about two weeks.”

Bipolar affective disorder is twice as common among individuals with MS as it is in the general population. The disorder is characterized by grandiosity, elevated mood, irritability, and increased motor activity. No data are available about treating bipolar affective disorder in patients with MS, so neurologists must consult the psychiatric literature. “Patients respond well to mood-stabilizing medication such as lithium or valproic acid,” said Dr. Feinstein. “If your patients are psychotic, occasionally you have to introduce an antipsychotic agent as well.”

Between 9% and 13% of patients with MS have euphoria, an exaggerated feeling of mental and physical well-being. People with MS and euphoria tend to have significant brain atrophy and heavy lesion load, and no treatments for euphoria exist. Treating the disorder might be undesirable anyway, although it adds to the burden on the patient’s caregiver, said Dr. Feinstein.

—Erik Greb

BOSTON—Neuropsychiatric disorders, particularly depression and anxiety, are more common among people with multiple sclerosis (MS) than among the general population, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Many of these disorders are treatable, and patients may respond well to medication.

“When you’ve got a disease without cure affecting young and middle-aged people, good symptom management becomes important,” said Anthony Feinstein, MBBCh, PhD, Associate Scientist at Sunnybrook Health Sciences Center in Toronto. Available therapies for neuropsychiatric disorders often can improve quality of life for patients with MS, “so the diagnosis should not be missed,” he added.

Major Depression
One in two patients with MS will develop major depression during his or her lifetime. Changes in appetite, insomnia, fatigue, and diminished ability to concentrate are hallmarks of depression, but MS also may cause these symptoms. Self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale can help neurologists determine whether a patient’s symptoms result from depression. The dexamethasone suppression test also may help confirm a diagnosis of depression. If a patient’s cortisol level remains high after a single dose of dexamethasone, then he or she may have depression.

For patients with MS and depression, a neurologist may first prescribe monotherapy with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine. If treatment fails, the neurologist may switch to another SSRI or a serotonin–norepinephrine reuptake inhibitor such as venlafaxine or mirtazapine. These agents sometimes cause sexual difficulties, but bupropion or mirtazepine can treat depression effectively without causing this side effect, said Dr. Feinstein. If the patient does not respond to monotherapy, combination therapy may be appropriate. Combination therapy could include an antidepressant plus methylphenidate or lithium carbonate.

If combination therapy is not effective and the patient is severely depressed and suicidal, electroconvulsive therapy (ECT) may be an option. The guidelines for this therapy are strict, and it is “a safe treatment for patients with MS,” said Dr. Feinstein. ECT carries a small risk of MS relapse, so a neurologist should determine whether the patient has active disease. “We give our patients a gadolinium-enhanced MRI before we consider ECT,” said Dr. Feinstein. “If there’s no contrast enhancement and no active disease, we think that ECT is quite safe, and the response rate is excellent.”

Patients who do not want to take medication may benefit from cognitive behavioral therapy (CBT). Evidence suggests that CBT, which Cochrane Review endorses, is as effective for depression as SSRIs. CBT can be administered to individuals, to groups, or by telephone. A variant of CBT called mindfulness-based therapy also has been effective in patients with MS and depression. The advantage of CBT is its lack of side effects, but not every neurologist has access to a cognitive behavioral therapist, said Dr. Feinstein.

Interest in exercise as a treatment for depression has been rising, but no study of exercise has yet had depression relief as its primary end point. Studies in which depression relief was a secondary end point suggest that exercise is beneficial, but until there’s a randomized controlled study of exercise with depression relief as a primary end point, “the jury’s going to be out on this,” said Dr. Feinstein.

Anxiety
Anxiety is more common than depression in patients with MS, and the two disorders often are comorbid. Like depression, anxiety has symptoms that may be ascribed mistakenly to MS. The Hospital Anxiety Depression Scale can help neurologists determine whether a patient with MS has anxiety.

Few researchers have studied the treatment of anxiety in patients with MS, and none have examined pharmacologic therapies. Current data do suggest that CBT is effective, however. Stress inoculation therapy, a form of CBT, is intended to reduce negative thoughts and minimize stress. This therapy “is potentially effective in reducing anxiety,” said Dr. Feinstein. Randomized controlled trials indicate that CBT helps to reduce the anxiety that results from a diagnosis of MS. Needle phobia, which affects compliance with treatment, also can respond well to CBT.

Pseudobulbar Affect and Other Disorders
Approximately 10% of patients with MS have pseudobulbar affect, which responds well to medication. Low-dose amitriptyline, SSRIs, levodopa, and amantadine treat this condition effectively. In addition, the FDA recently approved dextromethorphan–quinidine for the treatment of pseudobulbar affect, and a 2006 study published in Annals of Neurology showed that the combination was effective for patients with pseudobulbar affect and MS. “When you treat this particular syndrome, you’re going to get a response in about 48 to 72 hours,” said Dr. Feinstein. “If you treat someone with major depression with medication, the response time is usually about two weeks.”

Bipolar affective disorder is twice as common among individuals with MS as it is in the general population. The disorder is characterized by grandiosity, elevated mood, irritability, and increased motor activity. No data are available about treating bipolar affective disorder in patients with MS, so neurologists must consult the psychiatric literature. “Patients respond well to mood-stabilizing medication such as lithium or valproic acid,” said Dr. Feinstein. “If your patients are psychotic, occasionally you have to introduce an antipsychotic agent as well.”

Between 9% and 13% of patients with MS have euphoria, an exaggerated feeling of mental and physical well-being. People with MS and euphoria tend to have significant brain atrophy and heavy lesion load, and no treatments for euphoria exist. Treating the disorder might be undesirable anyway, although it adds to the burden on the patient’s caregiver, said Dr. Feinstein.

—Erik Greb

BOSTON—Neuropsychiatric disorders, particularly depression and anxiety, are more common among people with multiple sclerosis (MS) than among the general population, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Many of these disorders are treatable, and patients may respond well to medication.

“When you’ve got a disease without cure affecting young and middle-aged people, good symptom management becomes important,” said Anthony Feinstein, MBBCh, PhD, Associate Scientist at Sunnybrook Health Sciences Center in Toronto. Available therapies for neuropsychiatric disorders often can improve quality of life for patients with MS, “so the diagnosis should not be missed,” he added.

Major Depression
One in two patients with MS will develop major depression during his or her lifetime. Changes in appetite, insomnia, fatigue, and diminished ability to concentrate are hallmarks of depression, but MS also may cause these symptoms. Self-report questionnaires such as the Beck Depression Inventory and the Hospital Anxiety and Depression Scale can help neurologists determine whether a patient’s symptoms result from depression. The dexamethasone suppression test also may help confirm a diagnosis of depression. If a patient’s cortisol level remains high after a single dose of dexamethasone, then he or she may have depression.

For patients with MS and depression, a neurologist may first prescribe monotherapy with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine. If treatment fails, the neurologist may switch to another SSRI or a serotonin–norepinephrine reuptake inhibitor such as venlafaxine or mirtazapine. These agents sometimes cause sexual difficulties, but bupropion or mirtazepine can treat depression effectively without causing this side effect, said Dr. Feinstein. If the patient does not respond to monotherapy, combination therapy may be appropriate. Combination therapy could include an antidepressant plus methylphenidate or lithium carbonate.

If combination therapy is not effective and the patient is severely depressed and suicidal, electroconvulsive therapy (ECT) may be an option. The guidelines for this therapy are strict, and it is “a safe treatment for patients with MS,” said Dr. Feinstein. ECT carries a small risk of MS relapse, so a neurologist should determine whether the patient has active disease. “We give our patients a gadolinium-enhanced MRI before we consider ECT,” said Dr. Feinstein. “If there’s no contrast enhancement and no active disease, we think that ECT is quite safe, and the response rate is excellent.”

Patients who do not want to take medication may benefit from cognitive behavioral therapy (CBT). Evidence suggests that CBT, which Cochrane Review endorses, is as effective for depression as SSRIs. CBT can be administered to individuals, to groups, or by telephone. A variant of CBT called mindfulness-based therapy also has been effective in patients with MS and depression. The advantage of CBT is its lack of side effects, but not every neurologist has access to a cognitive behavioral therapist, said Dr. Feinstein.

Interest in exercise as a treatment for depression has been rising, but no study of exercise has yet had depression relief as its primary end point. Studies in which depression relief was a secondary end point suggest that exercise is beneficial, but until there’s a randomized controlled study of exercise with depression relief as a primary end point, “the jury’s going to be out on this,” said Dr. Feinstein.

Anxiety
Anxiety is more common than depression in patients with MS, and the two disorders often are comorbid. Like depression, anxiety has symptoms that may be ascribed mistakenly to MS. The Hospital Anxiety Depression Scale can help neurologists determine whether a patient with MS has anxiety.

Few researchers have studied the treatment of anxiety in patients with MS, and none have examined pharmacologic therapies. Current data do suggest that CBT is effective, however. Stress inoculation therapy, a form of CBT, is intended to reduce negative thoughts and minimize stress. This therapy “is potentially effective in reducing anxiety,” said Dr. Feinstein. Randomized controlled trials indicate that CBT helps to reduce the anxiety that results from a diagnosis of MS. Needle phobia, which affects compliance with treatment, also can respond well to CBT.

Pseudobulbar Affect and Other Disorders
Approximately 10% of patients with MS have pseudobulbar affect, which responds well to medication. Low-dose amitriptyline, SSRIs, levodopa, and amantadine treat this condition effectively. In addition, the FDA recently approved dextromethorphan–quinidine for the treatment of pseudobulbar affect, and a 2006 study published in Annals of Neurology showed that the combination was effective for patients with pseudobulbar affect and MS. “When you treat this particular syndrome, you’re going to get a response in about 48 to 72 hours,” said Dr. Feinstein. “If you treat someone with major depression with medication, the response time is usually about two weeks.”

Bipolar affective disorder is twice as common among individuals with MS as it is in the general population. The disorder is characterized by grandiosity, elevated mood, irritability, and increased motor activity. No data are available about treating bipolar affective disorder in patients with MS, so neurologists must consult the psychiatric literature. “Patients respond well to mood-stabilizing medication such as lithium or valproic acid,” said Dr. Feinstein. “If your patients are psychotic, occasionally you have to introduce an antipsychotic agent as well.”

Between 9% and 13% of patients with MS have euphoria, an exaggerated feeling of mental and physical well-being. People with MS and euphoria tend to have significant brain atrophy and heavy lesion load, and no treatments for euphoria exist. Treating the disorder might be undesirable anyway, although it adds to the burden on the patient’s caregiver, said Dr. Feinstein.

—Erik Greb

BOSTON—The emergence of many new disease-modifying therapies in the past 10 years has made it more challenging to choose a drug for a patient with multiple sclerosis (MS), according to an overview provided at the 2014 Joint ACTRIMS–ECTRIMS Meeting. In the United States, 12 FDA-approved therapies, including oral medications, are available for the long-term treatment of MS. These medications’ efficacy, tolerability, and safety differ widely, and patient-specific risk factors can be an important guide for choosing the appropriate treatment, said Robert Fox, MD, Vice Chair for Research at the Cleveland Clinic.

Head-to-head comparisons indicate great similarity among injectable MS therapies, which generally reduce annualized relapse rate by about 30%. The choice of an injectable therapy should be influenced by the expected side effect profile, the patient’s risk factors, patient preference about the frequency of administration, and the clinician’s comfort with the drug, said Dr. Fox. Risk stratification and mitigation should continue over time because risk factors can change, thus altering an individual’s risk for a complication.

Interferon and Glatiramer Acetate Interferon and glatiramer acetate are considered relatively safe medications, but they still require risk evaluation and mitigation, Dr. Fox said. Nonsteroidal anti-inflammatory agents and hydration can mitigate interferon’s flu-like side effects, and monitoring can reduce the drug’s associated risks of increased liver enzymes and leukopenia. Screening patients for headache, pain syndromes, and depression is also warranted before and during interferon treatment.

Glatiramer acetate entails risks of erythema, lipoatrophy, induration, and immediate post injection systemic reaction. Education and proper injection technique can mitigate the risk of skin reactions, and “education is of high importance for the post injection systemic reaction and can help avoid needless trips to the emergency room,” said Dr. Fox.

Natalizumab
Researchers have identified three main factors that can stratify the risk for progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab: John Cunningham virus (JCV) infection, prior immunosuppressant use, and duration of natalizumab treatment. Patient counseling and decision making depend greatly on which risk factors the patient has, said Dr. Fox.

Natalizumab is considered relatively safe for patients who are JCV negative, but seroconversion may occur over time. Neurologists can consider other therapies for individuals who are JCV positive, but if good alternatives are not available, the clinician may consider limiting natalizumab treatment to one to two years. Natalizumab should be avoided for patients with prior immunosuppressant use if reasonable alternatives are available. Neurologists should be vigilant for symptoms suggestive of PML and could consider performing an MRI at least every six months in JCV seropositive patients.

Antinatalizumab antibodies, which can develop particularly with prior natalizumab use, and history of anaphylaxis increase the risk of allergic reactions to natalizumab, Dr. Fox noted. Liver enzyme screening at baseline and close monitoring for patients with a history of liver disease can mitigate the risk of elevated liver enzymes.

Fingolimod
Fingolimod, particularly the first dose of the drug, entails a risk of cardiac events, and concomitant medications can increase this risk. Obtaining a cardiac history is advisable before patients start fingolimod. In addition, neurologists should perform baseline EKG, first-dose observation, and a post first-dose EKG for the patient. A standard observation lasts for six hours and includes frequent monitoring of vital signs. A 24-hour observation is indicated in patients with certain risk factors.

Fingolimod also carries a risk of macular edema that may be higher in older people or those with a history of diabetes or uveitis. Neurologists therefore should perform optical coherence tomography at baseline and at three months, said Dr. Fox. Patients with visual symptoms should be evaluated promptly for possible macular edema.

Because the drug is associated with a risk of herpes virus infections, patients should be screened for varicella zoster serology, even if they have a history of chicken pox. Seronegative patients require vaccination before starting fingolimod. Other risks include lymphopenia and leukopenia, and neurologists can monitor for these outcomes through intermittent complete blood count testing. Repeated liver function panels may mitigate the risk of increased liver enzymes, and headaches and back pain can be treated symptomatically.

Teriflunomide
Teratogenesis may be the biggest concern for patients treated with teriflunomide, which is labeled as pregnancy category X. Alternative therapies could be considered for people of childbearing potential, said Dr. Fox. Patients who receive teriflunomide should use contraception. Certain treatments can accelerate washout if a patient wants to become pregnant or inadvertently becomes pregnant while taking teriflunomide.

Teriflunomide may increase liver enzymes, therefore monitoring is appropriate. The drug is relatively contraindicated for patients with previous liver injury secondary to medications, liver disease, or tuberculosis, added Dr. Fox.

Dimethyl Fumarate
Flushing occurs in one-third of patients taking dimethyl fumarate. This side effect is benign and typically passes in 20 minutes. Taking aspirin daily can prevent flushing or reduce its severity.

One-third of patients may experience gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain. The symptoms typically improve after one month. Administering the drug with food, titrating the dose slowly, and providing symptomatic treatments may help.

Dimethyl fumarate also is associated with lymphopenia, which typically takes around 12 months to develop. It is reasonable to monitor patients for lymphopenia, particularly at 12 months, and for infections, said Dr. Fox.

The drug also may be associated with a risk of PML. Four cases of PML have been reported from a total experience of approximately 170,000 patient years. Patients with PML had been receiving a formulation of dimethyl fumarate used to treat psoriasis, and some had prior immunosuppressant use and prolonged lymphopenia. After the ECTRIMS meeting, the manufacturer reported a case of PML in a patient with MS receiving dimethyl fumarate who had low lymphocyte counts for 3.5 years. Compared with natalizumab, dimethyl fumarate is associated with a lower risk of PML. “Nonetheless, it’s something that we’re keeping in the back of our mind and watching for,” said Dr. Fox. Monitoring for severely reduced lymphocyte counts may mitigate the risk of PML, he concluded.

—Erik Greb

BOSTON—The emergence of many new disease-modifying therapies in the past 10 years has made it more challenging to choose a drug for a patient with multiple sclerosis (MS), according to an overview provided at the 2014 Joint ACTRIMS–ECTRIMS Meeting. In the United States, 12 FDA-approved therapies, including oral medications, are available for the long-term treatment of MS. These medications’ efficacy, tolerability, and safety differ widely, and patient-specific risk factors can be an important guide for choosing the appropriate treatment, said Robert Fox, MD, Vice Chair for Research at the Cleveland Clinic.

Head-to-head comparisons indicate great similarity among injectable MS therapies, which generally reduce annualized relapse rate by about 30%. The choice of an injectable therapy should be influenced by the expected side effect profile, the patient’s risk factors, patient preference about the frequency of administration, and the clinician’s comfort with the drug, said Dr. Fox. Risk stratification and mitigation should continue over time because risk factors can change, thus altering an individual’s risk for a complication.

Interferon and Glatiramer Acetate Interferon and glatiramer acetate are considered relatively safe medications, but they still require risk evaluation and mitigation, Dr. Fox said. Nonsteroidal anti-inflammatory agents and hydration can mitigate interferon’s flu-like side effects, and monitoring can reduce the drug’s associated risks of increased liver enzymes and leukopenia. Screening patients for headache, pain syndromes, and depression is also warranted before and during interferon treatment.

Glatiramer acetate entails risks of erythema, lipoatrophy, induration, and immediate post injection systemic reaction. Education and proper injection technique can mitigate the risk of skin reactions, and “education is of high importance for the post injection systemic reaction and can help avoid needless trips to the emergency room,” said Dr. Fox.

Natalizumab
Researchers have identified three main factors that can stratify the risk for progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab: John Cunningham virus (JCV) infection, prior immunosuppressant use, and duration of natalizumab treatment. Patient counseling and decision making depend greatly on which risk factors the patient has, said Dr. Fox.

Natalizumab is considered relatively safe for patients who are JCV negative, but seroconversion may occur over time. Neurologists can consider other therapies for individuals who are JCV positive, but if good alternatives are not available, the clinician may consider limiting natalizumab treatment to one to two years. Natalizumab should be avoided for patients with prior immunosuppressant use if reasonable alternatives are available. Neurologists should be vigilant for symptoms suggestive of PML and could consider performing an MRI at least every six months in JCV seropositive patients.

Antinatalizumab antibodies, which can develop particularly with prior natalizumab use, and history of anaphylaxis increase the risk of allergic reactions to natalizumab, Dr. Fox noted. Liver enzyme screening at baseline and close monitoring for patients with a history of liver disease can mitigate the risk of elevated liver enzymes.

Fingolimod
Fingolimod, particularly the first dose of the drug, entails a risk of cardiac events, and concomitant medications can increase this risk. Obtaining a cardiac history is advisable before patients start fingolimod. In addition, neurologists should perform baseline EKG, first-dose observation, and a post first-dose EKG for the patient. A standard observation lasts for six hours and includes frequent monitoring of vital signs. A 24-hour observation is indicated in patients with certain risk factors.

Fingolimod also carries a risk of macular edema that may be higher in older people or those with a history of diabetes or uveitis. Neurologists therefore should perform optical coherence tomography at baseline and at three months, said Dr. Fox. Patients with visual symptoms should be evaluated promptly for possible macular edema.

Because the drug is associated with a risk of herpes virus infections, patients should be screened for varicella zoster serology, even if they have a history of chicken pox. Seronegative patients require vaccination before starting fingolimod. Other risks include lymphopenia and leukopenia, and neurologists can monitor for these outcomes through intermittent complete blood count testing. Repeated liver function panels may mitigate the risk of increased liver enzymes, and headaches and back pain can be treated symptomatically.

Teriflunomide
Teratogenesis may be the biggest concern for patients treated with teriflunomide, which is labeled as pregnancy category X. Alternative therapies could be considered for people of childbearing potential, said Dr. Fox. Patients who receive teriflunomide should use contraception. Certain treatments can accelerate washout if a patient wants to become pregnant or inadvertently becomes pregnant while taking teriflunomide.

Teriflunomide may increase liver enzymes, therefore monitoring is appropriate. The drug is relatively contraindicated for patients with previous liver injury secondary to medications, liver disease, or tuberculosis, added Dr. Fox.

Dimethyl Fumarate
Flushing occurs in one-third of patients taking dimethyl fumarate. This side effect is benign and typically passes in 20 minutes. Taking aspirin daily can prevent flushing or reduce its severity.

One-third of patients may experience gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain. The symptoms typically improve after one month. Administering the drug with food, titrating the dose slowly, and providing symptomatic treatments may help.

Dimethyl fumarate also is associated with lymphopenia, which typically takes around 12 months to develop. It is reasonable to monitor patients for lymphopenia, particularly at 12 months, and for infections, said Dr. Fox.

The drug also may be associated with a risk of PML. Four cases of PML have been reported from a total experience of approximately 170,000 patient years. Patients with PML had been receiving a formulation of dimethyl fumarate used to treat psoriasis, and some had prior immunosuppressant use and prolonged lymphopenia. After the ECTRIMS meeting, the manufacturer reported a case of PML in a patient with MS receiving dimethyl fumarate who had low lymphocyte counts for 3.5 years. Compared with natalizumab, dimethyl fumarate is associated with a lower risk of PML. “Nonetheless, it’s something that we’re keeping in the back of our mind and watching for,” said Dr. Fox. Monitoring for severely reduced lymphocyte counts may mitigate the risk of PML, he concluded.

—Erik Greb

BOSTON—The emergence of many new disease-modifying therapies in the past 10 years has made it more challenging to choose a drug for a patient with multiple sclerosis (MS), according to an overview provided at the 2014 Joint ACTRIMS–ECTRIMS Meeting. In the United States, 12 FDA-approved therapies, including oral medications, are available for the long-term treatment of MS. These medications’ efficacy, tolerability, and safety differ widely, and patient-specific risk factors can be an important guide for choosing the appropriate treatment, said Robert Fox, MD, Vice Chair for Research at the Cleveland Clinic.

Head-to-head comparisons indicate great similarity among injectable MS therapies, which generally reduce annualized relapse rate by about 30%. The choice of an injectable therapy should be influenced by the expected side effect profile, the patient’s risk factors, patient preference about the frequency of administration, and the clinician’s comfort with the drug, said Dr. Fox. Risk stratification and mitigation should continue over time because risk factors can change, thus altering an individual’s risk for a complication.

Interferon and Glatiramer Acetate Interferon and glatiramer acetate are considered relatively safe medications, but they still require risk evaluation and mitigation, Dr. Fox said. Nonsteroidal anti-inflammatory agents and hydration can mitigate interferon’s flu-like side effects, and monitoring can reduce the drug’s associated risks of increased liver enzymes and leukopenia. Screening patients for headache, pain syndromes, and depression is also warranted before and during interferon treatment.

Glatiramer acetate entails risks of erythema, lipoatrophy, induration, and immediate post injection systemic reaction. Education and proper injection technique can mitigate the risk of skin reactions, and “education is of high importance for the post injection systemic reaction and can help avoid needless trips to the emergency room,” said Dr. Fox.

Natalizumab
Researchers have identified three main factors that can stratify the risk for progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab: John Cunningham virus (JCV) infection, prior immunosuppressant use, and duration of natalizumab treatment. Patient counseling and decision making depend greatly on which risk factors the patient has, said Dr. Fox.

Natalizumab is considered relatively safe for patients who are JCV negative, but seroconversion may occur over time. Neurologists can consider other therapies for individuals who are JCV positive, but if good alternatives are not available, the clinician may consider limiting natalizumab treatment to one to two years. Natalizumab should be avoided for patients with prior immunosuppressant use if reasonable alternatives are available. Neurologists should be vigilant for symptoms suggestive of PML and could consider performing an MRI at least every six months in JCV seropositive patients.

Antinatalizumab antibodies, which can develop particularly with prior natalizumab use, and history of anaphylaxis increase the risk of allergic reactions to natalizumab, Dr. Fox noted. Liver enzyme screening at baseline and close monitoring for patients with a history of liver disease can mitigate the risk of elevated liver enzymes.

Fingolimod
Fingolimod, particularly the first dose of the drug, entails a risk of cardiac events, and concomitant medications can increase this risk. Obtaining a cardiac history is advisable before patients start fingolimod. In addition, neurologists should perform baseline EKG, first-dose observation, and a post first-dose EKG for the patient. A standard observation lasts for six hours and includes frequent monitoring of vital signs. A 24-hour observation is indicated in patients with certain risk factors.

Fingolimod also carries a risk of macular edema that may be higher in older people or those with a history of diabetes or uveitis. Neurologists therefore should perform optical coherence tomography at baseline and at three months, said Dr. Fox. Patients with visual symptoms should be evaluated promptly for possible macular edema.

Because the drug is associated with a risk of herpes virus infections, patients should be screened for varicella zoster serology, even if they have a history of chicken pox. Seronegative patients require vaccination before starting fingolimod. Other risks include lymphopenia and leukopenia, and neurologists can monitor for these outcomes through intermittent complete blood count testing. Repeated liver function panels may mitigate the risk of increased liver enzymes, and headaches and back pain can be treated symptomatically.

Teriflunomide
Teratogenesis may be the biggest concern for patients treated with teriflunomide, which is labeled as pregnancy category X. Alternative therapies could be considered for people of childbearing potential, said Dr. Fox. Patients who receive teriflunomide should use contraception. Certain treatments can accelerate washout if a patient wants to become pregnant or inadvertently becomes pregnant while taking teriflunomide.

Teriflunomide may increase liver enzymes, therefore monitoring is appropriate. The drug is relatively contraindicated for patients with previous liver injury secondary to medications, liver disease, or tuberculosis, added Dr. Fox.

Dimethyl Fumarate
Flushing occurs in one-third of patients taking dimethyl fumarate. This side effect is benign and typically passes in 20 minutes. Taking aspirin daily can prevent flushing or reduce its severity.

One-third of patients may experience gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain. The symptoms typically improve after one month. Administering the drug with food, titrating the dose slowly, and providing symptomatic treatments may help.

Dimethyl fumarate also is associated with lymphopenia, which typically takes around 12 months to develop. It is reasonable to monitor patients for lymphopenia, particularly at 12 months, and for infections, said Dr. Fox.

The drug also may be associated with a risk of PML. Four cases of PML have been reported from a total experience of approximately 170,000 patient years. Patients with PML had been receiving a formulation of dimethyl fumarate used to treat psoriasis, and some had prior immunosuppressant use and prolonged lymphopenia. After the ECTRIMS meeting, the manufacturer reported a case of PML in a patient with MS receiving dimethyl fumarate who had low lymphocyte counts for 3.5 years. Compared with natalizumab, dimethyl fumarate is associated with a lower risk of PML. “Nonetheless, it’s something that we’re keeping in the back of our mind and watching for,” said Dr. Fox. Monitoring for severely reduced lymphocyte counts may mitigate the risk of PML, he concluded.

—Erik Greb

BOSTON—Bright spotty lesions on MRI can help neurologists distinguish neuromyelitis optica spectrum disorder (NMOSD) from other neurologic disorders, according to data presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. These lesions may be an additional MRI indicator of NMOSD, combined with aquaporin 4 antibody, which has modest sensitivity, and longitudinally extensive transverse myelitis, which is characteristic of but not a pathognomonic feature of NMOSD.

A Series of 127 MRIs
To examine the potential relationship between bright spotty lesions and NMOSD, Jae-Won Hyun, MD, a neurologist at Research Institute and Hospital of National Cancer Center in Goyang, South Korea, and colleagues analyzed 127 spinal MRIs of patients who were having an acute myelitis attack. The study was led by Ho Jin Kim, MD, PhD, Head of the MS Clinic at Research Institute and Hospital of National Cancer Center. Of the participants, 62 had NMOSD, 32 had multiple sclerosis (MS), and 33 had idiopathic transverse myelitis. One neuroradiologist and two neurologists without knowledge of the patients’ diagnoses reviewed the spinal MRIs independently. The investigators defined bright spotty lesions as hyperintense spotty lesions with signal intensities at least as high as, but not higher than, that of the surrounding CSF on a T2-weighted image without flow void effects, and not as low as that of the surrounding CSF on a T1-weighted image.

The male-to-female ratio, the mean age at attack onset, and the mean age at time of MRI were higher among people with idiopathic transverse myelitis than in participants with NMOSD and those with MS. All patients with NMOSD tested positive for aquaporin 4 antibodies. Participants with MS and those with idiopathic transverse myelitis were negative for aquaporin 4 antibodies following repeated assays using three different methods. All subjects with idiopathic transverse myelitis were negative for anti-myelin oligodendrocyte glycoprotein antibody as well.

The Lesions’ Clinical Relevance Is Uncertain
The researchers found bright spotty lesions exclusively in patients with NMOSD. Of the 62 patients with NMOSD, 17 had bright spotty lesions. Dr. Hyun and colleagues identified longitudinally extensive transverse myelitis in all study participants. MRI features, including bright spotty lesions, were completely different between patients with NMOSD and those with MS. Bright spotty lesions, however, were the only MRI feature that distinguished NMOSD from idiopathic transverse myelitis.

Among patients with NMOSD, demographic data were not significantly different between individuals with and without bright spotty lesions. The investigators thus could not draw conclusions about the bright spotty lesions’ clinical relevance. To determine whether the lesions indicated attack severity, the researchers estimated the Expanded Disability Status Scale score of 36 patients with first myelitis attacks, as well as disease duration and attack numbers for all patients with NMOSD. Again, the researchers found no significant differences between patients with NMOSD with and without lesions. The investigators concluded that bright spotty lesions could not represent attack severity. In addition, other MRI findings were not significantly different between the two groups.

Dr. Hyun and colleagues followed up the patients with bright spotty lesions longitudinally. They performed 14 follow-up MRIs at two to 20 months after baseline.

No bright spotty lesions were detectable on follow-up MRI, but high signal intensities on T2 images remained for some patients. The results suggest that bright spotty lesions exist in a transient state during the acute phase of myelitis and ultimately undergo a fundamental change in properties, like contrast-enhanced lesions do, said Dr. Hyun.

—Erik Greb

BOSTON—Bright spotty lesions on MRI can help neurologists distinguish neuromyelitis optica spectrum disorder (NMOSD) from other neurologic disorders, according to data presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. These lesions may be an additional MRI indicator of NMOSD, combined with aquaporin 4 antibody, which has modest sensitivity, and longitudinally extensive transverse myelitis, which is characteristic of but not a pathognomonic feature of NMOSD.

A Series of 127 MRIs
To examine the potential relationship between bright spotty lesions and NMOSD, Jae-Won Hyun, MD, a neurologist at Research Institute and Hospital of National Cancer Center in Goyang, South Korea, and colleagues analyzed 127 spinal MRIs of patients who were having an acute myelitis attack. The study was led by Ho Jin Kim, MD, PhD, Head of the MS Clinic at Research Institute and Hospital of National Cancer Center. Of the participants, 62 had NMOSD, 32 had multiple sclerosis (MS), and 33 had idiopathic transverse myelitis. One neuroradiologist and two neurologists without knowledge of the patients’ diagnoses reviewed the spinal MRIs independently. The investigators defined bright spotty lesions as hyperintense spotty lesions with signal intensities at least as high as, but not higher than, that of the surrounding CSF on a T2-weighted image without flow void effects, and not as low as that of the surrounding CSF on a T1-weighted image.

The male-to-female ratio, the mean age at attack onset, and the mean age at time of MRI were higher among people with idiopathic transverse myelitis than in participants with NMOSD and those with MS. All patients with NMOSD tested positive for aquaporin 4 antibodies. Participants with MS and those with idiopathic transverse myelitis were negative for aquaporin 4 antibodies following repeated assays using three different methods. All subjects with idiopathic transverse myelitis were negative for anti-myelin oligodendrocyte glycoprotein antibody as well.

The Lesions’ Clinical Relevance Is Uncertain
The researchers found bright spotty lesions exclusively in patients with NMOSD. Of the 62 patients with NMOSD, 17 had bright spotty lesions. Dr. Hyun and colleagues identified longitudinally extensive transverse myelitis in all study participants. MRI features, including bright spotty lesions, were completely different between patients with NMOSD and those with MS. Bright spotty lesions, however, were the only MRI feature that distinguished NMOSD from idiopathic transverse myelitis.

Among patients with NMOSD, demographic data were not significantly different between individuals with and without bright spotty lesions. The investigators thus could not draw conclusions about the bright spotty lesions’ clinical relevance. To determine whether the lesions indicated attack severity, the researchers estimated the Expanded Disability Status Scale score of 36 patients with first myelitis attacks, as well as disease duration and attack numbers for all patients with NMOSD. Again, the researchers found no significant differences between patients with NMOSD with and without lesions. The investigators concluded that bright spotty lesions could not represent attack severity. In addition, other MRI findings were not significantly different between the two groups.

Dr. Hyun and colleagues followed up the patients with bright spotty lesions longitudinally. They performed 14 follow-up MRIs at two to 20 months after baseline.

No bright spotty lesions were detectable on follow-up MRI, but high signal intensities on T2 images remained for some patients. The results suggest that bright spotty lesions exist in a transient state during the acute phase of myelitis and ultimately undergo a fundamental change in properties, like contrast-enhanced lesions do, said Dr. Hyun.

—Erik Greb

BOSTON—Bright spotty lesions on MRI can help neurologists distinguish neuromyelitis optica spectrum disorder (NMOSD) from other neurologic disorders, according to data presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. These lesions may be an additional MRI indicator of NMOSD, combined with aquaporin 4 antibody, which has modest sensitivity, and longitudinally extensive transverse myelitis, which is characteristic of but not a pathognomonic feature of NMOSD.

A Series of 127 MRIs
To examine the potential relationship between bright spotty lesions and NMOSD, Jae-Won Hyun, MD, a neurologist at Research Institute and Hospital of National Cancer Center in Goyang, South Korea, and colleagues analyzed 127 spinal MRIs of patients who were having an acute myelitis attack. The study was led by Ho Jin Kim, MD, PhD, Head of the MS Clinic at Research Institute and Hospital of National Cancer Center. Of the participants, 62 had NMOSD, 32 had multiple sclerosis (MS), and 33 had idiopathic transverse myelitis. One neuroradiologist and two neurologists without knowledge of the patients’ diagnoses reviewed the spinal MRIs independently. The investigators defined bright spotty lesions as hyperintense spotty lesions with signal intensities at least as high as, but not higher than, that of the surrounding CSF on a T2-weighted image without flow void effects, and not as low as that of the surrounding CSF on a T1-weighted image.

The male-to-female ratio, the mean age at attack onset, and the mean age at time of MRI were higher among people with idiopathic transverse myelitis than in participants with NMOSD and those with MS. All patients with NMOSD tested positive for aquaporin 4 antibodies. Participants with MS and those with idiopathic transverse myelitis were negative for aquaporin 4 antibodies following repeated assays using three different methods. All subjects with idiopathic transverse myelitis were negative for anti-myelin oligodendrocyte glycoprotein antibody as well.

The Lesions’ Clinical Relevance Is Uncertain
The researchers found bright spotty lesions exclusively in patients with NMOSD. Of the 62 patients with NMOSD, 17 had bright spotty lesions. Dr. Hyun and colleagues identified longitudinally extensive transverse myelitis in all study participants. MRI features, including bright spotty lesions, were completely different between patients with NMOSD and those with MS. Bright spotty lesions, however, were the only MRI feature that distinguished NMOSD from idiopathic transverse myelitis.

Among patients with NMOSD, demographic data were not significantly different between individuals with and without bright spotty lesions. The investigators thus could not draw conclusions about the bright spotty lesions’ clinical relevance. To determine whether the lesions indicated attack severity, the researchers estimated the Expanded Disability Status Scale score of 36 patients with first myelitis attacks, as well as disease duration and attack numbers for all patients with NMOSD. Again, the researchers found no significant differences between patients with NMOSD with and without lesions. The investigators concluded that bright spotty lesions could not represent attack severity. In addition, other MRI findings were not significantly different between the two groups.

Dr. Hyun and colleagues followed up the patients with bright spotty lesions longitudinally. They performed 14 follow-up MRIs at two to 20 months after baseline.

No bright spotty lesions were detectable on follow-up MRI, but high signal intensities on T2 images remained for some patients. The results suggest that bright spotty lesions exist in a transient state during the acute phase of myelitis and ultimately undergo a fundamental change in properties, like contrast-enhanced lesions do, said Dr. Hyun.

—Erik Greb

BOSTON—Neurologists may consider changing the medication for a patient with relapsing-remitting multiple sclerosis (MS) who has ongoing disease activity despite treatment, according to a presentation at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Patients with a poor response to their initial treatment often benefit from a change to a new drug.

“The rationale for escalating treatment strategies in MS is based on a combination of clinical experience, expected benefit, and calculated risk,” said Xavier Montalban, MD, Chair of Neurology and Neuroimmunology at University Hospital and Research Institute, Vall d’Hebron in Barcelona. Yet neurologists must remember that “we do not have good class I evidence for switching patients from a platform therapy to a second-line treatment strategy,” he added.

Assessing Treatment Response
Treatment response is a major element of a treatment algorithm and can be defined in various ways. A common definition includes two clinical parameters (ie, relapses and disability progression) and MRI activity.

In an article published in Multiple Sclerosis in 2009, Río et al proposed a multicomponent score to assess treatment failure. The Río score incorporates the following three criteria: one or more relapse during the first 12 months, an increase in Expanded Disability Status Scale (EDSS) score of one point that is confirmed at six months, and three or more active new T2 or gadolinium-enhancing lesions on MRI. The authors found that patients who met two of these criteria had an odds ratio (OR) of 5.9 for clinical activity within three years. Fulfilling all three criteria was associated with an OR of 13.2 for this outcome.

Río and colleagues recently completed a study examining potential predictors of long-term outcomes. The investigators monitored clinical activity among 234 patients with MS during the first two years of treatment with interferon beta. They followed patients for 12 years and tracked three outcomes: the development of progressive MS, confinement to a wheelchair, and an increase in EDSS score of 5 or more points. The researchers found that clinical activity during the first two years of treatment increased the likelihood of the three end points at 12 years. These results are consistent with those of a 2013 study by Bermel et al, said Dr. Montalban.

The Results of Switching Treatments
If a neurologist decides that a change in therapy is advisable, one option is to switch from one first-line treatment to another. In a 2012 study, Río and colleagues found that patients who switched from an interferon to another interferon, from an interferon to glatiramer acetate, or from glatiramer acetate to an interferon had a decreased annualized relapse rate at 12 months.

A 2009 trial by Gajofatto and colleagues resulted in similar findings. Patients who switched from interferon beta or glatiramer acetate to natalizumab had greater reductions in annualized relapse rate at 24 months than participants who switched from one first-line therapy to another. In a similar study conducted in 2012, Prosperini and colleagues found no significant differences in disease activity at 12 months between patients switching from one first-line treatment to another and patients switching from a first-line to a second-line treatment. At 24 months freedom from disease activity was more common among patients who had escalated therapies than among patients who had switched between first-line treatments.

Few studies have examined the results of escalating to fingolimod, but their results generally have been positive. In a retrospective study, Bergvall and colleagues found a 59% reduction in the probability of having a relapse in patients who switched to fingolimod, compared with patients who switched to glatiramer acetate. In a 2011 extension of the TRANSFORMS trial, patients who had been treated with interferon beta-1a for one year were switched to fingolimod. These patients had a 50% reduction in annualized relapse rate after the switch, and the benefits were sustained for 4.5 years.

Considering Factors Beyond Clinical Efficacy
When neurologists consider switching a patient’s therapy because of clinical inefficacy, they must take other factors such as side effects, convenience, patient preferences, and cost into account, said Dr. Montalban. Disease severity, in terms of the numbers and volumes of gadolinium-enhancing and T2 lesions and the presence of oligoclonal bands, also should be considered. Apart from clinical activity, gender, age, the desire to become pregnant, comorbidities, and concomitant drugs may influence treatment decisions.

If a patient taking a first-line therapy has mild disease activity, it would be reasonable to consider switching him or her to another first-line therapy, to teriflunomide, or to dimethyl fumarate, said Dr. Montalban. But for a patient who has moderately severe disease activity despite treatment with a first- or second-line medicine, the neurologist might consider switching to a more potent drug such as natalizumab, fingolimod, or alemtuzumab.

Finally, the neurologist must remember that a change in treatment may require a washout period. If a patient will switch from natalizumab to fingolimod, teriflunomide, or dimethyl fumarate, a two- to three-month washout period is recommended. Switching from teriflunomide to other MS therapies may require a 3.5-month washout, but an accelerated elimination procedure may be used, said Dr. Montalban. To change from fingolimod to teriflunomide or natalizumab requires one to two months to allow lymphocytes to return to the normal range. For similar reasons, a neurologist may recommend a two- or three-month washout when a patient switches from fingolimod or natalizumab to alemtuzumab.

Switching a patient to or from interferon beta or glatiramer acetate, however, does not require a washout period, said Dr. Montalban. Likewise, no washout period is needed when moving a patient from dimethyl fumarate to alemtuzumab, natalizumab, or fingolimod.

—Erik Greb

BOSTON—Neurologists may consider changing the medication for a patient with relapsing-remitting multiple sclerosis (MS) who has ongoing disease activity despite treatment, according to a presentation at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Patients with a poor response to their initial treatment often benefit from a change to a new drug.

“The rationale for escalating treatment strategies in MS is based on a combination of clinical experience, expected benefit, and calculated risk,” said Xavier Montalban, MD, Chair of Neurology and Neuroimmunology at University Hospital and Research Institute, Vall d’Hebron in Barcelona. Yet neurologists must remember that “we do not have good class I evidence for switching patients from a platform therapy to a second-line treatment strategy,” he added.

Assessing Treatment Response
Treatment response is a major element of a treatment algorithm and can be defined in various ways. A common definition includes two clinical parameters (ie, relapses and disability progression) and MRI activity.

In an article published in Multiple Sclerosis in 2009, Río et al proposed a multicomponent score to assess treatment failure. The Río score incorporates the following three criteria: one or more relapse during the first 12 months, an increase in Expanded Disability Status Scale (EDSS) score of one point that is confirmed at six months, and three or more active new T2 or gadolinium-enhancing lesions on MRI. The authors found that patients who met two of these criteria had an odds ratio (OR) of 5.9 for clinical activity within three years. Fulfilling all three criteria was associated with an OR of 13.2 for this outcome.

Río and colleagues recently completed a study examining potential predictors of long-term outcomes. The investigators monitored clinical activity among 234 patients with MS during the first two years of treatment with interferon beta. They followed patients for 12 years and tracked three outcomes: the development of progressive MS, confinement to a wheelchair, and an increase in EDSS score of 5 or more points. The researchers found that clinical activity during the first two years of treatment increased the likelihood of the three end points at 12 years. These results are consistent with those of a 2013 study by Bermel et al, said Dr. Montalban.

The Results of Switching Treatments
If a neurologist decides that a change in therapy is advisable, one option is to switch from one first-line treatment to another. In a 2012 study, Río and colleagues found that patients who switched from an interferon to another interferon, from an interferon to glatiramer acetate, or from glatiramer acetate to an interferon had a decreased annualized relapse rate at 12 months.

A 2009 trial by Gajofatto and colleagues resulted in similar findings. Patients who switched from interferon beta or glatiramer acetate to natalizumab had greater reductions in annualized relapse rate at 24 months than participants who switched from one first-line therapy to another. In a similar study conducted in 2012, Prosperini and colleagues found no significant differences in disease activity at 12 months between patients switching from one first-line treatment to another and patients switching from a first-line to a second-line treatment. At 24 months freedom from disease activity was more common among patients who had escalated therapies than among patients who had switched between first-line treatments.

Few studies have examined the results of escalating to fingolimod, but their results generally have been positive. In a retrospective study, Bergvall and colleagues found a 59% reduction in the probability of having a relapse in patients who switched to fingolimod, compared with patients who switched to glatiramer acetate. In a 2011 extension of the TRANSFORMS trial, patients who had been treated with interferon beta-1a for one year were switched to fingolimod. These patients had a 50% reduction in annualized relapse rate after the switch, and the benefits were sustained for 4.5 years.

Considering Factors Beyond Clinical Efficacy
When neurologists consider switching a patient’s therapy because of clinical inefficacy, they must take other factors such as side effects, convenience, patient preferences, and cost into account, said Dr. Montalban. Disease severity, in terms of the numbers and volumes of gadolinium-enhancing and T2 lesions and the presence of oligoclonal bands, also should be considered. Apart from clinical activity, gender, age, the desire to become pregnant, comorbidities, and concomitant drugs may influence treatment decisions.

If a patient taking a first-line therapy has mild disease activity, it would be reasonable to consider switching him or her to another first-line therapy, to teriflunomide, or to dimethyl fumarate, said Dr. Montalban. But for a patient who has moderately severe disease activity despite treatment with a first- or second-line medicine, the neurologist might consider switching to a more potent drug such as natalizumab, fingolimod, or alemtuzumab.

Finally, the neurologist must remember that a change in treatment may require a washout period. If a patient will switch from natalizumab to fingolimod, teriflunomide, or dimethyl fumarate, a two- to three-month washout period is recommended. Switching from teriflunomide to other MS therapies may require a 3.5-month washout, but an accelerated elimination procedure may be used, said Dr. Montalban. To change from fingolimod to teriflunomide or natalizumab requires one to two months to allow lymphocytes to return to the normal range. For similar reasons, a neurologist may recommend a two- or three-month washout when a patient switches from fingolimod or natalizumab to alemtuzumab.

Switching a patient to or from interferon beta or glatiramer acetate, however, does not require a washout period, said Dr. Montalban. Likewise, no washout period is needed when moving a patient from dimethyl fumarate to alemtuzumab, natalizumab, or fingolimod.

—Erik Greb

BOSTON—Neurologists may consider changing the medication for a patient with relapsing-remitting multiple sclerosis (MS) who has ongoing disease activity despite treatment, according to a presentation at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Patients with a poor response to their initial treatment often benefit from a change to a new drug.

“The rationale for escalating treatment strategies in MS is based on a combination of clinical experience, expected benefit, and calculated risk,” said Xavier Montalban, MD, Chair of Neurology and Neuroimmunology at University Hospital and Research Institute, Vall d’Hebron in Barcelona. Yet neurologists must remember that “we do not have good class I evidence for switching patients from a platform therapy to a second-line treatment strategy,” he added.

Assessing Treatment Response
Treatment response is a major element of a treatment algorithm and can be defined in various ways. A common definition includes two clinical parameters (ie, relapses and disability progression) and MRI activity.

In an article published in Multiple Sclerosis in 2009, Río et al proposed a multicomponent score to assess treatment failure. The Río score incorporates the following three criteria: one or more relapse during the first 12 months, an increase in Expanded Disability Status Scale (EDSS) score of one point that is confirmed at six months, and three or more active new T2 or gadolinium-enhancing lesions on MRI. The authors found that patients who met two of these criteria had an odds ratio (OR) of 5.9 for clinical activity within three years. Fulfilling all three criteria was associated with an OR of 13.2 for this outcome.

Río and colleagues recently completed a study examining potential predictors of long-term outcomes. The investigators monitored clinical activity among 234 patients with MS during the first two years of treatment with interferon beta. They followed patients for 12 years and tracked three outcomes: the development of progressive MS, confinement to a wheelchair, and an increase in EDSS score of 5 or more points. The researchers found that clinical activity during the first two years of treatment increased the likelihood of the three end points at 12 years. These results are consistent with those of a 2013 study by Bermel et al, said Dr. Montalban.

The Results of Switching Treatments
If a neurologist decides that a change in therapy is advisable, one option is to switch from one first-line treatment to another. In a 2012 study, Río and colleagues found that patients who switched from an interferon to another interferon, from an interferon to glatiramer acetate, or from glatiramer acetate to an interferon had a decreased annualized relapse rate at 12 months.

A 2009 trial by Gajofatto and colleagues resulted in similar findings. Patients who switched from interferon beta or glatiramer acetate to natalizumab had greater reductions in annualized relapse rate at 24 months than participants who switched from one first-line therapy to another. In a similar study conducted in 2012, Prosperini and colleagues found no significant differences in disease activity at 12 months between patients switching from one first-line treatment to another and patients switching from a first-line to a second-line treatment. At 24 months freedom from disease activity was more common among patients who had escalated therapies than among patients who had switched between first-line treatments.

Few studies have examined the results of escalating to fingolimod, but their results generally have been positive. In a retrospective study, Bergvall and colleagues found a 59% reduction in the probability of having a relapse in patients who switched to fingolimod, compared with patients who switched to glatiramer acetate. In a 2011 extension of the TRANSFORMS trial, patients who had been treated with interferon beta-1a for one year were switched to fingolimod. These patients had a 50% reduction in annualized relapse rate after the switch, and the benefits were sustained for 4.5 years.

Considering Factors Beyond Clinical Efficacy
When neurologists consider switching a patient’s therapy because of clinical inefficacy, they must take other factors such as side effects, convenience, patient preferences, and cost into account, said Dr. Montalban. Disease severity, in terms of the numbers and volumes of gadolinium-enhancing and T2 lesions and the presence of oligoclonal bands, also should be considered. Apart from clinical activity, gender, age, the desire to become pregnant, comorbidities, and concomitant drugs may influence treatment decisions.

If a patient taking a first-line therapy has mild disease activity, it would be reasonable to consider switching him or her to another first-line therapy, to teriflunomide, or to dimethyl fumarate, said Dr. Montalban. But for a patient who has moderately severe disease activity despite treatment with a first- or second-line medicine, the neurologist might consider switching to a more potent drug such as natalizumab, fingolimod, or alemtuzumab.

Finally, the neurologist must remember that a change in treatment may require a washout period. If a patient will switch from natalizumab to fingolimod, teriflunomide, or dimethyl fumarate, a two- to three-month washout period is recommended. Switching from teriflunomide to other MS therapies may require a 3.5-month washout, but an accelerated elimination procedure may be used, said Dr. Montalban. To change from fingolimod to teriflunomide or natalizumab requires one to two months to allow lymphocytes to return to the normal range. For similar reasons, a neurologist may recommend a two- or three-month washout when a patient switches from fingolimod or natalizumab to alemtuzumab.

Switching a patient to or from interferon beta or glatiramer acetate, however, does not require a washout period, said Dr. Montalban. Likewise, no washout period is needed when moving a patient from dimethyl fumarate to alemtuzumab, natalizumab, or fingolimod.

—Erik Greb

BOSTON—Along with baseline characteristics, clinical and MRI changes during the first year after diagnosis of clinically isolated syndrome (CIS) can improve neurologists’ estimation of a patient’s prognosis, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The presence of MRI lesions at baseline and the emergence of new T2 lesions during the first year after CIS diagnosis predict the occurrence of a second attack, said Mar Tintoré, MD. Treatment after the first attack, however, may protect against further attacks.

The presence of oligoclonal bands, the emergence of new T2 lesions during the first year after CIS diagnosis, and incomplete recovery from the first attack are independent predictors of the accumulation of disability, said Dr. Tintoré, Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

A Prospective Study of Patients With CIS
In a previous prospective study of patients with CIS, Dr. Tintoré and colleagues concluded that baseline MRI was of great value in predicting future attacks and accumulation of disability. The presence of oligoclonal bands at baseline is a medium-impact prognostic factor for these outcomes, and demographic characteristics and topography of CIS are low-impact prognostic factors, the investigators concluded.

The researchers next decided to investigate the added value of clinical and brain MRI changes during the first year after a diagnosis of CIS for predicting conversion to multiple sclerosis (MS) or disability accumulation. For this investigation, Dr. Tintoré’s group began prospectively following patients with CIS in 1995. Eligible patients were younger than 50. During regular clinical follow-up, neurologists monitored patients for a second attack and disability accumulation. Participants also underwent regular MRI monitoring.

Age, gender, topography of CIS, date of disease-modifying therapy initiation (if applicable), number of T2 lesions, presence of gadolinium-enhancing lesions, and presence of oligoclonal bands were the baseline variables that the investigators examined. First-year variables included the presence of a second attack and recovery from the first attack, which was measured as Expanded Disability Status Scale (EDSS) score at year one. Incomplete recovery was defined as an EDSS score of 2 or higher. The investigators also looked at the number of new T2 lesions and the presence of gadolinium-enhancing lesions at 12 months.

The total cohort included 1,058 participants, but the investigators excluded 43 people who were ineligible. The researchers have more than 12 months of follow-up data for 887 patients. Approximately 68% of participants were female, and the cohort’s mean age was 31. Oligoclonal bands were performed for about 82% of patients, and the mean follow-up duration was 7.7 years.

New T2 Lesions at One Year Were Common
At baseline, approximately one-third of patients had a normal MRI, and 41.4% had 10 or more T2 lesions. In addition, 23% of participants had gadolinium-enhancing lesions at baseline.

During the first year after CIS diagnosis, 17% of patients had a relapse, and 24% of participants had incomplete recovery from the first attack. Approximately 43% of patients had new T2 lesions at 12 months, and approximately 20% had gadolinium-enhancing lesions at 12 months.

Multivariate analysis indicated that gender and topography did not affect the risk of having a second attack. Younger age, however, was associated with a higher risk of having a second attack. The presence of T2 lesions on baseline MRI was a strong predictor of new relapses, as was the presence of new T2 lesions at 12 months.

A separate multivariate analysis suggested that gender and age did not predict the accumulation of disability, which was defined as a confirmed EDSS score of 3. Oligoclonal bands, however, increased the risk of disability accumulation. Incomplete recovery from the first attack also was “a clear predictor of disability in the long term,” said Dr. Tintoré.

—Erik Greb

BOSTON—Along with baseline characteristics, clinical and MRI changes during the first year after diagnosis of clinically isolated syndrome (CIS) can improve neurologists’ estimation of a patient’s prognosis, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The presence of MRI lesions at baseline and the emergence of new T2 lesions during the first year after CIS diagnosis predict the occurrence of a second attack, said Mar Tintoré, MD. Treatment after the first attack, however, may protect against further attacks.

The presence of oligoclonal bands, the emergence of new T2 lesions during the first year after CIS diagnosis, and incomplete recovery from the first attack are independent predictors of the accumulation of disability, said Dr. Tintoré, Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

A Prospective Study of Patients With CIS
In a previous prospective study of patients with CIS, Dr. Tintoré and colleagues concluded that baseline MRI was of great value in predicting future attacks and accumulation of disability. The presence of oligoclonal bands at baseline is a medium-impact prognostic factor for these outcomes, and demographic characteristics and topography of CIS are low-impact prognostic factors, the investigators concluded.

The researchers next decided to investigate the added value of clinical and brain MRI changes during the first year after a diagnosis of CIS for predicting conversion to multiple sclerosis (MS) or disability accumulation. For this investigation, Dr. Tintoré’s group began prospectively following patients with CIS in 1995. Eligible patients were younger than 50. During regular clinical follow-up, neurologists monitored patients for a second attack and disability accumulation. Participants also underwent regular MRI monitoring.

Age, gender, topography of CIS, date of disease-modifying therapy initiation (if applicable), number of T2 lesions, presence of gadolinium-enhancing lesions, and presence of oligoclonal bands were the baseline variables that the investigators examined. First-year variables included the presence of a second attack and recovery from the first attack, which was measured as Expanded Disability Status Scale (EDSS) score at year one. Incomplete recovery was defined as an EDSS score of 2 or higher. The investigators also looked at the number of new T2 lesions and the presence of gadolinium-enhancing lesions at 12 months.

The total cohort included 1,058 participants, but the investigators excluded 43 people who were ineligible. The researchers have more than 12 months of follow-up data for 887 patients. Approximately 68% of participants were female, and the cohort’s mean age was 31. Oligoclonal bands were performed for about 82% of patients, and the mean follow-up duration was 7.7 years.

New T2 Lesions at One Year Were Common
At baseline, approximately one-third of patients had a normal MRI, and 41.4% had 10 or more T2 lesions. In addition, 23% of participants had gadolinium-enhancing lesions at baseline.

During the first year after CIS diagnosis, 17% of patients had a relapse, and 24% of participants had incomplete recovery from the first attack. Approximately 43% of patients had new T2 lesions at 12 months, and approximately 20% had gadolinium-enhancing lesions at 12 months.

Multivariate analysis indicated that gender and topography did not affect the risk of having a second attack. Younger age, however, was associated with a higher risk of having a second attack. The presence of T2 lesions on baseline MRI was a strong predictor of new relapses, as was the presence of new T2 lesions at 12 months.

A separate multivariate analysis suggested that gender and age did not predict the accumulation of disability, which was defined as a confirmed EDSS score of 3. Oligoclonal bands, however, increased the risk of disability accumulation. Incomplete recovery from the first attack also was “a clear predictor of disability in the long term,” said Dr. Tintoré.

—Erik Greb

BOSTON—Along with baseline characteristics, clinical and MRI changes during the first year after diagnosis of clinically isolated syndrome (CIS) can improve neurologists’ estimation of a patient’s prognosis, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The presence of MRI lesions at baseline and the emergence of new T2 lesions during the first year after CIS diagnosis predict the occurrence of a second attack, said Mar Tintoré, MD. Treatment after the first attack, however, may protect against further attacks.

The presence of oligoclonal bands, the emergence of new T2 lesions during the first year after CIS diagnosis, and incomplete recovery from the first attack are independent predictors of the accumulation of disability, said Dr. Tintoré, Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

A Prospective Study of Patients With CIS
In a previous prospective study of patients with CIS, Dr. Tintoré and colleagues concluded that baseline MRI was of great value in predicting future attacks and accumulation of disability. The presence of oligoclonal bands at baseline is a medium-impact prognostic factor for these outcomes, and demographic characteristics and topography of CIS are low-impact prognostic factors, the investigators concluded.

The researchers next decided to investigate the added value of clinical and brain MRI changes during the first year after a diagnosis of CIS for predicting conversion to multiple sclerosis (MS) or disability accumulation. For this investigation, Dr. Tintoré’s group began prospectively following patients with CIS in 1995. Eligible patients were younger than 50. During regular clinical follow-up, neurologists monitored patients for a second attack and disability accumulation. Participants also underwent regular MRI monitoring.

Age, gender, topography of CIS, date of disease-modifying therapy initiation (if applicable), number of T2 lesions, presence of gadolinium-enhancing lesions, and presence of oligoclonal bands were the baseline variables that the investigators examined. First-year variables included the presence of a second attack and recovery from the first attack, which was measured as Expanded Disability Status Scale (EDSS) score at year one. Incomplete recovery was defined as an EDSS score of 2 or higher. The investigators also looked at the number of new T2 lesions and the presence of gadolinium-enhancing lesions at 12 months.

The total cohort included 1,058 participants, but the investigators excluded 43 people who were ineligible. The researchers have more than 12 months of follow-up data for 887 patients. Approximately 68% of participants were female, and the cohort’s mean age was 31. Oligoclonal bands were performed for about 82% of patients, and the mean follow-up duration was 7.7 years.

New T2 Lesions at One Year Were Common
At baseline, approximately one-third of patients had a normal MRI, and 41.4% had 10 or more T2 lesions. In addition, 23% of participants had gadolinium-enhancing lesions at baseline.

During the first year after CIS diagnosis, 17% of patients had a relapse, and 24% of participants had incomplete recovery from the first attack. Approximately 43% of patients had new T2 lesions at 12 months, and approximately 20% had gadolinium-enhancing lesions at 12 months.

Multivariate analysis indicated that gender and topography did not affect the risk of having a second attack. Younger age, however, was associated with a higher risk of having a second attack. The presence of T2 lesions on baseline MRI was a strong predictor of new relapses, as was the presence of new T2 lesions at 12 months.

A separate multivariate analysis suggested that gender and age did not predict the accumulation of disability, which was defined as a confirmed EDSS score of 3. Oligoclonal bands, however, increased the risk of disability accumulation. Incomplete recovery from the first attack also was “a clear predictor of disability in the long term,” said Dr. Tintoré.

—Erik Greb

BOSTON—Delivering subcutaneous glatiramer acetate as a 40-mg/mL dose three times weekly, rather than 20 mg/mL daily, may reduce the annualized rate of injection-related adverse events by half, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The results are from a randomized, open-label, phase III b trial of patients with relapsing-remitting multiple sclerosis (MS).

The reduction in the annualized rate of moderate and severe injection-related adverse events in patients who received lower-frequency dosing was about 60%, said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas Health Science Center at Houston. The trial was called Glatiramer Acetate Low Frequency Safety and Patient Experience (GLACIER).

“As we all know, long-term, frequent injections are required for the first-line therapies for relapsing forms of MS, and this form of drug delivery presents a challenge for patients. Modification of the treatment regimen, such as using alternative dosages and lower-frequency administration schedules for these drugs with long-term proven efficacy, has the potential to improve the patient experience by reducing, perhaps, the number of adverse experiences that he or she has, improving tolerability, and, in particular, potentially increasing adherence to treatments, especially in the longer-term,” said Dr. Wolinsky. The GLACIER trial was designed, in part, to test the regimen’s potential to yield these improvements.

Patients May Prefer Fewer Injections
Glatiramer acetate 20 mg/mL administered by daily subcutaneous injection is a well-characterized treatment with a good long-term safety profile. The drug has been used for more than 20 years, has accumulated more than two million patient-years of overall exposures, and has established efficacy for the treatment of relapsing-remitting MS. In January 2014, the FDA approved a supplemental New Drug Application for the 40-mg/mL three times weekly regimen after it was shown to have an efficacy and safety profile similar to that of the daily 20-mg/mL regimen.

The GLACIER findings suggest that the 40-mg/mL dosing regimen of glatiramer acetate is a favorable treatment option for some patients, particularly people who want to be on glatiramer acetate, but who prefer to take fewer injections and have more convenient dosing, concluded Dr. Wolinsky.

The annualized rate of injection-related adverse events in 108 adult patients with relapsing-remitting MS who were randomized to receive the thrice-weekly injections was 35.3, compared with 70.4 in 101 patients who received daily injections (relative risk, 0.50). The annualized rate of moderate and severe injection-related adverse events was 0.88 vs 2.2 in the groups, respectively (relative risk, 0.40), said Dr. Wolinsky.

The most common injection-site reactions were pain, erythema, mass, swelling, and pruritus, and all of these reactions were substantially reduced with lower-frequency dosing, compared with daily dosing. For example, the annualized rate of pain events was 24.8 with lower-frequency dosing vs 55.3 with higher-frequency dosing, and the annualized rate of erythema events was 21.4 vs 43.5.

Patients Had Experience With Glatiramer Acetate
Patients in the GLACIER trial were age 18 or older (mean age, 51) with a diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score between 0 and 5.5. Most participants (82%) were women, and 94% of patients were Caucasian.

All participants had been treated continuously with the 20-mg/mL daily dosing regimen for at least six months and were stable on that regimen for at least two months prior to screening for the GLACIER trial.

At least 75% treatment compliance was achieved by 99% of the GLACIER trial patients, and only 10 people withdrew before completing the four-month treatment phase, including three participants in the daily dosing group and seven patients in the lower-frequency dosing group. One patient withdrew because of an adverse event, said Dr. Wolinsky.

—Sharon Worcester

BOSTON—Delivering subcutaneous glatiramer acetate as a 40-mg/mL dose three times weekly, rather than 20 mg/mL daily, may reduce the annualized rate of injection-related adverse events by half, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The results are from a randomized, open-label, phase III b trial of patients with relapsing-remitting multiple sclerosis (MS).

The reduction in the annualized rate of moderate and severe injection-related adverse events in patients who received lower-frequency dosing was about 60%, said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas Health Science Center at Houston. The trial was called Glatiramer Acetate Low Frequency Safety and Patient Experience (GLACIER).

“As we all know, long-term, frequent injections are required for the first-line therapies for relapsing forms of MS, and this form of drug delivery presents a challenge for patients. Modification of the treatment regimen, such as using alternative dosages and lower-frequency administration schedules for these drugs with long-term proven efficacy, has the potential to improve the patient experience by reducing, perhaps, the number of adverse experiences that he or she has, improving tolerability, and, in particular, potentially increasing adherence to treatments, especially in the longer-term,” said Dr. Wolinsky. The GLACIER trial was designed, in part, to test the regimen’s potential to yield these improvements.

Patients May Prefer Fewer Injections
Glatiramer acetate 20 mg/mL administered by daily subcutaneous injection is a well-characterized treatment with a good long-term safety profile. The drug has been used for more than 20 years, has accumulated more than two million patient-years of overall exposures, and has established efficacy for the treatment of relapsing-remitting MS. In January 2014, the FDA approved a supplemental New Drug Application for the 40-mg/mL three times weekly regimen after it was shown to have an efficacy and safety profile similar to that of the daily 20-mg/mL regimen.

The GLACIER findings suggest that the 40-mg/mL dosing regimen of glatiramer acetate is a favorable treatment option for some patients, particularly people who want to be on glatiramer acetate, but who prefer to take fewer injections and have more convenient dosing, concluded Dr. Wolinsky.

The annualized rate of injection-related adverse events in 108 adult patients with relapsing-remitting MS who were randomized to receive the thrice-weekly injections was 35.3, compared with 70.4 in 101 patients who received daily injections (relative risk, 0.50). The annualized rate of moderate and severe injection-related adverse events was 0.88 vs 2.2 in the groups, respectively (relative risk, 0.40), said Dr. Wolinsky.

The most common injection-site reactions were pain, erythema, mass, swelling, and pruritus, and all of these reactions were substantially reduced with lower-frequency dosing, compared with daily dosing. For example, the annualized rate of pain events was 24.8 with lower-frequency dosing vs 55.3 with higher-frequency dosing, and the annualized rate of erythema events was 21.4 vs 43.5.

Patients Had Experience With Glatiramer Acetate
Patients in the GLACIER trial were age 18 or older (mean age, 51) with a diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score between 0 and 5.5. Most participants (82%) were women, and 94% of patients were Caucasian.

All participants had been treated continuously with the 20-mg/mL daily dosing regimen for at least six months and were stable on that regimen for at least two months prior to screening for the GLACIER trial.

At least 75% treatment compliance was achieved by 99% of the GLACIER trial patients, and only 10 people withdrew before completing the four-month treatment phase, including three participants in the daily dosing group and seven patients in the lower-frequency dosing group. One patient withdrew because of an adverse event, said Dr. Wolinsky.

—Sharon Worcester

BOSTON—Delivering subcutaneous glatiramer acetate as a 40-mg/mL dose three times weekly, rather than 20 mg/mL daily, may reduce the annualized rate of injection-related adverse events by half, according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The results are from a randomized, open-label, phase III b trial of patients with relapsing-remitting multiple sclerosis (MS).

The reduction in the annualized rate of moderate and severe injection-related adverse events in patients who received lower-frequency dosing was about 60%, said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas Health Science Center at Houston. The trial was called Glatiramer Acetate Low Frequency Safety and Patient Experience (GLACIER).

“As we all know, long-term, frequent injections are required for the first-line therapies for relapsing forms of MS, and this form of drug delivery presents a challenge for patients. Modification of the treatment regimen, such as using alternative dosages and lower-frequency administration schedules for these drugs with long-term proven efficacy, has the potential to improve the patient experience by reducing, perhaps, the number of adverse experiences that he or she has, improving tolerability, and, in particular, potentially increasing adherence to treatments, especially in the longer-term,” said Dr. Wolinsky. The GLACIER trial was designed, in part, to test the regimen’s potential to yield these improvements.

Patients May Prefer Fewer Injections
Glatiramer acetate 20 mg/mL administered by daily subcutaneous injection is a well-characterized treatment with a good long-term safety profile. The drug has been used for more than 20 years, has accumulated more than two million patient-years of overall exposures, and has established efficacy for the treatment of relapsing-remitting MS. In January 2014, the FDA approved a supplemental New Drug Application for the 40-mg/mL three times weekly regimen after it was shown to have an efficacy and safety profile similar to that of the daily 20-mg/mL regimen.

The GLACIER findings suggest that the 40-mg/mL dosing regimen of glatiramer acetate is a favorable treatment option for some patients, particularly people who want to be on glatiramer acetate, but who prefer to take fewer injections and have more convenient dosing, concluded Dr. Wolinsky.

The annualized rate of injection-related adverse events in 108 adult patients with relapsing-remitting MS who were randomized to receive the thrice-weekly injections was 35.3, compared with 70.4 in 101 patients who received daily injections (relative risk, 0.50). The annualized rate of moderate and severe injection-related adverse events was 0.88 vs 2.2 in the groups, respectively (relative risk, 0.40), said Dr. Wolinsky.

The most common injection-site reactions were pain, erythema, mass, swelling, and pruritus, and all of these reactions were substantially reduced with lower-frequency dosing, compared with daily dosing. For example, the annualized rate of pain events was 24.8 with lower-frequency dosing vs 55.3 with higher-frequency dosing, and the annualized rate of erythema events was 21.4 vs 43.5.

Patients Had Experience With Glatiramer Acetate
Patients in the GLACIER trial were age 18 or older (mean age, 51) with a diagnosis of relapsing-remitting MS and an Expanded Disability Status Scale score between 0 and 5.5. Most participants (82%) were women, and 94% of patients were Caucasian.

All participants had been treated continuously with the 20-mg/mL daily dosing regimen for at least six months and were stable on that regimen for at least two months prior to screening for the GLACIER trial.

At least 75% treatment compliance was achieved by 99% of the GLACIER trial patients, and only 10 people withdrew before completing the four-month treatment phase, including three participants in the daily dosing group and seven patients in the lower-frequency dosing group. One patient withdrew because of an adverse event, said Dr. Wolinsky.

—Sharon Worcester