ICYMI Multiple Sclerosis

NATIONAL HARBOR, MD—After eight years of fingolimod treatment, disability improves or remains stable for a majority of patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting.

The two-year phase III FREEDOMS and FREEDOMS II trial data revealed that fingolimod reduced confirmed disability progression in patients with MS, but evaluating disability over a longer time span may help to determine the full impact of treatment. Shannon Ritter, MD, an employee of Novartis Pharmaceuticals, and her colleagues examined trends in changes in Expanded Disability Status Scale (EDSS) scores over a maximum of eight years. Their objective was to investigate patients’ evolving disability patterns and the impact of fingolimod treatment on long-term disability.

The investigators conducted post hoc analyses that included data collected for as long as 96 months from baseline from patients randomized to fingolimod 0.5 mg or placebo in both two- year FREEDOMS trials. In addition, patients who switched or continued 0.5 mg fingolimod in the extension trials, and those who continuously received 0.5 mg fingolimod in the LONGTERMS trial, were also included in the analysis.

Disability progression was considered minimal if there was an increase or decrease of 0.5 points from a baseline EDSS score of 5.5 or lower, or if there was no change in a baseline score greater than 5.5. Disability was considered to have improved if the baseline EDSS score decreased by 1.0 or more points, either confirmed at six months only, or confirmed at six months and sustained until month 24, 48, or 96. Worsening was defined as an increase of 1.0 point or more from the baseline EDSS score, either confirmed at six months only or confirmed at six months and sustained until month 24, 48, and 96. Stable/improving was defined as the minimal and improving categories combined, and fluctuating was identified as changes in the EDSS score that were different from those defined in other categories.

Results showed that significant improvements were more likely to be noted after longer periods of continuous fingolimod treatment. Disability fluctuated or changed minimally at 24 months, and the proportion of patients in these categories decreased by almost 50% at 96 months. Researchers noted that 22.6% of patients in the continuous fingolimod group were improving, 22.6% were worsening, and 54.7% of patients had minimal change or were fluctuating at 96 months. However, 20% of patients in the switch group were improving, 28% were worsening, and 52% had changed minimally or were fluctuating at 96 months. Overall, the proportion of patients improving or worsening was larger at 96 months than at 24 months.

Researchers also investigated the impact of delaying fingolimod treatment on long-term disability and concluded that patients with worsening disability over 96 months benefited from early fingolimod treatment. Fewer patients in the continuous fingolimod group had worsening disability, compared with the switch group, at 24 months. By 96 months, the continuous fingolimod group maintained proportionally fewer patients with worsening disability, compared with the switch group. The data indicate that the majority of patients receiving continuous fingolimod treatment were either stable or improving at 96 months. Proportionally more patients had improving disability at 96 months, compared to 24 months. These results support the practice of longer follow-up periods to properly detect the impact of treatment.

This study was supported by Oxford PharmaGenesis in Oxford UK, and funded by Novartis Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—After eight years of fingolimod treatment, disability improves or remains stable for a majority of patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting.

The two-year phase III FREEDOMS and FREEDOMS II trial data revealed that fingolimod reduced confirmed disability progression in patients with MS, but evaluating disability over a longer time span may help to determine the full impact of treatment. Shannon Ritter, MD, an employee of Novartis Pharmaceuticals, and her colleagues examined trends in changes in Expanded Disability Status Scale (EDSS) scores over a maximum of eight years. Their objective was to investigate patients’ evolving disability patterns and the impact of fingolimod treatment on long-term disability.

The investigators conducted post hoc analyses that included data collected for as long as 96 months from baseline from patients randomized to fingolimod 0.5 mg or placebo in both two- year FREEDOMS trials. In addition, patients who switched or continued 0.5 mg fingolimod in the extension trials, and those who continuously received 0.5 mg fingolimod in the LONGTERMS trial, were also included in the analysis.

Disability progression was considered minimal if there was an increase or decrease of 0.5 points from a baseline EDSS score of 5.5 or lower, or if there was no change in a baseline score greater than 5.5. Disability was considered to have improved if the baseline EDSS score decreased by 1.0 or more points, either confirmed at six months only, or confirmed at six months and sustained until month 24, 48, or 96. Worsening was defined as an increase of 1.0 point or more from the baseline EDSS score, either confirmed at six months only or confirmed at six months and sustained until month 24, 48, and 96. Stable/improving was defined as the minimal and improving categories combined, and fluctuating was identified as changes in the EDSS score that were different from those defined in other categories.

Results showed that significant improvements were more likely to be noted after longer periods of continuous fingolimod treatment. Disability fluctuated or changed minimally at 24 months, and the proportion of patients in these categories decreased by almost 50% at 96 months. Researchers noted that 22.6% of patients in the continuous fingolimod group were improving, 22.6% were worsening, and 54.7% of patients had minimal change or were fluctuating at 96 months. However, 20% of patients in the switch group were improving, 28% were worsening, and 52% had changed minimally or were fluctuating at 96 months. Overall, the proportion of patients improving or worsening was larger at 96 months than at 24 months.

Researchers also investigated the impact of delaying fingolimod treatment on long-term disability and concluded that patients with worsening disability over 96 months benefited from early fingolimod treatment. Fewer patients in the continuous fingolimod group had worsening disability, compared with the switch group, at 24 months. By 96 months, the continuous fingolimod group maintained proportionally fewer patients with worsening disability, compared with the switch group. The data indicate that the majority of patients receiving continuous fingolimod treatment were either stable or improving at 96 months. Proportionally more patients had improving disability at 96 months, compared to 24 months. These results support the practice of longer follow-up periods to properly detect the impact of treatment.

This study was supported by Oxford PharmaGenesis in Oxford UK, and funded by Novartis Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—After eight years of fingolimod treatment, disability improves or remains stable for a majority of patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting.

The two-year phase III FREEDOMS and FREEDOMS II trial data revealed that fingolimod reduced confirmed disability progression in patients with MS, but evaluating disability over a longer time span may help to determine the full impact of treatment. Shannon Ritter, MD, an employee of Novartis Pharmaceuticals, and her colleagues examined trends in changes in Expanded Disability Status Scale (EDSS) scores over a maximum of eight years. Their objective was to investigate patients’ evolving disability patterns and the impact of fingolimod treatment on long-term disability.

The investigators conducted post hoc analyses that included data collected for as long as 96 months from baseline from patients randomized to fingolimod 0.5 mg or placebo in both two- year FREEDOMS trials. In addition, patients who switched or continued 0.5 mg fingolimod in the extension trials, and those who continuously received 0.5 mg fingolimod in the LONGTERMS trial, were also included in the analysis.

Disability progression was considered minimal if there was an increase or decrease of 0.5 points from a baseline EDSS score of 5.5 or lower, or if there was no change in a baseline score greater than 5.5. Disability was considered to have improved if the baseline EDSS score decreased by 1.0 or more points, either confirmed at six months only, or confirmed at six months and sustained until month 24, 48, or 96. Worsening was defined as an increase of 1.0 point or more from the baseline EDSS score, either confirmed at six months only or confirmed at six months and sustained until month 24, 48, and 96. Stable/improving was defined as the minimal and improving categories combined, and fluctuating was identified as changes in the EDSS score that were different from those defined in other categories.

Results showed that significant improvements were more likely to be noted after longer periods of continuous fingolimod treatment. Disability fluctuated or changed minimally at 24 months, and the proportion of patients in these categories decreased by almost 50% at 96 months. Researchers noted that 22.6% of patients in the continuous fingolimod group were improving, 22.6% were worsening, and 54.7% of patients had minimal change or were fluctuating at 96 months. However, 20% of patients in the switch group were improving, 28% were worsening, and 52% had changed minimally or were fluctuating at 96 months. Overall, the proportion of patients improving or worsening was larger at 96 months than at 24 months.

Researchers also investigated the impact of delaying fingolimod treatment on long-term disability and concluded that patients with worsening disability over 96 months benefited from early fingolimod treatment. Fewer patients in the continuous fingolimod group had worsening disability, compared with the switch group, at 24 months. By 96 months, the continuous fingolimod group maintained proportionally fewer patients with worsening disability, compared with the switch group. The data indicate that the majority of patients receiving continuous fingolimod treatment were either stable or improving at 96 months. Proportionally more patients had improving disability at 96 months, compared to 24 months. These results support the practice of longer follow-up periods to properly detect the impact of treatment.

This study was supported by Oxford PharmaGenesis in Oxford UK, and funded by Novartis Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—Risk of new or additional flu-like symptoms in patients with multiple sclerosis (MS) transitioning from nonpegylated interferon beta-1a to pegylated interferon beta-1a is low, according to a report at the 2016 CMSC Annual Meeting. Scheduled naproxen therapy may be a beneficial prophylactic strategy, according to researchers. “Ninety percent of patients did not experience new or worsening flu-like symptoms,” said Robert T. Naismith, MD, Associate Professor, Washington University School of Medicine, St. Louis, Missouri, and colleagues.

Robert T. Naismith, MD

Dr. Naismith and coinvestigators conducted the ALLOW study, a one-year, phase IIIb open-label, randomized trial to characterize flu-like symptoms in patients with relapsing MS who transitioned from nonpegylated interferon beta-1a to pegylated interferon beta-1a. The study included patients age 18 to 65 with relapsing MS who had been treated with a stable dose of nonpegylated interferon for four months or more prior to screening. Their drug regimen was continued throughout a four-week run-in period for evaluation of flu-like symptoms including influenza-like illness, myalgia, pyrexia, or asthenia on that regimen. All patients were then switched to pegylated interferon beta-1a titrated to 125 μg every two weeks. Patients were randomized one-to-one to continue their current flu-like symptom management or to commence a regimen of naproxen 500 mg twice daily, starting 24 hours before each dose of pegylated interferon beta-1a and continuing for 48 hours after, for the first eight weeks of treatment.

The primary end point was the proportion of patients experiencing new or worsening flu-like symptoms, which was defined as a 2 or more point increase in flu-like symptom score. Secondary end points were flu-like symptom severity over 48 weeks and impact of naproxen, the onset and duration of flu-like symptoms following pegylated interferon beta-1a injection, the incidence of adverse events, and walking as measured by the Patient Determined Disease Steps (PDDS), a self-assessment walking scale that ranges from normal (0) to bedridden (8).

Of 201 patients who were randomized, 81.6% within each arm completed the study. Baseline characteristics were balanced between the two arms. A majority (89.6%) of patients did not experience new or worsening flu-like symptoms during the first eight weeks of following treatment switch. Flu-like symptom severity remained low across all study populations through week 48, with a majority of the symptoms being mild to moderate. Naproxen did not reduce flu-like symptom severity compared with current flu-like symptom management regimen. Following injection, overall flu-like symptom onset occurred between a mean of 12.0 and 12.8 hours and lasted for a mean duration of 13.8 to 17.0 hours. The most common adverse events were injection-site erythema, injection-site reaction, and influenza-like illness. No significant increase in walking disability was reported by patients who completed the study.

This study was sponsored by Biogen.

—Glenn S. Williams

NATIONAL HARBOR, MD—Risk of new or additional flu-like symptoms in patients with multiple sclerosis (MS) transitioning from nonpegylated interferon beta-1a to pegylated interferon beta-1a is low, according to a report at the 2016 CMSC Annual Meeting. Scheduled naproxen therapy may be a beneficial prophylactic strategy, according to researchers. “Ninety percent of patients did not experience new or worsening flu-like symptoms,” said Robert T. Naismith, MD, Associate Professor, Washington University School of Medicine, St. Louis, Missouri, and colleagues.

Robert T. Naismith, MD

Dr. Naismith and coinvestigators conducted the ALLOW study, a one-year, phase IIIb open-label, randomized trial to characterize flu-like symptoms in patients with relapsing MS who transitioned from nonpegylated interferon beta-1a to pegylated interferon beta-1a. The study included patients age 18 to 65 with relapsing MS who had been treated with a stable dose of nonpegylated interferon for four months or more prior to screening. Their drug regimen was continued throughout a four-week run-in period for evaluation of flu-like symptoms including influenza-like illness, myalgia, pyrexia, or asthenia on that regimen. All patients were then switched to pegylated interferon beta-1a titrated to 125 μg every two weeks. Patients were randomized one-to-one to continue their current flu-like symptom management or to commence a regimen of naproxen 500 mg twice daily, starting 24 hours before each dose of pegylated interferon beta-1a and continuing for 48 hours after, for the first eight weeks of treatment.

The primary end point was the proportion of patients experiencing new or worsening flu-like symptoms, which was defined as a 2 or more point increase in flu-like symptom score. Secondary end points were flu-like symptom severity over 48 weeks and impact of naproxen, the onset and duration of flu-like symptoms following pegylated interferon beta-1a injection, the incidence of adverse events, and walking as measured by the Patient Determined Disease Steps (PDDS), a self-assessment walking scale that ranges from normal (0) to bedridden (8).

Of 201 patients who were randomized, 81.6% within each arm completed the study. Baseline characteristics were balanced between the two arms. A majority (89.6%) of patients did not experience new or worsening flu-like symptoms during the first eight weeks of following treatment switch. Flu-like symptom severity remained low across all study populations through week 48, with a majority of the symptoms being mild to moderate. Naproxen did not reduce flu-like symptom severity compared with current flu-like symptom management regimen. Following injection, overall flu-like symptom onset occurred between a mean of 12.0 and 12.8 hours and lasted for a mean duration of 13.8 to 17.0 hours. The most common adverse events were injection-site erythema, injection-site reaction, and influenza-like illness. No significant increase in walking disability was reported by patients who completed the study.

This study was sponsored by Biogen.

—Glenn S. Williams

NATIONAL HARBOR, MD—Risk of new or additional flu-like symptoms in patients with multiple sclerosis (MS) transitioning from nonpegylated interferon beta-1a to pegylated interferon beta-1a is low, according to a report at the 2016 CMSC Annual Meeting. Scheduled naproxen therapy may be a beneficial prophylactic strategy, according to researchers. “Ninety percent of patients did not experience new or worsening flu-like symptoms,” said Robert T. Naismith, MD, Associate Professor, Washington University School of Medicine, St. Louis, Missouri, and colleagues.

Robert T. Naismith, MD

Dr. Naismith and coinvestigators conducted the ALLOW study, a one-year, phase IIIb open-label, randomized trial to characterize flu-like symptoms in patients with relapsing MS who transitioned from nonpegylated interferon beta-1a to pegylated interferon beta-1a. The study included patients age 18 to 65 with relapsing MS who had been treated with a stable dose of nonpegylated interferon for four months or more prior to screening. Their drug regimen was continued throughout a four-week run-in period for evaluation of flu-like symptoms including influenza-like illness, myalgia, pyrexia, or asthenia on that regimen. All patients were then switched to pegylated interferon beta-1a titrated to 125 μg every two weeks. Patients were randomized one-to-one to continue their current flu-like symptom management or to commence a regimen of naproxen 500 mg twice daily, starting 24 hours before each dose of pegylated interferon beta-1a and continuing for 48 hours after, for the first eight weeks of treatment.

The primary end point was the proportion of patients experiencing new or worsening flu-like symptoms, which was defined as a 2 or more point increase in flu-like symptom score. Secondary end points were flu-like symptom severity over 48 weeks and impact of naproxen, the onset and duration of flu-like symptoms following pegylated interferon beta-1a injection, the incidence of adverse events, and walking as measured by the Patient Determined Disease Steps (PDDS), a self-assessment walking scale that ranges from normal (0) to bedridden (8).

Of 201 patients who were randomized, 81.6% within each arm completed the study. Baseline characteristics were balanced between the two arms. A majority (89.6%) of patients did not experience new or worsening flu-like symptoms during the first eight weeks of following treatment switch. Flu-like symptom severity remained low across all study populations through week 48, with a majority of the symptoms being mild to moderate. Naproxen did not reduce flu-like symptom severity compared with current flu-like symptom management regimen. Following injection, overall flu-like symptom onset occurred between a mean of 12.0 and 12.8 hours and lasted for a mean duration of 13.8 to 17.0 hours. The most common adverse events were injection-site erythema, injection-site reaction, and influenza-like illness. No significant increase in walking disability was reported by patients who completed the study.

This study was sponsored by Biogen.

—Glenn S. Williams

NATIONAL HARBOR, MD. – Updated imaging protocols for patients with multiple sclerosis from a panel of North American neurology and radiology experts promise to improve the accuracy of diagnosis and monitoring.

The guidelines emphasize the use of three-dimensional MRI to provide complete coverage of the brain, monitoring for progressive multifocal leukoencephalopathy (PML), and optical orbit MRI for severe optic neuritis.

Key clinical guideline changes include more specific timing of brain MRI when monitoring patients receiving disease modifying therapy, timing of brain MRI to monitor for PML, updated evidence of the value of MRI changes in determining the effectiveness of treatment, and the inclusion of radiologic isolated syndrome.

Dr. Anthony Traboulsee of the University of British Columbia, Vancouver, discussed the latest MRI guidelines at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“MS is a life-long disorder and MRI is one of the best ways to monitor for new lesions that can be occurring in the absence of new symptoms (clinically silent disease activity). These lesions accumulate and lead to future disability. In order to accurately determine if changes are occurring, we need MRIs that are similar in quality over time regardless of where the patient had an MRI performed. A standardized MRI protocol provides this quality of data,” Dr. Traboulsee said.

The guidelines, published in the American Journal of Neuroradiology (Am J Neuroradiol. 2015 Nov 12. doi: 10.3174/ajnr.A4539), recommend a first MRI as soon as a physician suspects MS in a patient, with subsequent MRIs typically done annually to determine whether the disease is stable or progressive, which could prompt a change in treatment. “Breakthrough activity on MRI that is occurring while on treatment can lead to future disability and is an opportunity to consider switching therapy,” Dr. Traboulsee said.

More frequent scans could be appropriate for patients with a more aggressive and active disease course, and when treatment has been changed. More frequent monitoring and diffusion-weighted imaging is also recommended for patients taking natalizumab (Tysabri), since they are at high risk for PML.

Another goal of the guidelines is to describe how best to use MRI to support an early diagnosis of MS and to help avoid misdiagnosis. Early treatment depends on an early diagnosis. “We find the biggest impact of our disease-modifying therapy is in the first decade. The goal is to prevent new injury and optimize brain health through treatment and lifestyle,” said Dr. Traboulsee.

MRI scans alone should not be diagnostic. Clinical information is also needed, such as numbness or problems with balance. Abnormal brain MRIs occur in about 5% of people without MS and white spots in the brain that are unrelated to MS can naturally develop as people age.

If clinically isolated syndrome is suspected, a cervical cord MRI should be done along with a brain MRI. Use of a gadolinium contrast agent is recommended to better determine disease activity and speed diagnosis.

Dr. Traboulsee received grant support from Biogen, Chugai, Hoffman la Roche, and Sanofi Genzyme. He reported being a steering committee member for Hoffman la Roche and has been a consultant to Biogen, Chugai, EMD Serono, Hoffman la Roche, MedImmune, Sanofi Genzyme, and Teva Neuroscience.

NATIONAL HARBOR, MD. – Updated imaging protocols for patients with multiple sclerosis from a panel of North American neurology and radiology experts promise to improve the accuracy of diagnosis and monitoring.

The guidelines emphasize the use of three-dimensional MRI to provide complete coverage of the brain, monitoring for progressive multifocal leukoencephalopathy (PML), and optical orbit MRI for severe optic neuritis.

Key clinical guideline changes include more specific timing of brain MRI when monitoring patients receiving disease modifying therapy, timing of brain MRI to monitor for PML, updated evidence of the value of MRI changes in determining the effectiveness of treatment, and the inclusion of radiologic isolated syndrome.

Dr. Anthony Traboulsee of the University of British Columbia, Vancouver, discussed the latest MRI guidelines at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“MS is a life-long disorder and MRI is one of the best ways to monitor for new lesions that can be occurring in the absence of new symptoms (clinically silent disease activity). These lesions accumulate and lead to future disability. In order to accurately determine if changes are occurring, we need MRIs that are similar in quality over time regardless of where the patient had an MRI performed. A standardized MRI protocol provides this quality of data,” Dr. Traboulsee said.

The guidelines, published in the American Journal of Neuroradiology (Am J Neuroradiol. 2015 Nov 12. doi: 10.3174/ajnr.A4539), recommend a first MRI as soon as a physician suspects MS in a patient, with subsequent MRIs typically done annually to determine whether the disease is stable or progressive, which could prompt a change in treatment. “Breakthrough activity on MRI that is occurring while on treatment can lead to future disability and is an opportunity to consider switching therapy,” Dr. Traboulsee said.

More frequent scans could be appropriate for patients with a more aggressive and active disease course, and when treatment has been changed. More frequent monitoring and diffusion-weighted imaging is also recommended for patients taking natalizumab (Tysabri), since they are at high risk for PML.

Another goal of the guidelines is to describe how best to use MRI to support an early diagnosis of MS and to help avoid misdiagnosis. Early treatment depends on an early diagnosis. “We find the biggest impact of our disease-modifying therapy is in the first decade. The goal is to prevent new injury and optimize brain health through treatment and lifestyle,” said Dr. Traboulsee.

MRI scans alone should not be diagnostic. Clinical information is also needed, such as numbness or problems with balance. Abnormal brain MRIs occur in about 5% of people without MS and white spots in the brain that are unrelated to MS can naturally develop as people age.

If clinically isolated syndrome is suspected, a cervical cord MRI should be done along with a brain MRI. Use of a gadolinium contrast agent is recommended to better determine disease activity and speed diagnosis.

Dr. Traboulsee received grant support from Biogen, Chugai, Hoffman la Roche, and Sanofi Genzyme. He reported being a steering committee member for Hoffman la Roche and has been a consultant to Biogen, Chugai, EMD Serono, Hoffman la Roche, MedImmune, Sanofi Genzyme, and Teva Neuroscience.

NATIONAL HARBOR, MD. – Updated imaging protocols for patients with multiple sclerosis from a panel of North American neurology and radiology experts promise to improve the accuracy of diagnosis and monitoring.

The guidelines emphasize the use of three-dimensional MRI to provide complete coverage of the brain, monitoring for progressive multifocal leukoencephalopathy (PML), and optical orbit MRI for severe optic neuritis.

Key clinical guideline changes include more specific timing of brain MRI when monitoring patients receiving disease modifying therapy, timing of brain MRI to monitor for PML, updated evidence of the value of MRI changes in determining the effectiveness of treatment, and the inclusion of radiologic isolated syndrome.

Dr. Anthony Traboulsee of the University of British Columbia, Vancouver, discussed the latest MRI guidelines at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“MS is a life-long disorder and MRI is one of the best ways to monitor for new lesions that can be occurring in the absence of new symptoms (clinically silent disease activity). These lesions accumulate and lead to future disability. In order to accurately determine if changes are occurring, we need MRIs that are similar in quality over time regardless of where the patient had an MRI performed. A standardized MRI protocol provides this quality of data,” Dr. Traboulsee said.

The guidelines, published in the American Journal of Neuroradiology (Am J Neuroradiol. 2015 Nov 12. doi: 10.3174/ajnr.A4539), recommend a first MRI as soon as a physician suspects MS in a patient, with subsequent MRIs typically done annually to determine whether the disease is stable or progressive, which could prompt a change in treatment. “Breakthrough activity on MRI that is occurring while on treatment can lead to future disability and is an opportunity to consider switching therapy,” Dr. Traboulsee said.

More frequent scans could be appropriate for patients with a more aggressive and active disease course, and when treatment has been changed. More frequent monitoring and diffusion-weighted imaging is also recommended for patients taking natalizumab (Tysabri), since they are at high risk for PML.

Another goal of the guidelines is to describe how best to use MRI to support an early diagnosis of MS and to help avoid misdiagnosis. Early treatment depends on an early diagnosis. “We find the biggest impact of our disease-modifying therapy is in the first decade. The goal is to prevent new injury and optimize brain health through treatment and lifestyle,” said Dr. Traboulsee.

MRI scans alone should not be diagnostic. Clinical information is also needed, such as numbness or problems with balance. Abnormal brain MRIs occur in about 5% of people without MS and white spots in the brain that are unrelated to MS can naturally develop as people age.

If clinically isolated syndrome is suspected, a cervical cord MRI should be done along with a brain MRI. Use of a gadolinium contrast agent is recommended to better determine disease activity and speed diagnosis.

Dr. Traboulsee received grant support from Biogen, Chugai, Hoffman la Roche, and Sanofi Genzyme. He reported being a steering committee member for Hoffman la Roche and has been a consultant to Biogen, Chugai, EMD Serono, Hoffman la Roche, MedImmune, Sanofi Genzyme, and Teva Neuroscience.

NATIONAL HARBOR, MD—In a real-world comparison in patients with multiple sclerosis (MS), dimethyl fumarate and fingolimod were associated with the largest reduction in unadjusted relapse rates after initiation of disease-modifying therapy (DMT), according to data presented at the 2016 CMSC Annual Meeting. In addition, dimethyl fumarate was associated with significantly fewer arrhythmias, compared with glatiramer acetate, interferon beta, and teriflunomide after initiation of DMT.

Real-world data on the comparative effectiveness of DMTs for MS management are limited. The goal of this study, led by Aaron Boster, MD, Systems Medical Chief of Neuroimmunology for OhioHealth in Columbus, Ohio, and his colleagues was to compare the annual relapse rate in patients initiating delayed-release dimethyl fumarate, glatiramer acetate, interferon beta, fingolimod, or teriflunomide.

For this investigation, researchers used data from the Truven MarketScan Claim database, which includes information from 80 million commercially insured people in the United States. Patients with MS between ages 18 and 64 who initiated a DMT of choice in 2013 were included in the study.

Aaron Boster, MD

Dr. Boster and his colleagues calculated arrhythmias based on the number of MS-related relapses within one year after DMT initiation and examined chronic disease burden and MS-related symptoms. Composite scores depended on the presence of 22 chronic conditions, including diabetes, peptic ulcer, liver disease, and cancer. The Poisson regression model was used to estimate adjusted incidence rate ratios of relapse rate. The researchers adjusted the data for demographic and clinical characteristics such as age, sex, region, and place of residence.

The most significant decreases in unadjusted relapse rate were among patients receiving dimethyl fumarate or fingolimod. Dimethyl fumarate was associated with a lower number of arrhythmias, compared with other DMTs. Overall, patients initiating dimethyl fumarate or fingolimod were more adherent to treatment than patients receiving teriflunomide, glatiramer acetate, or interferon beta in the first year after DMT initiation. “Insights provided by real-world data, and the implications for differences in real-world comparative effectiveness of available DMTs, should be taken into account when making decisions on appropriate therapy for the management of MS,” said Dr. Boster and colleagues.

Some limitations of the study were that the data were not collected specifically for clinical research and that the results that did not provide certain clinical information required to assess disease severity properly.

—Erica Robinson

NATIONAL HARBOR, MD—In a real-world comparison in patients with multiple sclerosis (MS), dimethyl fumarate and fingolimod were associated with the largest reduction in unadjusted relapse rates after initiation of disease-modifying therapy (DMT), according to data presented at the 2016 CMSC Annual Meeting. In addition, dimethyl fumarate was associated with significantly fewer arrhythmias, compared with glatiramer acetate, interferon beta, and teriflunomide after initiation of DMT.

Real-world data on the comparative effectiveness of DMTs for MS management are limited. The goal of this study, led by Aaron Boster, MD, Systems Medical Chief of Neuroimmunology for OhioHealth in Columbus, Ohio, and his colleagues was to compare the annual relapse rate in patients initiating delayed-release dimethyl fumarate, glatiramer acetate, interferon beta, fingolimod, or teriflunomide.

For this investigation, researchers used data from the Truven MarketScan Claim database, which includes information from 80 million commercially insured people in the United States. Patients with MS between ages 18 and 64 who initiated a DMT of choice in 2013 were included in the study.

Aaron Boster, MD

Dr. Boster and his colleagues calculated arrhythmias based on the number of MS-related relapses within one year after DMT initiation and examined chronic disease burden and MS-related symptoms. Composite scores depended on the presence of 22 chronic conditions, including diabetes, peptic ulcer, liver disease, and cancer. The Poisson regression model was used to estimate adjusted incidence rate ratios of relapse rate. The researchers adjusted the data for demographic and clinical characteristics such as age, sex, region, and place of residence.

The most significant decreases in unadjusted relapse rate were among patients receiving dimethyl fumarate or fingolimod. Dimethyl fumarate was associated with a lower number of arrhythmias, compared with other DMTs. Overall, patients initiating dimethyl fumarate or fingolimod were more adherent to treatment than patients receiving teriflunomide, glatiramer acetate, or interferon beta in the first year after DMT initiation. “Insights provided by real-world data, and the implications for differences in real-world comparative effectiveness of available DMTs, should be taken into account when making decisions on appropriate therapy for the management of MS,” said Dr. Boster and colleagues.

Some limitations of the study were that the data were not collected specifically for clinical research and that the results that did not provide certain clinical information required to assess disease severity properly.

—Erica Robinson

NATIONAL HARBOR, MD—In a real-world comparison in patients with multiple sclerosis (MS), dimethyl fumarate and fingolimod were associated with the largest reduction in unadjusted relapse rates after initiation of disease-modifying therapy (DMT), according to data presented at the 2016 CMSC Annual Meeting. In addition, dimethyl fumarate was associated with significantly fewer arrhythmias, compared with glatiramer acetate, interferon beta, and teriflunomide after initiation of DMT.

Real-world data on the comparative effectiveness of DMTs for MS management are limited. The goal of this study, led by Aaron Boster, MD, Systems Medical Chief of Neuroimmunology for OhioHealth in Columbus, Ohio, and his colleagues was to compare the annual relapse rate in patients initiating delayed-release dimethyl fumarate, glatiramer acetate, interferon beta, fingolimod, or teriflunomide.

For this investigation, researchers used data from the Truven MarketScan Claim database, which includes information from 80 million commercially insured people in the United States. Patients with MS between ages 18 and 64 who initiated a DMT of choice in 2013 were included in the study.

Aaron Boster, MD

Dr. Boster and his colleagues calculated arrhythmias based on the number of MS-related relapses within one year after DMT initiation and examined chronic disease burden and MS-related symptoms. Composite scores depended on the presence of 22 chronic conditions, including diabetes, peptic ulcer, liver disease, and cancer. The Poisson regression model was used to estimate adjusted incidence rate ratios of relapse rate. The researchers adjusted the data for demographic and clinical characteristics such as age, sex, region, and place of residence.

The most significant decreases in unadjusted relapse rate were among patients receiving dimethyl fumarate or fingolimod. Dimethyl fumarate was associated with a lower number of arrhythmias, compared with other DMTs. Overall, patients initiating dimethyl fumarate or fingolimod were more adherent to treatment than patients receiving teriflunomide, glatiramer acetate, or interferon beta in the first year after DMT initiation. “Insights provided by real-world data, and the implications for differences in real-world comparative effectiveness of available DMTs, should be taken into account when making decisions on appropriate therapy for the management of MS,” said Dr. Boster and colleagues.

Some limitations of the study were that the data were not collected specifically for clinical research and that the results that did not provide certain clinical information required to assess disease severity properly.

—Erica Robinson

NATIONAL HARBOR, MD—Patients with highly active relapsing-remitting multiple sclerosis (RRMS) have durable improvement for more than five years with alemtuzumab use, according to data presented at the 2016 CMSC Annual Meeting. In a phase III trial, 45% of patients treated with alemtuzumab also sustained a six-month reduction in disability.

Barry A. Singer, MD

In the CARE-MS II study, alemtuzumab was associated with more significant improvement in clinical and MRI outcomes over two years, compared with subcutaneous interferon beta-1a, in patients with active RRMS who had had a poor response to prior therapy at baseline. An extension study was initiated to evaluate the five-year efficacy of alemtuzumab treatment in a subset of patients with RRMS and highly active disease at baseline. Barry A. Singer, MD, Assistant Professor of Clinical Neurology at Washington University in St. Louis, and his colleagues defined highly active disease as two or more relapses in the year before randomization and gadolinium-enhanced lesions at baseline. In the study, 24% of patients receiving alemtuzumab met the criteria for highly active disease.

During the trial, patients randomized to alemtuzumab (12 mg/day) were given two courses of treatment for five consecutive days at baseline and treatment for three consecutive days in the 12th month. In the extension study, patients were only allowed to receive alemtuzumab retreatment if they had a relapse or MRI activity on disease-modifying treatment.

In more than five years, at least 80% of patients receiving alemtuzumab who had had an inadequate response to prior therapy were free of relapses in each individual year. Sixty-two percent of patients had no alemtuzumab retreatment or other disease-modifying therapies. Results also showed that 97% of patients did not receive another disease-modifying therapy.

In this cohort, no evidence of disease activity was reported in 71%, 63%, and 67% of patients during years three, four, and five, as well as in 53% of patients during years zero to five. Arrhythmias remained low in each individual year of the extension study. Expanded Disability Status Scale (EDSS) scores also showed improvement with alemtuzumab use through years zero to five. In addition, sustained reduction in disability was achieved by 53% of patients during years zero to five.

“Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for patients with highly active RRMS,” said Dr. Singer and his colleagues.

This study was supported by Genzyme and Bayer HealthCare Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—Patients with highly active relapsing-remitting multiple sclerosis (RRMS) have durable improvement for more than five years with alemtuzumab use, according to data presented at the 2016 CMSC Annual Meeting. In a phase III trial, 45% of patients treated with alemtuzumab also sustained a six-month reduction in disability.

Barry A. Singer, MD

In the CARE-MS II study, alemtuzumab was associated with more significant improvement in clinical and MRI outcomes over two years, compared with subcutaneous interferon beta-1a, in patients with active RRMS who had had a poor response to prior therapy at baseline. An extension study was initiated to evaluate the five-year efficacy of alemtuzumab treatment in a subset of patients with RRMS and highly active disease at baseline. Barry A. Singer, MD, Assistant Professor of Clinical Neurology at Washington University in St. Louis, and his colleagues defined highly active disease as two or more relapses in the year before randomization and gadolinium-enhanced lesions at baseline. In the study, 24% of patients receiving alemtuzumab met the criteria for highly active disease.

During the trial, patients randomized to alemtuzumab (12 mg/day) were given two courses of treatment for five consecutive days at baseline and treatment for three consecutive days in the 12th month. In the extension study, patients were only allowed to receive alemtuzumab retreatment if they had a relapse or MRI activity on disease-modifying treatment.

In more than five years, at least 80% of patients receiving alemtuzumab who had had an inadequate response to prior therapy were free of relapses in each individual year. Sixty-two percent of patients had no alemtuzumab retreatment or other disease-modifying therapies. Results also showed that 97% of patients did not receive another disease-modifying therapy.

In this cohort, no evidence of disease activity was reported in 71%, 63%, and 67% of patients during years three, four, and five, as well as in 53% of patients during years zero to five. Arrhythmias remained low in each individual year of the extension study. Expanded Disability Status Scale (EDSS) scores also showed improvement with alemtuzumab use through years zero to five. In addition, sustained reduction in disability was achieved by 53% of patients during years zero to five.

“Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for patients with highly active RRMS,” said Dr. Singer and his colleagues.

This study was supported by Genzyme and Bayer HealthCare Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—Patients with highly active relapsing-remitting multiple sclerosis (RRMS) have durable improvement for more than five years with alemtuzumab use, according to data presented at the 2016 CMSC Annual Meeting. In a phase III trial, 45% of patients treated with alemtuzumab also sustained a six-month reduction in disability.

Barry A. Singer, MD

In the CARE-MS II study, alemtuzumab was associated with more significant improvement in clinical and MRI outcomes over two years, compared with subcutaneous interferon beta-1a, in patients with active RRMS who had had a poor response to prior therapy at baseline. An extension study was initiated to evaluate the five-year efficacy of alemtuzumab treatment in a subset of patients with RRMS and highly active disease at baseline. Barry A. Singer, MD, Assistant Professor of Clinical Neurology at Washington University in St. Louis, and his colleagues defined highly active disease as two or more relapses in the year before randomization and gadolinium-enhanced lesions at baseline. In the study, 24% of patients receiving alemtuzumab met the criteria for highly active disease.

During the trial, patients randomized to alemtuzumab (12 mg/day) were given two courses of treatment for five consecutive days at baseline and treatment for three consecutive days in the 12th month. In the extension study, patients were only allowed to receive alemtuzumab retreatment if they had a relapse or MRI activity on disease-modifying treatment.

In more than five years, at least 80% of patients receiving alemtuzumab who had had an inadequate response to prior therapy were free of relapses in each individual year. Sixty-two percent of patients had no alemtuzumab retreatment or other disease-modifying therapies. Results also showed that 97% of patients did not receive another disease-modifying therapy.

In this cohort, no evidence of disease activity was reported in 71%, 63%, and 67% of patients during years three, four, and five, as well as in 53% of patients during years zero to five. Arrhythmias remained low in each individual year of the extension study. Expanded Disability Status Scale (EDSS) scores also showed improvement with alemtuzumab use through years zero to five. In addition, sustained reduction in disability was achieved by 53% of patients during years zero to five.

“Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continuous treatment for patients with highly active RRMS,” said Dr. Singer and his colleagues.

This study was supported by Genzyme and Bayer HealthCare Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—Long-term follow-up from the BENEFIT trial, in which patients with clinically isolated syndrome (CIS) were treated with interferon beta-1b, confirmed the relationship between MRI metrics and clinical outcomes after 11 years of treatment, according to data presented at the 2016 CMSC Annual Meeting. Results also indicated that patients with more active disease tended to have smaller cervical spinal cord volumes and that cognition (as measured by mental processing speed) was related to number of lesions.

Patients with CIS who had early treatment with interferon beta-1b in the BENEFIT trial maintained an overall favorable disease course, with some clinical differences that favored treatment start at CIS, including lower annualized relapse rate (ARR), higher Paced Auditory Serial Addition Task (PASAT) score, and longer time to clinically definite multiple sclerosis (MS). “The 11-year follow-up of this trial provides an opportunity to assess the relationship between long-term clinical outcomes and structural assessments by MRI and optical coherence tomography (OCT),” said Edward J. Fox, MD, PhD, a neurologist at Central Texas Neurology Consultants in Round Rock, Texas, and colleagues.

Edward J. Fox, MD, PhD

The objective of the present study was to assess correlations between clinical, MRI, and OCT outcomes over 11 years. In the original BENEFIT trial, patients with CIS who had two or more silent brain lesions were randomized to 250 µg of interferon beta-1b (ie, early treatment) or placebo (ie, delayed treatment) subcutaneously every other day. Patients remained on placebo until conversion to clinically definite MS or for two years, whichever came first. Eleven years after initial randomization, all patients were approached to undergo cross-sectional follow-up that included clinical, MRI, and OCT assessment.

Clinical parameters included ARR, Expanded Disability Status Score (EDSS), Kurtzke Functional Status Scale (KFSS), MS Functional Composite (MSFC), PASAT score, and Symbol-Digit Modality Test (SDMT). Correlation was also assessed between mental processing speed (the sum of the z scores for PASAT and SDMT adjusted for education status, age, and sex) and selected MRI parameters.

Of the 468 patients originally randomized, 278 (71.3%) participated in the BENEFIT 11 follow-up study. This population included 167 patients in the original early-treatment group (57.2% of the original cohort) and 111 patients from the original delayed-treatment group (63.1% of the original cohort).

Year 11 MRI and OCT assessments were conducted in 191 patients (68.7%) and 86 patients (30.9%, two patients missing data), respectively. Little difference between the early- and delayed-treatments groups, with respect to MRI and OCT findings, was noted, with the exception of a difference in median number of T1-hypointense lesions. The early-treatment group had 4.0 lesions, and the delayed-treatment group had 2.0 lesions.

Regarding MRI, significant positive correlations in the overall BENEFIT 11 population were observed between ARR and volume of T1 lesions (r = 0.212), ARR and volume of T2 lesions (r = 0.216), EDSS score and T1 hypointensity volume (r = 0.281), and EDSS and T2 volume (r = 0.244). Significant negative correlations in the overall BENEFIT 11 population were observed between ARR and mean upper cervical cord area (MUCCA) (r = –0.208), EDSS and MUCCA (r = –0.194), and MSFC and T1 lesion volume (r = –0.183) and T2 lesion volume (r = –0.213). Mental processing speed correlated negatively with number of T1 lesions (r = –0.176).

Regarding OCT, significant positive correlations in the BENEFIT 11 population were observed between PASAT and minimum global retinal nerve fiber layer thickness (r = 0.271). Significant negative correlations were observed between ARR and global retinal nerve fiber layer thickness (r = –0.233) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.239), T1 lesion volume and minimum global retinal nerve fiber layer thickness (r = 0.255) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.340), and T2 lesion volume and global retinal nerve fiber layer thickness (r = 0.307) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.392). No significant correlations were found between OCT parameters and EDSS, KFSS, MSFC, SDMT, normalized brain volume, mean cortical thickness, normalized thalamic volume, or visual acuity.

“Results from BENEFIT 11 confirmed the relationship between MRI measures of disease and long-term outcomes,” said Dr. Fox and colleagues. “Significant correlations of lesion volume with EDSS, ARR, and MSFC, as well as with minimum global retinal nerve fiber layer thickness and papillomacular bundle-retinal nerve fiber layer thickness were found, while MUCCA significantly correlated with EDSS and ARR.” These findings, the researchers said, highlight the importance of monitoring MRI activity for assessing disease status.

This study was supported by Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

NATIONAL HARBOR, MD—Long-term follow-up from the BENEFIT trial, in which patients with clinically isolated syndrome (CIS) were treated with interferon beta-1b, confirmed the relationship between MRI metrics and clinical outcomes after 11 years of treatment, according to data presented at the 2016 CMSC Annual Meeting. Results also indicated that patients with more active disease tended to have smaller cervical spinal cord volumes and that cognition (as measured by mental processing speed) was related to number of lesions.

Patients with CIS who had early treatment with interferon beta-1b in the BENEFIT trial maintained an overall favorable disease course, with some clinical differences that favored treatment start at CIS, including lower annualized relapse rate (ARR), higher Paced Auditory Serial Addition Task (PASAT) score, and longer time to clinically definite multiple sclerosis (MS). “The 11-year follow-up of this trial provides an opportunity to assess the relationship between long-term clinical outcomes and structural assessments by MRI and optical coherence tomography (OCT),” said Edward J. Fox, MD, PhD, a neurologist at Central Texas Neurology Consultants in Round Rock, Texas, and colleagues.

Edward J. Fox, MD, PhD

The objective of the present study was to assess correlations between clinical, MRI, and OCT outcomes over 11 years. In the original BENEFIT trial, patients with CIS who had two or more silent brain lesions were randomized to 250 µg of interferon beta-1b (ie, early treatment) or placebo (ie, delayed treatment) subcutaneously every other day. Patients remained on placebo until conversion to clinically definite MS or for two years, whichever came first. Eleven years after initial randomization, all patients were approached to undergo cross-sectional follow-up that included clinical, MRI, and OCT assessment.

Clinical parameters included ARR, Expanded Disability Status Score (EDSS), Kurtzke Functional Status Scale (KFSS), MS Functional Composite (MSFC), PASAT score, and Symbol-Digit Modality Test (SDMT). Correlation was also assessed between mental processing speed (the sum of the z scores for PASAT and SDMT adjusted for education status, age, and sex) and selected MRI parameters.

Of the 468 patients originally randomized, 278 (71.3%) participated in the BENEFIT 11 follow-up study. This population included 167 patients in the original early-treatment group (57.2% of the original cohort) and 111 patients from the original delayed-treatment group (63.1% of the original cohort).

Year 11 MRI and OCT assessments were conducted in 191 patients (68.7%) and 86 patients (30.9%, two patients missing data), respectively. Little difference between the early- and delayed-treatments groups, with respect to MRI and OCT findings, was noted, with the exception of a difference in median number of T1-hypointense lesions. The early-treatment group had 4.0 lesions, and the delayed-treatment group had 2.0 lesions.

Regarding MRI, significant positive correlations in the overall BENEFIT 11 population were observed between ARR and volume of T1 lesions (r = 0.212), ARR and volume of T2 lesions (r = 0.216), EDSS score and T1 hypointensity volume (r = 0.281), and EDSS and T2 volume (r = 0.244). Significant negative correlations in the overall BENEFIT 11 population were observed between ARR and mean upper cervical cord area (MUCCA) (r = –0.208), EDSS and MUCCA (r = –0.194), and MSFC and T1 lesion volume (r = –0.183) and T2 lesion volume (r = –0.213). Mental processing speed correlated negatively with number of T1 lesions (r = –0.176).

Regarding OCT, significant positive correlations in the BENEFIT 11 population were observed between PASAT and minimum global retinal nerve fiber layer thickness (r = 0.271). Significant negative correlations were observed between ARR and global retinal nerve fiber layer thickness (r = –0.233) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.239), T1 lesion volume and minimum global retinal nerve fiber layer thickness (r = 0.255) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.340), and T2 lesion volume and global retinal nerve fiber layer thickness (r = 0.307) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.392). No significant correlations were found between OCT parameters and EDSS, KFSS, MSFC, SDMT, normalized brain volume, mean cortical thickness, normalized thalamic volume, or visual acuity.

“Results from BENEFIT 11 confirmed the relationship between MRI measures of disease and long-term outcomes,” said Dr. Fox and colleagues. “Significant correlations of lesion volume with EDSS, ARR, and MSFC, as well as with minimum global retinal nerve fiber layer thickness and papillomacular bundle-retinal nerve fiber layer thickness were found, while MUCCA significantly correlated with EDSS and ARR.” These findings, the researchers said, highlight the importance of monitoring MRI activity for assessing disease status.

This study was supported by Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

NATIONAL HARBOR, MD—Long-term follow-up from the BENEFIT trial, in which patients with clinically isolated syndrome (CIS) were treated with interferon beta-1b, confirmed the relationship between MRI metrics and clinical outcomes after 11 years of treatment, according to data presented at the 2016 CMSC Annual Meeting. Results also indicated that patients with more active disease tended to have smaller cervical spinal cord volumes and that cognition (as measured by mental processing speed) was related to number of lesions.

Patients with CIS who had early treatment with interferon beta-1b in the BENEFIT trial maintained an overall favorable disease course, with some clinical differences that favored treatment start at CIS, including lower annualized relapse rate (ARR), higher Paced Auditory Serial Addition Task (PASAT) score, and longer time to clinically definite multiple sclerosis (MS). “The 11-year follow-up of this trial provides an opportunity to assess the relationship between long-term clinical outcomes and structural assessments by MRI and optical coherence tomography (OCT),” said Edward J. Fox, MD, PhD, a neurologist at Central Texas Neurology Consultants in Round Rock, Texas, and colleagues.

Edward J. Fox, MD, PhD

The objective of the present study was to assess correlations between clinical, MRI, and OCT outcomes over 11 years. In the original BENEFIT trial, patients with CIS who had two or more silent brain lesions were randomized to 250 µg of interferon beta-1b (ie, early treatment) or placebo (ie, delayed treatment) subcutaneously every other day. Patients remained on placebo until conversion to clinically definite MS or for two years, whichever came first. Eleven years after initial randomization, all patients were approached to undergo cross-sectional follow-up that included clinical, MRI, and OCT assessment.

Clinical parameters included ARR, Expanded Disability Status Score (EDSS), Kurtzke Functional Status Scale (KFSS), MS Functional Composite (MSFC), PASAT score, and Symbol-Digit Modality Test (SDMT). Correlation was also assessed between mental processing speed (the sum of the z scores for PASAT and SDMT adjusted for education status, age, and sex) and selected MRI parameters.

Of the 468 patients originally randomized, 278 (71.3%) participated in the BENEFIT 11 follow-up study. This population included 167 patients in the original early-treatment group (57.2% of the original cohort) and 111 patients from the original delayed-treatment group (63.1% of the original cohort).

Year 11 MRI and OCT assessments were conducted in 191 patients (68.7%) and 86 patients (30.9%, two patients missing data), respectively. Little difference between the early- and delayed-treatments groups, with respect to MRI and OCT findings, was noted, with the exception of a difference in median number of T1-hypointense lesions. The early-treatment group had 4.0 lesions, and the delayed-treatment group had 2.0 lesions.

Regarding MRI, significant positive correlations in the overall BENEFIT 11 population were observed between ARR and volume of T1 lesions (r = 0.212), ARR and volume of T2 lesions (r = 0.216), EDSS score and T1 hypointensity volume (r = 0.281), and EDSS and T2 volume (r = 0.244). Significant negative correlations in the overall BENEFIT 11 population were observed between ARR and mean upper cervical cord area (MUCCA) (r = –0.208), EDSS and MUCCA (r = –0.194), and MSFC and T1 lesion volume (r = –0.183) and T2 lesion volume (r = –0.213). Mental processing speed correlated negatively with number of T1 lesions (r = –0.176).

Regarding OCT, significant positive correlations in the BENEFIT 11 population were observed between PASAT and minimum global retinal nerve fiber layer thickness (r = 0.271). Significant negative correlations were observed between ARR and global retinal nerve fiber layer thickness (r = –0.233) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.239), T1 lesion volume and minimum global retinal nerve fiber layer thickness (r = 0.255) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.340), and T2 lesion volume and global retinal nerve fiber layer thickness (r = 0.307) and papillomacular bundle-retinal nerve fiber layer thickness (r = –0.392). No significant correlations were found between OCT parameters and EDSS, KFSS, MSFC, SDMT, normalized brain volume, mean cortical thickness, normalized thalamic volume, or visual acuity.

“Results from BENEFIT 11 confirmed the relationship between MRI measures of disease and long-term outcomes,” said Dr. Fox and colleagues. “Significant correlations of lesion volume with EDSS, ARR, and MSFC, as well as with minimum global retinal nerve fiber layer thickness and papillomacular bundle-retinal nerve fiber layer thickness were found, while MUCCA significantly correlated with EDSS and ARR.” These findings, the researchers said, highlight the importance of monitoring MRI activity for assessing disease status.

This study was supported by Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

NATIONAL HARBOR, MD—Patients and prescribers agree that efficacy is the highest priority in decision making for first-line multiple sclerosis (MS) treatment, according to the results of an online survey reported at the 2016 CMSC Annual Meeting. Preferences were similar across segments of patient age categories, sex, education, insurance, and disease severity. Furthermore, prescribers place higher importance on the risk of serious side effects than do patients for first-line disease-modifying treatments (DMTs).

Edward J. Fox, MD, PhD

“Even though this study suggests that patients and neurologists prefer high-efficacy agents, real-world practice and market share of DMTs do not reflect this preference,” said Edward J. Fox, MD, PhD, a neurologist at Central Texas Neurology Consultants in Round Rock, Texas, and his coauthors. “Knowledge of preferred attributes for first-line treatment from the patient and neurologist perspectives can help to better inform communication regarding treatment decision making.”

To evaluate preferences for features of first-line DMTs among patients with relapsing-remitting MS and neurologists, Dr. Fox and his coinvestigators used PatientsLikeMe, an online, patient-powered social networking community, to recruit patients. Neurologists were recruited from the WebMD network. Maximum Difference Scaling (MDS), a type of best–worst scaling, was used to design online choice experiments in which respondents were shown a series of items and asked to indicate what they consider the most and least important factor when selecting a DMT. The factors included efficacy parameters (ie, slowing of disability progression, prevention of new MRI lesions, and reduction of relapse frequency), risk of serious side effects, tolerability, route of administration (ie, oral, injectable, infusion), cost, and neurologist recommendation.

A total of 193 patients and 225 neurologists responded. Preferences among patients and neurologists were similar. Items related to efficacy were of high importance among both groups. For both patients and neurologists, the items related to efficacy were preferred similarly, in decreasing order of importance: slowing disability progression, decreasing relapse frequency, and preventing new MRI lesions.

For first-line treatment selection, neurologists considered risk of serious side effects of higher importance than preventing new MRI lesions, but of lower importance than slowing disability progression or reducing relapse severity. Patients ranked the risk of serious side effects as of average importance, compared with the three efficacy items.

Patients and neurologists viewed tolerable side effects as an important factor after efficacy and safety in first-line and switch DMT preference. In both groups, parenteral drug administration was least preferred, in comparison with all other factors.

This study was supported by Novartis Pharmaceuticals.

—Glenn S. Williams

NATIONAL HARBOR, MD—Patients and prescribers agree that efficacy is the highest priority in decision making for first-line multiple sclerosis (MS) treatment, according to the results of an online survey reported at the 2016 CMSC Annual Meeting. Preferences were similar across segments of patient age categories, sex, education, insurance, and disease severity. Furthermore, prescribers place higher importance on the risk of serious side effects than do patients for first-line disease-modifying treatments (DMTs).

Edward J. Fox, MD, PhD

“Even though this study suggests that patients and neurologists prefer high-efficacy agents, real-world practice and market share of DMTs do not reflect this preference,” said Edward J. Fox, MD, PhD, a neurologist at Central Texas Neurology Consultants in Round Rock, Texas, and his coauthors. “Knowledge of preferred attributes for first-line treatment from the patient and neurologist perspectives can help to better inform communication regarding treatment decision making.”

To evaluate preferences for features of first-line DMTs among patients with relapsing-remitting MS and neurologists, Dr. Fox and his coinvestigators used PatientsLikeMe, an online, patient-powered social networking community, to recruit patients. Neurologists were recruited from the WebMD network. Maximum Difference Scaling (MDS), a type of best–worst scaling, was used to design online choice experiments in which respondents were shown a series of items and asked to indicate what they consider the most and least important factor when selecting a DMT. The factors included efficacy parameters (ie, slowing of disability progression, prevention of new MRI lesions, and reduction of relapse frequency), risk of serious side effects, tolerability, route of administration (ie, oral, injectable, infusion), cost, and neurologist recommendation.

A total of 193 patients and 225 neurologists responded. Preferences among patients and neurologists were similar. Items related to efficacy were of high importance among both groups. For both patients and neurologists, the items related to efficacy were preferred similarly, in decreasing order of importance: slowing disability progression, decreasing relapse frequency, and preventing new MRI lesions.

For first-line treatment selection, neurologists considered risk of serious side effects of higher importance than preventing new MRI lesions, but of lower importance than slowing disability progression or reducing relapse severity. Patients ranked the risk of serious side effects as of average importance, compared with the three efficacy items.

Patients and neurologists viewed tolerable side effects as an important factor after efficacy and safety in first-line and switch DMT preference. In both groups, parenteral drug administration was least preferred, in comparison with all other factors.

This study was supported by Novartis Pharmaceuticals.

—Glenn S. Williams

NATIONAL HARBOR, MD—Patients and prescribers agree that efficacy is the highest priority in decision making for first-line multiple sclerosis (MS) treatment, according to the results of an online survey reported at the 2016 CMSC Annual Meeting. Preferences were similar across segments of patient age categories, sex, education, insurance, and disease severity. Furthermore, prescribers place higher importance on the risk of serious side effects than do patients for first-line disease-modifying treatments (DMTs).

Edward J. Fox, MD, PhD

“Even though this study suggests that patients and neurologists prefer high-efficacy agents, real-world practice and market share of DMTs do not reflect this preference,” said Edward J. Fox, MD, PhD, a neurologist at Central Texas Neurology Consultants in Round Rock, Texas, and his coauthors. “Knowledge of preferred attributes for first-line treatment from the patient and neurologist perspectives can help to better inform communication regarding treatment decision making.”

To evaluate preferences for features of first-line DMTs among patients with relapsing-remitting MS and neurologists, Dr. Fox and his coinvestigators used PatientsLikeMe, an online, patient-powered social networking community, to recruit patients. Neurologists were recruited from the WebMD network. Maximum Difference Scaling (MDS), a type of best–worst scaling, was used to design online choice experiments in which respondents were shown a series of items and asked to indicate what they consider the most and least important factor when selecting a DMT. The factors included efficacy parameters (ie, slowing of disability progression, prevention of new MRI lesions, and reduction of relapse frequency), risk of serious side effects, tolerability, route of administration (ie, oral, injectable, infusion), cost, and neurologist recommendation.

A total of 193 patients and 225 neurologists responded. Preferences among patients and neurologists were similar. Items related to efficacy were of high importance among both groups. For both patients and neurologists, the items related to efficacy were preferred similarly, in decreasing order of importance: slowing disability progression, decreasing relapse frequency, and preventing new MRI lesions.

For first-line treatment selection, neurologists considered risk of serious side effects of higher importance than preventing new MRI lesions, but of lower importance than slowing disability progression or reducing relapse severity. Patients ranked the risk of serious side effects as of average importance, compared with the three efficacy items.

Patients and neurologists viewed tolerable side effects as an important factor after efficacy and safety in first-line and switch DMT preference. In both groups, parenteral drug administration was least preferred, in comparison with all other factors.

This study was supported by Novartis Pharmaceuticals.

—Glenn S. Williams

VANCOUVER—The misdiagnosis of multiple sclerosis (MS) is a problem with significant consequences for patients, as well as the health care system, according to Andrew J. Solomon, MD, Assistant Professor in the Department of Neurological Sciences at the University of Vermont in Burlington. “Overreliance on MRI abnormalities in the setting of atypical syndromes and unverified prior symptoms may be a major cause of misdiagnosis,” Dr. Solomon said at the 68th Annual Meeting of the American Academy of Neurology.

Dr. Solomon and colleagues conducted a simple survey in 2012. They asked 122 MS specialists if they recalled seeing a patient who was incorrectly diagnosed with MS over the last year. Nearly all (95%) had evaluated such patients. As a follow-up, Dr. Solomon and colleagues designed the present study, which evaluated the characteristics of a large population of patients who had been misdiagnosed with MS. “We wanted to determine what the diagnoses were that were being mistaken for MS and what the risks were that were associated with these misdiagnoses.” Their pilot study also probed the causes of misdiagnosis, particularly relating to the current McDonald MS diagnostic criteria.

Twenty-three MS specialists from the University of Vermont, Oregon Health and Science University, Washington University, and the Mayo Clinic participated in this study. The investigators defined two categories: definite and probable misdiagnosis. Patients were identified by participating neurologists during clinical evaluations either prospectively during the 13 months of the study or shortly prior to study initiation. Patients were classified as having definite misdiagnosis when an alternative diagnosis was definitively made based on clinical, laboratory, and neuroimaging evaluation and probable misdiagnosis when an alternative diagnosis was suspected and diagnostic criteria for MS were not met.

Migraine Was Mistaken for MS

The researchers identified 110 patients who were misdiagnosed with MS; 85% were women, and the mean age was 49. About one-quarter (24%) were initially misdiagnosed by a neurologist with fellowship training or a practice focus in MS, and 32% were initially misdiagnosed by a neurologist without such training. For 42%, it was difficult to determine the level of training of the initial neurologist. Nearly half (46%) were classified as definite misdiagnosis, and 54% fell into the probable misdiagnosis category. Neurologists informed 107 (97%) of the patients that their MS diagnosis was incorrect. Almost 30% had been misdiagnosed with MS for three to nine years; 33% had been misdiagnosed for 10 years or longer.

Of the syndromes and diagnoses that were commonly mistaken for MS, the top five represented two-thirds (66%) of all the misdiagnoses that were identified. Migraine, alone or in combination with other disorders, accounted for 22%. Fibromyalgia, along with another alternative cause of MRI abnormalities, accounted for 15%. A category labeled nonspecific or nonlocalized neurologic symptoms—symptoms that were not typical of demyelinating injury or CNS injury—with an abnormal MRI accounted for 12%. Conversion or psychogenic disorder accounted for 11%, and neuromyelitis optica (NMO) spectrum disorder accounted for 6%.

Disease-modifying therapy (DMT) had been initiated in 70% of these patients. About one-third (36%) had received more than one DMT for MS, and a number had received two, three, or four therapies. Thirteen percent had been exposed to natalizumab, a number had received oral therapies for MS, and a few patients had received mitoxantrone. Nearly one-quarter (24%) at some time were on a DMT with a known risk of PML. Almost 30% had been exposed to DMT for three to nine years. Almost 30% had been on DMT for 10 years or longer.

Cerebrospinal fluid (CSF) was available for 52 patients from the time of initial diagnosis, prior to study entry. In 54%, the CSF was normal, including oligoclonal bands and normal IgG. In eight patients, the study neurologists thought that there was an erroneous interpretation of CSF, meaning, for instance, oligoclonal bands were positive in CSF as well as serum.

The study neurologists concluded that 30% of the patients experienced some morbidity as a direct result of an MS misdiagnosis. Morbidities included inadequate treatment of their correct diagnosis, exposure to DMT, and other consequences. In 72% of all patients, study neurologists identified clear evidence of an earlier missed opportunity to make the correct diagnosis.

Imaging and Misdiagnosis

In 65% of cases, study neurologists concluded that inappropriate application of MS diagnostic criteria to a neurologic symptom atypical for a demyelinating attack contributed to misdiagnosis. Inappropriate application of diagnostic criteria to a historical episode of neurologic symptoms without any corroborating objective evidence of a lesion was noted in almost half the cases.

In more than 30% of cases, an erroneous determination of juxtacortical or periventricular lesion location was thought to have contributed to misdiagnosis. In 60%, the study neurologists cited misdiagnosis related to overreliance on MRI abnormalities, meaning dissemination in time, to confirm a diagnosis of MS in a patient with nonspecific neurologic symptoms.

“We all know the differential diagnosis of MS is broad, and a number of rare disorders can mimic MS,” Dr. Solomon said. “But here it was migraine, fibromyalgia, and a number of other disorders that are quite common that mimicked MS and were mistaken for MS.” Most of these diagnoses, with the exception of NMO, lack a specific biomarker. “What this means is that the correct diagnosis in many of these cases relies on our clinical skills and critical thinking, not just MRI. The problem is not confined to nonspecialists. MS specialists can also make mistakes.”

Study neurologists reported that in almost two-thirds of cases, atypical symptoms for a demyelinating attack contributed to misdiagnosis. “Perhaps this reflects a misunderstanding of what constitutes a typical demyelinating attack and when we should rely on our diagnostic criteria alone,” Dr. Solomon said. In half, historical episodes of neurologic dysfunction, without corroborating objective findings, contributed to misdiagnosis. “This means that patients came in and they had reported historical episodes—episodes of numbness or tingling or blurry vision—where there were no objective exam findings, evoked potentials, imaging findings, to corroborate those symptoms, yet perhaps these episodes were used to meet dissemination in time.”

MRI abnormalities incorrectly attributed to MS in patients without typical demyelinating symptoms contributed to more than half of the misdiagnoses. “It is important to highlight that our MRI criteria, as part of our MS diagnostic criteria, were not developed to differentiate MS from other disorders. The MRI criteria for MS were meant to identify patients at high risk for MS after typical clinical presentations for demyelination,” Dr. Solomon said.

The Importance of Diagnostic Criteria

“Making a diagnosis of MS is challenging. It is important to acknowledge that,” Dr. Solomon said. Common diagnoses and syndromes are often mistaken for MS. But there is significant risk and morbidity associated with misdiagnosis. “The best way to prevent misdiagnosis may be strict adherence and proper use of our MS diagnostic criteria. In patients with atypical clinical presentations or in patients with nonspecific MRI abnormalities, we may need to do more. We may need to monitor longer, do more imaging, make sure we get CSF. That may prevent misdiagnosis in a number of cases.”

Dr. Solomon also stressed the need for continued vigilance for misdiagnosis in patients with an existing MS diagnosis. “We should be thinking, ‘Is this really MS?’ each time we see a new patient, rather than simply accepting that diagnosis.” And lastly, Dr. Solomon recommended that future MS diagnostic criteria should balance the benefit of prompt diagnosis and initiation of DMT versus the potential risks of misdiagnosis.

—Glenn S. Williams

VANCOUVER—The misdiagnosis of multiple sclerosis (MS) is a problem with significant consequences for patients, as well as the health care system, according to Andrew J. Solomon, MD, Assistant Professor in the Department of Neurological Sciences at the University of Vermont in Burlington. “Overreliance on MRI abnormalities in the setting of atypical syndromes and unverified prior symptoms may be a major cause of misdiagnosis,” Dr. Solomon said at the 68th Annual Meeting of the American Academy of Neurology.

Dr. Solomon and colleagues conducted a simple survey in 2012. They asked 122 MS specialists if they recalled seeing a patient who was incorrectly diagnosed with MS over the last year. Nearly all (95%) had evaluated such patients. As a follow-up, Dr. Solomon and colleagues designed the present study, which evaluated the characteristics of a large population of patients who had been misdiagnosed with MS. “We wanted to determine what the diagnoses were that were being mistaken for MS and what the risks were that were associated with these misdiagnoses.” Their pilot study also probed the causes of misdiagnosis, particularly relating to the current McDonald MS diagnostic criteria.

Twenty-three MS specialists from the University of Vermont, Oregon Health and Science University, Washington University, and the Mayo Clinic participated in this study. The investigators defined two categories: definite and probable misdiagnosis. Patients were identified by participating neurologists during clinical evaluations either prospectively during the 13 months of the study or shortly prior to study initiation. Patients were classified as having definite misdiagnosis when an alternative diagnosis was definitively made based on clinical, laboratory, and neuroimaging evaluation and probable misdiagnosis when an alternative diagnosis was suspected and diagnostic criteria for MS were not met.

Migraine Was Mistaken for MS

The researchers identified 110 patients who were misdiagnosed with MS; 85% were women, and the mean age was 49. About one-quarter (24%) were initially misdiagnosed by a neurologist with fellowship training or a practice focus in MS, and 32% were initially misdiagnosed by a neurologist without such training. For 42%, it was difficult to determine the level of training of the initial neurologist. Nearly half (46%) were classified as definite misdiagnosis, and 54% fell into the probable misdiagnosis category. Neurologists informed 107 (97%) of the patients that their MS diagnosis was incorrect. Almost 30% had been misdiagnosed with MS for three to nine years; 33% had been misdiagnosed for 10 years or longer.

Of the syndromes and diagnoses that were commonly mistaken for MS, the top five represented two-thirds (66%) of all the misdiagnoses that were identified. Migraine, alone or in combination with other disorders, accounted for 22%. Fibromyalgia, along with another alternative cause of MRI abnormalities, accounted for 15%. A category labeled nonspecific or nonlocalized neurologic symptoms—symptoms that were not typical of demyelinating injury or CNS injury—with an abnormal MRI accounted for 12%. Conversion or psychogenic disorder accounted for 11%, and neuromyelitis optica (NMO) spectrum disorder accounted for 6%.

Disease-modifying therapy (DMT) had been initiated in 70% of these patients. About one-third (36%) had received more than one DMT for MS, and a number had received two, three, or four therapies. Thirteen percent had been exposed to natalizumab, a number had received oral therapies for MS, and a few patients had received mitoxantrone. Nearly one-quarter (24%) at some time were on a DMT with a known risk of PML. Almost 30% had been exposed to DMT for three to nine years. Almost 30% had been on DMT for 10 years or longer.

Cerebrospinal fluid (CSF) was available for 52 patients from the time of initial diagnosis, prior to study entry. In 54%, the CSF was normal, including oligoclonal bands and normal IgG. In eight patients, the study neurologists thought that there was an erroneous interpretation of CSF, meaning, for instance, oligoclonal bands were positive in CSF as well as serum.

The study neurologists concluded that 30% of the patients experienced some morbidity as a direct result of an MS misdiagnosis. Morbidities included inadequate treatment of their correct diagnosis, exposure to DMT, and other consequences. In 72% of all patients, study neurologists identified clear evidence of an earlier missed opportunity to make the correct diagnosis.

Imaging and Misdiagnosis

In 65% of cases, study neurologists concluded that inappropriate application of MS diagnostic criteria to a neurologic symptom atypical for a demyelinating attack contributed to misdiagnosis. Inappropriate application of diagnostic criteria to a historical episode of neurologic symptoms without any corroborating objective evidence of a lesion was noted in almost half the cases.

In more than 30% of cases, an erroneous determination of juxtacortical or periventricular lesion location was thought to have contributed to misdiagnosis. In 60%, the study neurologists cited misdiagnosis related to overreliance on MRI abnormalities, meaning dissemination in time, to confirm a diagnosis of MS in a patient with nonspecific neurologic symptoms.

“We all know the differential diagnosis of MS is broad, and a number of rare disorders can mimic MS,” Dr. Solomon said. “But here it was migraine, fibromyalgia, and a number of other disorders that are quite common that mimicked MS and were mistaken for MS.” Most of these diagnoses, with the exception of NMO, lack a specific biomarker. “What this means is that the correct diagnosis in many of these cases relies on our clinical skills and critical thinking, not just MRI. The problem is not confined to nonspecialists. MS specialists can also make mistakes.”

Study neurologists reported that in almost two-thirds of cases, atypical symptoms for a demyelinating attack contributed to misdiagnosis. “Perhaps this reflects a misunderstanding of what constitutes a typical demyelinating attack and when we should rely on our diagnostic criteria alone,” Dr. Solomon said. In half, historical episodes of neurologic dysfunction, without corroborating objective findings, contributed to misdiagnosis. “This means that patients came in and they had reported historical episodes—episodes of numbness or tingling or blurry vision—where there were no objective exam findings, evoked potentials, imaging findings, to corroborate those symptoms, yet perhaps these episodes were used to meet dissemination in time.”

MRI abnormalities incorrectly attributed to MS in patients without typical demyelinating symptoms contributed to more than half of the misdiagnoses. “It is important to highlight that our MRI criteria, as part of our MS diagnostic criteria, were not developed to differentiate MS from other disorders. The MRI criteria for MS were meant to identify patients at high risk for MS after typical clinical presentations for demyelination,” Dr. Solomon said.

The Importance of Diagnostic Criteria

“Making a diagnosis of MS is challenging. It is important to acknowledge that,” Dr. Solomon said. Common diagnoses and syndromes are often mistaken for MS. But there is significant risk and morbidity associated with misdiagnosis. “The best way to prevent misdiagnosis may be strict adherence and proper use of our MS diagnostic criteria. In patients with atypical clinical presentations or in patients with nonspecific MRI abnormalities, we may need to do more. We may need to monitor longer, do more imaging, make sure we get CSF. That may prevent misdiagnosis in a number of cases.”

Dr. Solomon also stressed the need for continued vigilance for misdiagnosis in patients with an existing MS diagnosis. “We should be thinking, ‘Is this really MS?’ each time we see a new patient, rather than simply accepting that diagnosis.” And lastly, Dr. Solomon recommended that future MS diagnostic criteria should balance the benefit of prompt diagnosis and initiation of DMT versus the potential risks of misdiagnosis.

—Glenn S. Williams

VANCOUVER—The misdiagnosis of multiple sclerosis (MS) is a problem with significant consequences for patients, as well as the health care system, according to Andrew J. Solomon, MD, Assistant Professor in the Department of Neurological Sciences at the University of Vermont in Burlington. “Overreliance on MRI abnormalities in the setting of atypical syndromes and unverified prior symptoms may be a major cause of misdiagnosis,” Dr. Solomon said at the 68th Annual Meeting of the American Academy of Neurology.

Dr. Solomon and colleagues conducted a simple survey in 2012. They asked 122 MS specialists if they recalled seeing a patient who was incorrectly diagnosed with MS over the last year. Nearly all (95%) had evaluated such patients. As a follow-up, Dr. Solomon and colleagues designed the present study, which evaluated the characteristics of a large population of patients who had been misdiagnosed with MS. “We wanted to determine what the diagnoses were that were being mistaken for MS and what the risks were that were associated with these misdiagnoses.” Their pilot study also probed the causes of misdiagnosis, particularly relating to the current McDonald MS diagnostic criteria.

Twenty-three MS specialists from the University of Vermont, Oregon Health and Science University, Washington University, and the Mayo Clinic participated in this study. The investigators defined two categories: definite and probable misdiagnosis. Patients were identified by participating neurologists during clinical evaluations either prospectively during the 13 months of the study or shortly prior to study initiation. Patients were classified as having definite misdiagnosis when an alternative diagnosis was definitively made based on clinical, laboratory, and neuroimaging evaluation and probable misdiagnosis when an alternative diagnosis was suspected and diagnostic criteria for MS were not met.

Migraine Was Mistaken for MS

The researchers identified 110 patients who were misdiagnosed with MS; 85% were women, and the mean age was 49. About one-quarter (24%) were initially misdiagnosed by a neurologist with fellowship training or a practice focus in MS, and 32% were initially misdiagnosed by a neurologist without such training. For 42%, it was difficult to determine the level of training of the initial neurologist. Nearly half (46%) were classified as definite misdiagnosis, and 54% fell into the probable misdiagnosis category. Neurologists informed 107 (97%) of the patients that their MS diagnosis was incorrect. Almost 30% had been misdiagnosed with MS for three to nine years; 33% had been misdiagnosed for 10 years or longer.

Of the syndromes and diagnoses that were commonly mistaken for MS, the top five represented two-thirds (66%) of all the misdiagnoses that were identified. Migraine, alone or in combination with other disorders, accounted for 22%. Fibromyalgia, along with another alternative cause of MRI abnormalities, accounted for 15%. A category labeled nonspecific or nonlocalized neurologic symptoms—symptoms that were not typical of demyelinating injury or CNS injury—with an abnormal MRI accounted for 12%. Conversion or psychogenic disorder accounted for 11%, and neuromyelitis optica (NMO) spectrum disorder accounted for 6%.

Disease-modifying therapy (DMT) had been initiated in 70% of these patients. About one-third (36%) had received more than one DMT for MS, and a number had received two, three, or four therapies. Thirteen percent had been exposed to natalizumab, a number had received oral therapies for MS, and a few patients had received mitoxantrone. Nearly one-quarter (24%) at some time were on a DMT with a known risk of PML. Almost 30% had been exposed to DMT for three to nine years. Almost 30% had been on DMT for 10 years or longer.

Cerebrospinal fluid (CSF) was available for 52 patients from the time of initial diagnosis, prior to study entry. In 54%, the CSF was normal, including oligoclonal bands and normal IgG. In eight patients, the study neurologists thought that there was an erroneous interpretation of CSF, meaning, for instance, oligoclonal bands were positive in CSF as well as serum.

The study neurologists concluded that 30% of the patients experienced some morbidity as a direct result of an MS misdiagnosis. Morbidities included inadequate treatment of their correct diagnosis, exposure to DMT, and other consequences. In 72% of all patients, study neurologists identified clear evidence of an earlier missed opportunity to make the correct diagnosis.

Imaging and Misdiagnosis

In 65% of cases, study neurologists concluded that inappropriate application of MS diagnostic criteria to a neurologic symptom atypical for a demyelinating attack contributed to misdiagnosis. Inappropriate application of diagnostic criteria to a historical episode of neurologic symptoms without any corroborating objective evidence of a lesion was noted in almost half the cases.

In more than 30% of cases, an erroneous determination of juxtacortical or periventricular lesion location was thought to have contributed to misdiagnosis. In 60%, the study neurologists cited misdiagnosis related to overreliance on MRI abnormalities, meaning dissemination in time, to confirm a diagnosis of MS in a patient with nonspecific neurologic symptoms.

“We all know the differential diagnosis of MS is broad, and a number of rare disorders can mimic MS,” Dr. Solomon said. “But here it was migraine, fibromyalgia, and a number of other disorders that are quite common that mimicked MS and were mistaken for MS.” Most of these diagnoses, with the exception of NMO, lack a specific biomarker. “What this means is that the correct diagnosis in many of these cases relies on our clinical skills and critical thinking, not just MRI. The problem is not confined to nonspecialists. MS specialists can also make mistakes.”

Study neurologists reported that in almost two-thirds of cases, atypical symptoms for a demyelinating attack contributed to misdiagnosis. “Perhaps this reflects a misunderstanding of what constitutes a typical demyelinating attack and when we should rely on our diagnostic criteria alone,” Dr. Solomon said. In half, historical episodes of neurologic dysfunction, without corroborating objective findings, contributed to misdiagnosis. “This means that patients came in and they had reported historical episodes—episodes of numbness or tingling or blurry vision—where there were no objective exam findings, evoked potentials, imaging findings, to corroborate those symptoms, yet perhaps these episodes were used to meet dissemination in time.”

MRI abnormalities incorrectly attributed to MS in patients without typical demyelinating symptoms contributed to more than half of the misdiagnoses. “It is important to highlight that our MRI criteria, as part of our MS diagnostic criteria, were not developed to differentiate MS from other disorders. The MRI criteria for MS were meant to identify patients at high risk for MS after typical clinical presentations for demyelination,” Dr. Solomon said.

The Importance of Diagnostic Criteria

“Making a diagnosis of MS is challenging. It is important to acknowledge that,” Dr. Solomon said. Common diagnoses and syndromes are often mistaken for MS. But there is significant risk and morbidity associated with misdiagnosis. “The best way to prevent misdiagnosis may be strict adherence and proper use of our MS diagnostic criteria. In patients with atypical clinical presentations or in patients with nonspecific MRI abnormalities, we may need to do more. We may need to monitor longer, do more imaging, make sure we get CSF. That may prevent misdiagnosis in a number of cases.”

Dr. Solomon also stressed the need for continued vigilance for misdiagnosis in patients with an existing MS diagnosis. “We should be thinking, ‘Is this really MS?’ each time we see a new patient, rather than simply accepting that diagnosis.” And lastly, Dr. Solomon recommended that future MS diagnostic criteria should balance the benefit of prompt diagnosis and initiation of DMT versus the potential risks of misdiagnosis.

—Glenn S. Williams

Daclizumab (Zinbryta) has been approved as a patient-injected, once-monthly treatment for adults with relapsing forms of multiple sclerosis (MS), according to the Food and Drug Administration.

Daclizumab has serious safety risks, including severe and potentially life-threatening liver injury and immune disorders, and should generally be used only when patients have an inadequate response to two or more MS drugs, the FDA said in a press release. The drug has a boxed warning and is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

Liver function tests should be performed before starting daclizumab, and liver function should be monitored monthly before each dose, and for up to 6 months after the last dose. Immune disorders associated with use of daclizumab include noninfectious colitis, skin reactions, and lymphadenopathy. Other highlighted warnings include anaphylaxis and angioedema, increased risk of infections, and symptoms of depression and suicidal ideation.

Daclizumab was associated with a reduction in clinical relapses in a comparator trial of 1,841 participants who received either daclizumab or interferon beta-1a (Avonex) and were studied for 144 weeks. Fewer relapses also were seen with daclizumab than with placebo in a second 52-week study of 412 participants.

The most common adverse reactions reported by patients receiving daclizumab in the comparator trial included nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, eczema, and enlargement of lymph nodes. The most common adverse reactions reported in the placebo trial were depression, rash, and increased levels of alanine aminotransferase.

Daclizumab will be marketed as Zinbryta by Biogen.

Read the FDA’s full statement on the FDA website.

acruz@frontlinemedcom.com

Daclizumab (Zinbryta) has been approved as a patient-injected, once-monthly treatment for adults with relapsing forms of multiple sclerosis (MS), according to the Food and Drug Administration.

Daclizumab has serious safety risks, including severe and potentially life-threatening liver injury and immune disorders, and should generally be used only when patients have an inadequate response to two or more MS drugs, the FDA said in a press release. The drug has a boxed warning and is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

Liver function tests should be performed before starting daclizumab, and liver function should be monitored monthly before each dose, and for up to 6 months after the last dose. Immune disorders associated with use of daclizumab include noninfectious colitis, skin reactions, and lymphadenopathy. Other highlighted warnings include anaphylaxis and angioedema, increased risk of infections, and symptoms of depression and suicidal ideation.

Daclizumab was associated with a reduction in clinical relapses in a comparator trial of 1,841 participants who received either daclizumab or interferon beta-1a (Avonex) and were studied for 144 weeks. Fewer relapses also were seen with daclizumab than with placebo in a second 52-week study of 412 participants.

The most common adverse reactions reported by patients receiving daclizumab in the comparator trial included nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, eczema, and enlargement of lymph nodes. The most common adverse reactions reported in the placebo trial were depression, rash, and increased levels of alanine aminotransferase.

Daclizumab will be marketed as Zinbryta by Biogen.

Read the FDA’s full statement on the FDA website.

acruz@frontlinemedcom.com

Daclizumab (Zinbryta) has been approved as a patient-injected, once-monthly treatment for adults with relapsing forms of multiple sclerosis (MS), according to the Food and Drug Administration.

Daclizumab has serious safety risks, including severe and potentially life-threatening liver injury and immune disorders, and should generally be used only when patients have an inadequate response to two or more MS drugs, the FDA said in a press release. The drug has a boxed warning and is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

Liver function tests should be performed before starting daclizumab, and liver function should be monitored monthly before each dose, and for up to 6 months after the last dose. Immune disorders associated with use of daclizumab include noninfectious colitis, skin reactions, and lymphadenopathy. Other highlighted warnings include anaphylaxis and angioedema, increased risk of infections, and symptoms of depression and suicidal ideation.

Daclizumab was associated with a reduction in clinical relapses in a comparator trial of 1,841 participants who received either daclizumab or interferon beta-1a (Avonex) and were studied for 144 weeks. Fewer relapses also were seen with daclizumab than with placebo in a second 52-week study of 412 participants.

The most common adverse reactions reported by patients receiving daclizumab in the comparator trial included nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, eczema, and enlargement of lymph nodes. The most common adverse reactions reported in the placebo trial were depression, rash, and increased levels of alanine aminotransferase.

Daclizumab will be marketed as Zinbryta by Biogen.

Read the FDA’s full statement on the FDA website.

acruz@frontlinemedcom.com

VANCOUVER—“This exploratory analysis supports the original findings in ORACLE-MS: treatment with two short courses of cladribine tablets significantly delayed conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome,” said lead author Mark S. Freedman, HBSc, MSc, MD, at the 68th Annual Meeting of the American Academy of Neurology. In addition, Dr. Freedman and colleagues found that, compared with placebo, cladribine tablets (3.5 mg/kg) significantly reduce the risk of next attack or disability worsening in patients with early relapsing MS, as defined by the McDonald 2010 criteria.

Mark S. Freedman, HBSc, MSc, MD

In 2014, the ORACLE-MS study in patients with a first clinical demyelinating event who were at high risk of converting to MS showed that cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of clinically definite MS, compared with placebo. The ORACLE-MS study recruited patients with early-stage disease by excluding patients who were already considered to have MS according to the McDonald 2005 diagnostic criteria. The revision of the McDonald criteria in 2010 allowed a diagnosis of MS in patients with a single event and evidence of dissemination in time and space from a single MRI scan.

For the present study, Dr. Freedman, who is Professor of Neurology at the University of Ottawa, and colleagues conducted an exploratory analysis of whether cladribine tablets reduced the risk of a second attack or confirmed disability progression in patients who would now be described as having early relapsing MS, according to the McDonald 2010 criteria.

In the ORACLE-MS study cohort, patients were between ages 18 and 55 with a first demyelinating event within 75 days before screening, two or more clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, and an Expanded Disability Status Scale (EDSS) score of 5 or less. Patients were randomized in equal groups to placebo, cladribine 3.5 mg/kg, or cladribine 5.25 mg/kg. For the present study, baseline MRI scans (excluding the spinal cord) were retrospectively reviewed for MS diagnosis according to the McDonald 2010 criteria.

The exploratory end point in this analysis was time to next attack or EDSS progression in patients who met McDonald 2010 criteria at baseline and in those patients who did not fulfill the revised criteria (ie, those with clinically isolated syndrome).

After applying the McDonald 2010 MS diagnostic criteria, Dr. Freedman and colleagues considered 223 (36.2%) of the 616 participants in ORACLE-MS to have had MS at baseline.

Among these patients, cladribine tablets 3.5 mg/kg significantly reduced the risk of next attack or disability worsening by 74% versus placebo.

In patients who did not meet the McDonald 2010 criteria at baseline, cladribine tablets 3.5 mg/kg also significantly reduced the risk of next attack or disability worsening by 63% versus placebo. Cladribine tablets 5.25 mg/kg also significantly reduced the risk of next attack or disability worsening by 75% versus placebo. This study was sponsored by EMD Serono.

—Glenn S. Williams

VANCOUVER—“This exploratory analysis supports the original findings in ORACLE-MS: treatment with two short courses of cladribine tablets significantly delayed conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome,” said lead author Mark S. Freedman, HBSc, MSc, MD, at the 68th Annual Meeting of the American Academy of Neurology. In addition, Dr. Freedman and colleagues found that, compared with placebo, cladribine tablets (3.5 mg/kg) significantly reduce the risk of next attack or disability worsening in patients with early relapsing MS, as defined by the McDonald 2010 criteria.

Mark S. Freedman, HBSc, MSc, MD

In 2014, the ORACLE-MS study in patients with a first clinical demyelinating event who were at high risk of converting to MS showed that cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of clinically definite MS, compared with placebo. The ORACLE-MS study recruited patients with early-stage disease by excluding patients who were already considered to have MS according to the McDonald 2005 diagnostic criteria. The revision of the McDonald criteria in 2010 allowed a diagnosis of MS in patients with a single event and evidence of dissemination in time and space from a single MRI scan.

For the present study, Dr. Freedman, who is Professor of Neurology at the University of Ottawa, and colleagues conducted an exploratory analysis of whether cladribine tablets reduced the risk of a second attack or confirmed disability progression in patients who would now be described as having early relapsing MS, according to the McDonald 2010 criteria.

In the ORACLE-MS study cohort, patients were between ages 18 and 55 with a first demyelinating event within 75 days before screening, two or more clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, and an Expanded Disability Status Scale (EDSS) score of 5 or less. Patients were randomized in equal groups to placebo, cladribine 3.5 mg/kg, or cladribine 5.25 mg/kg. For the present study, baseline MRI scans (excluding the spinal cord) were retrospectively reviewed for MS diagnosis according to the McDonald 2010 criteria.

The exploratory end point in this analysis was time to next attack or EDSS progression in patients who met McDonald 2010 criteria at baseline and in those patients who did not fulfill the revised criteria (ie, those with clinically isolated syndrome).

After applying the McDonald 2010 MS diagnostic criteria, Dr. Freedman and colleagues considered 223 (36.2%) of the 616 participants in ORACLE-MS to have had MS at baseline.

Among these patients, cladribine tablets 3.5 mg/kg significantly reduced the risk of next attack or disability worsening by 74% versus placebo.

In patients who did not meet the McDonald 2010 criteria at baseline, cladribine tablets 3.5 mg/kg also significantly reduced the risk of next attack or disability worsening by 63% versus placebo. Cladribine tablets 5.25 mg/kg also significantly reduced the risk of next attack or disability worsening by 75% versus placebo. This study was sponsored by EMD Serono.

—Glenn S. Williams

VANCOUVER—“This exploratory analysis supports the original findings in ORACLE-MS: treatment with two short courses of cladribine tablets significantly delayed conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome,” said lead author Mark S. Freedman, HBSc, MSc, MD, at the 68th Annual Meeting of the American Academy of Neurology. In addition, Dr. Freedman and colleagues found that, compared with placebo, cladribine tablets (3.5 mg/kg) significantly reduce the risk of next attack or disability worsening in patients with early relapsing MS, as defined by the McDonald 2010 criteria.

Mark S. Freedman, HBSc, MSc, MD

In 2014, the ORACLE-MS study in patients with a first clinical demyelinating event who were at high risk of converting to MS showed that cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of clinically definite MS, compared with placebo. The ORACLE-MS study recruited patients with early-stage disease by excluding patients who were already considered to have MS according to the McDonald 2005 diagnostic criteria. The revision of the McDonald criteria in 2010 allowed a diagnosis of MS in patients with a single event and evidence of dissemination in time and space from a single MRI scan.

For the present study, Dr. Freedman, who is Professor of Neurology at the University of Ottawa, and colleagues conducted an exploratory analysis of whether cladribine tablets reduced the risk of a second attack or confirmed disability progression in patients who would now be described as having early relapsing MS, according to the McDonald 2010 criteria.

In the ORACLE-MS study cohort, patients were between ages 18 and 55 with a first demyelinating event within 75 days before screening, two or more clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, and an Expanded Disability Status Scale (EDSS) score of 5 or less. Patients were randomized in equal groups to placebo, cladribine 3.5 mg/kg, or cladribine 5.25 mg/kg. For the present study, baseline MRI scans (excluding the spinal cord) were retrospectively reviewed for MS diagnosis according to the McDonald 2010 criteria.

The exploratory end point in this analysis was time to next attack or EDSS progression in patients who met McDonald 2010 criteria at baseline and in those patients who did not fulfill the revised criteria (ie, those with clinically isolated syndrome).

After applying the McDonald 2010 MS diagnostic criteria, Dr. Freedman and colleagues considered 223 (36.2%) of the 616 participants in ORACLE-MS to have had MS at baseline.

Among these patients, cladribine tablets 3.5 mg/kg significantly reduced the risk of next attack or disability worsening by 74% versus placebo.

In patients who did not meet the McDonald 2010 criteria at baseline, cladribine tablets 3.5 mg/kg also significantly reduced the risk of next attack or disability worsening by 63% versus placebo. Cladribine tablets 5.25 mg/kg also significantly reduced the risk of next attack or disability worsening by 75% versus placebo. This study was sponsored by EMD Serono.

—Glenn S. Williams