Multiple Sclerosis Hub

PARIS—Ozanimod is superior to interferon beta-1a on clinical and MRI measures in patients with relapsing-remitting multiple sclerosis (MS), according to the results of two studies presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug could become a safe and effective oral medication for this population, said the investigators.

Scientists at the Scripps Research Institute developed ozanimod, a selective sphingosine 1-phosphate 1 and 5 receptor modulator. “Receptor specificity for subtypes 1 and 5 is anticipated to preserve efficacy, but to lessen off-target treatment effects, as compared to nonselective sphingosine 1-phosphate receptor modulators,” said Jeffrey Cohen, MD, a neurologist at the Cleveland Clinic and an investigator on both of the studies.

The SUNBEAM Study

SUNBEAM was the first of the two trials of ozanimod to be presented at the meeting. Eligible participants were between ages 18 and 55, had relapsing-remitting MS, had had at least one documented relapse in the previous year, had not had a relapse in the previous 30 days, and had no history of cardiac conditions. The trial randomized participants to 0.5 mg/day of oral ozanimod, 1 mg/day of oral ozanimod, or weekly intramuscular injections of interferon beta-1a (30 µg). Patients in the ozanimod groups underwent a seven-day dose escalation as an initiation.

The trial’s primary end point was annualized relapse rate. Among the secondary end points were new and enlarging T2 lesions from baseline to month 12 and T1, gadolinium-enhancing lesions at month 12. The investigators carried out a prespecified evaluation of disability progression, based on Expanded Disability Status Scale (EDSS), using a pooled analysis of SUNBEAM and RADIANCE, the other phase III study.

The researchers enrolled 1,346 patients in 20 countries. The treatment groups were well balanced at baseline. Participants’ mean age was 36, and 66% of the population was female. Mean EDSS score at baseline was 2.6, mean number of relapses in the prior year was 1.3, and 47% of participants had gadolinium-enhancing lesions. In addition, 31% of participants previously had been treated with disease-modifying therapy.

The mean treatment duration in SUNBEAM was 13.6 months. The annualized relapse rate was reduced by 31% with 0.5 mg/day of ozanimod and by 48% with 1 mg/day of ozanimod, compared with interferon beta-1a. Overall, ozanimod reduced MRI activity by 63%, compared with interferon beta-1a. The number of new or enlarging T2 lesions and the adjusted mean number of gadolinium-enhancing lesions at month 12 were significantly reduced in the ozanimod groups, compared with the interferon group. The investigators observed a consistent dose response to ozanimod for all efficacy end points.

The majority of treatment-emergent adverse events were mild, and serious adverse events were uncommon. The rate of adverse events was similar for all treatment groups. The rate of discontinuation due to adverse events also was low and similar between treatment groups. The researchers observed no first-dose, clinically relevant cases of bradycardia.

The RADIANCE Trial

The eligibility criteria for the RADIANCE trial were the same as those of the SUNBEAM study. Participants were randomized to 0.5-mg/day or 1-mg/day doses of ozanimod or to 30 µg/week of interferon beta-1a. The primary end point in RADIANCE was annualized relapse rate at two years. Secondary end points included measures of MRI lesion activity, brain volume loss over two years, and a pooled analysis of confirmed disability worsening. Disability was assessed during a clinical evaluation every three months and at the time of potential relapse.

The investigators enrolled 1,313 patients into the study, and their baseline characteristics were similar across treatment groups. Participants’ mean age was 36, and 67% of the population was female. Mean EDSS score at baseline was 2.5, and mean number of relapses in the prior year was 1.3. About 43% of patients had gadolinium-enhancing lesions at baseline, and 29% previously had received disease-modifying therapy. Overall, 86% of the participants completed the trial, and the discontinuation rate was similar in all treatment arms.

The 0.5-mg dose of ozanimod was associated with a 21% reduction in annualized relapse rate, compared with interferon, and the 1-mg dose of ozanimod was associated with a 38% reduction in this measure. The adjusted mean number of new or enlarging T2 lesions per scan was reduced by 42% with ozanimod 1 mg and by 35% with 0.5 mg of ozanimod, compared with interferon. The adjusted mean number of gadolinium-enhancing lesions at 24 months also was reduced by 53% with 1 mg of ozanimod and by 47% with 0.5 mg of ozanimod, compared with interferon.

In addition, the study demonstrated an approximately 25% reduction in whole-brain volume loss in the two ozanimod arms, compared with the interferon group. Ozanimod also reduced segmented cortical gray volume loss and segmented thalamic volume loss to a similar extent, compared with interferon.

In the pooled analysis of both trials, the rate of confirmed disability worsening was low. The investigators did not observe any difference in this outcome between the three treatment arms.

Ozanimod was well tolerated. Liver enzyme elevations associated with the drug tended to be mild and resolved despite continuation of study drug. The drug was associated with a minimal change in heart rate, and the researchers observed no cases of second-degree or higher heart block. “It appears that the first-dose escalation protocol effectively mitigated cardiac effects,” said Dr. Cohen.

Celgene, the company developing the drug, expects to submit the compound for FDA approval and introduce it to the market by the end of 2018, according to a press release.

—Erik Greb

Suggested Reading

Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.

Sørensen PS. Ozanimod: a better or just another S1P receptor modulator? Lancet Neurol. 2016;15(4):345-347.

PARIS—Ozanimod is superior to interferon beta-1a on clinical and MRI measures in patients with relapsing-remitting multiple sclerosis (MS), according to the results of two studies presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug could become a safe and effective oral medication for this population, said the investigators.

Scientists at the Scripps Research Institute developed ozanimod, a selective sphingosine 1-phosphate 1 and 5 receptor modulator. “Receptor specificity for subtypes 1 and 5 is anticipated to preserve efficacy, but to lessen off-target treatment effects, as compared to nonselective sphingosine 1-phosphate receptor modulators,” said Jeffrey Cohen, MD, a neurologist at the Cleveland Clinic and an investigator on both of the studies.

The SUNBEAM Study

SUNBEAM was the first of the two trials of ozanimod to be presented at the meeting. Eligible participants were between ages 18 and 55, had relapsing-remitting MS, had had at least one documented relapse in the previous year, had not had a relapse in the previous 30 days, and had no history of cardiac conditions. The trial randomized participants to 0.5 mg/day of oral ozanimod, 1 mg/day of oral ozanimod, or weekly intramuscular injections of interferon beta-1a (30 µg). Patients in the ozanimod groups underwent a seven-day dose escalation as an initiation.

The trial’s primary end point was annualized relapse rate. Among the secondary end points were new and enlarging T2 lesions from baseline to month 12 and T1, gadolinium-enhancing lesions at month 12. The investigators carried out a prespecified evaluation of disability progression, based on Expanded Disability Status Scale (EDSS), using a pooled analysis of SUNBEAM and RADIANCE, the other phase III study.

The researchers enrolled 1,346 patients in 20 countries. The treatment groups were well balanced at baseline. Participants’ mean age was 36, and 66% of the population was female. Mean EDSS score at baseline was 2.6, mean number of relapses in the prior year was 1.3, and 47% of participants had gadolinium-enhancing lesions. In addition, 31% of participants previously had been treated with disease-modifying therapy.

The mean treatment duration in SUNBEAM was 13.6 months. The annualized relapse rate was reduced by 31% with 0.5 mg/day of ozanimod and by 48% with 1 mg/day of ozanimod, compared with interferon beta-1a. Overall, ozanimod reduced MRI activity by 63%, compared with interferon beta-1a. The number of new or enlarging T2 lesions and the adjusted mean number of gadolinium-enhancing lesions at month 12 were significantly reduced in the ozanimod groups, compared with the interferon group. The investigators observed a consistent dose response to ozanimod for all efficacy end points.

The majority of treatment-emergent adverse events were mild, and serious adverse events were uncommon. The rate of adverse events was similar for all treatment groups. The rate of discontinuation due to adverse events also was low and similar between treatment groups. The researchers observed no first-dose, clinically relevant cases of bradycardia.

The RADIANCE Trial

The eligibility criteria for the RADIANCE trial were the same as those of the SUNBEAM study. Participants were randomized to 0.5-mg/day or 1-mg/day doses of ozanimod or to 30 µg/week of interferon beta-1a. The primary end point in RADIANCE was annualized relapse rate at two years. Secondary end points included measures of MRI lesion activity, brain volume loss over two years, and a pooled analysis of confirmed disability worsening. Disability was assessed during a clinical evaluation every three months and at the time of potential relapse.

The investigators enrolled 1,313 patients into the study, and their baseline characteristics were similar across treatment groups. Participants’ mean age was 36, and 67% of the population was female. Mean EDSS score at baseline was 2.5, and mean number of relapses in the prior year was 1.3. About 43% of patients had gadolinium-enhancing lesions at baseline, and 29% previously had received disease-modifying therapy. Overall, 86% of the participants completed the trial, and the discontinuation rate was similar in all treatment arms.

The 0.5-mg dose of ozanimod was associated with a 21% reduction in annualized relapse rate, compared with interferon, and the 1-mg dose of ozanimod was associated with a 38% reduction in this measure. The adjusted mean number of new or enlarging T2 lesions per scan was reduced by 42% with ozanimod 1 mg and by 35% with 0.5 mg of ozanimod, compared with interferon. The adjusted mean number of gadolinium-enhancing lesions at 24 months also was reduced by 53% with 1 mg of ozanimod and by 47% with 0.5 mg of ozanimod, compared with interferon.

In addition, the study demonstrated an approximately 25% reduction in whole-brain volume loss in the two ozanimod arms, compared with the interferon group. Ozanimod also reduced segmented cortical gray volume loss and segmented thalamic volume loss to a similar extent, compared with interferon.

In the pooled analysis of both trials, the rate of confirmed disability worsening was low. The investigators did not observe any difference in this outcome between the three treatment arms.

Ozanimod was well tolerated. Liver enzyme elevations associated with the drug tended to be mild and resolved despite continuation of study drug. The drug was associated with a minimal change in heart rate, and the researchers observed no cases of second-degree or higher heart block. “It appears that the first-dose escalation protocol effectively mitigated cardiac effects,” said Dr. Cohen.

Celgene, the company developing the drug, expects to submit the compound for FDA approval and introduce it to the market by the end of 2018, according to a press release.

—Erik Greb

Suggested Reading

Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.

Sørensen PS. Ozanimod: a better or just another S1P receptor modulator? Lancet Neurol. 2016;15(4):345-347.

PARIS—Ozanimod is superior to interferon beta-1a on clinical and MRI measures in patients with relapsing-remitting multiple sclerosis (MS), according to the results of two studies presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug could become a safe and effective oral medication for this population, said the investigators.

Scientists at the Scripps Research Institute developed ozanimod, a selective sphingosine 1-phosphate 1 and 5 receptor modulator. “Receptor specificity for subtypes 1 and 5 is anticipated to preserve efficacy, but to lessen off-target treatment effects, as compared to nonselective sphingosine 1-phosphate receptor modulators,” said Jeffrey Cohen, MD, a neurologist at the Cleveland Clinic and an investigator on both of the studies.

The SUNBEAM Study

SUNBEAM was the first of the two trials of ozanimod to be presented at the meeting. Eligible participants were between ages 18 and 55, had relapsing-remitting MS, had had at least one documented relapse in the previous year, had not had a relapse in the previous 30 days, and had no history of cardiac conditions. The trial randomized participants to 0.5 mg/day of oral ozanimod, 1 mg/day of oral ozanimod, or weekly intramuscular injections of interferon beta-1a (30 µg). Patients in the ozanimod groups underwent a seven-day dose escalation as an initiation.

The trial’s primary end point was annualized relapse rate. Among the secondary end points were new and enlarging T2 lesions from baseline to month 12 and T1, gadolinium-enhancing lesions at month 12. The investigators carried out a prespecified evaluation of disability progression, based on Expanded Disability Status Scale (EDSS), using a pooled analysis of SUNBEAM and RADIANCE, the other phase III study.

The researchers enrolled 1,346 patients in 20 countries. The treatment groups were well balanced at baseline. Participants’ mean age was 36, and 66% of the population was female. Mean EDSS score at baseline was 2.6, mean number of relapses in the prior year was 1.3, and 47% of participants had gadolinium-enhancing lesions. In addition, 31% of participants previously had been treated with disease-modifying therapy.

The mean treatment duration in SUNBEAM was 13.6 months. The annualized relapse rate was reduced by 31% with 0.5 mg/day of ozanimod and by 48% with 1 mg/day of ozanimod, compared with interferon beta-1a. Overall, ozanimod reduced MRI activity by 63%, compared with interferon beta-1a. The number of new or enlarging T2 lesions and the adjusted mean number of gadolinium-enhancing lesions at month 12 were significantly reduced in the ozanimod groups, compared with the interferon group. The investigators observed a consistent dose response to ozanimod for all efficacy end points.

The majority of treatment-emergent adverse events were mild, and serious adverse events were uncommon. The rate of adverse events was similar for all treatment groups. The rate of discontinuation due to adverse events also was low and similar between treatment groups. The researchers observed no first-dose, clinically relevant cases of bradycardia.

The RADIANCE Trial

The eligibility criteria for the RADIANCE trial were the same as those of the SUNBEAM study. Participants were randomized to 0.5-mg/day or 1-mg/day doses of ozanimod or to 30 µg/week of interferon beta-1a. The primary end point in RADIANCE was annualized relapse rate at two years. Secondary end points included measures of MRI lesion activity, brain volume loss over two years, and a pooled analysis of confirmed disability worsening. Disability was assessed during a clinical evaluation every three months and at the time of potential relapse.

The investigators enrolled 1,313 patients into the study, and their baseline characteristics were similar across treatment groups. Participants’ mean age was 36, and 67% of the population was female. Mean EDSS score at baseline was 2.5, and mean number of relapses in the prior year was 1.3. About 43% of patients had gadolinium-enhancing lesions at baseline, and 29% previously had received disease-modifying therapy. Overall, 86% of the participants completed the trial, and the discontinuation rate was similar in all treatment arms.

The 0.5-mg dose of ozanimod was associated with a 21% reduction in annualized relapse rate, compared with interferon, and the 1-mg dose of ozanimod was associated with a 38% reduction in this measure. The adjusted mean number of new or enlarging T2 lesions per scan was reduced by 42% with ozanimod 1 mg and by 35% with 0.5 mg of ozanimod, compared with interferon. The adjusted mean number of gadolinium-enhancing lesions at 24 months also was reduced by 53% with 1 mg of ozanimod and by 47% with 0.5 mg of ozanimod, compared with interferon.

In addition, the study demonstrated an approximately 25% reduction in whole-brain volume loss in the two ozanimod arms, compared with the interferon group. Ozanimod also reduced segmented cortical gray volume loss and segmented thalamic volume loss to a similar extent, compared with interferon.

In the pooled analysis of both trials, the rate of confirmed disability worsening was low. The investigators did not observe any difference in this outcome between the three treatment arms.

Ozanimod was well tolerated. Liver enzyme elevations associated with the drug tended to be mild and resolved despite continuation of study drug. The drug was associated with a minimal change in heart rate, and the researchers observed no cases of second-degree or higher heart block. “It appears that the first-dose escalation protocol effectively mitigated cardiac effects,” said Dr. Cohen.

Celgene, the company developing the drug, expects to submit the compound for FDA approval and introduce it to the market by the end of 2018, according to a press release.

—Erik Greb

Suggested Reading

Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.

Sørensen PS. Ozanimod: a better or just another S1P receptor modulator? Lancet Neurol. 2016;15(4):345-347.

PARIS—Recommended revisions to the 2010 McDonald diagnostic criteria for multiple sclerosis (MS) include changes that are intended to enable neurologists to diagnose MS sooner in patients with a high likelihood of the disease. One addition allows the use of CSF-specific oligoclonal bands in lieu of demonstration of dissemination in time to make a diagnosis of MS in patients with a clinically isolated syndrome and demonstration of dissemination in space clinically or by MRI. Symptomatic and cortical lesions also may satisfy diagnostic criteria, according to the recommendations. In addition, the revised criteria include guidance to reduce the risk of misdiagnosing MS.

Jeffrey A. Cohen, MD, a neurologist with the Cleveland Clinic’s Mellen Center for MS Treatment and Research, presented the 2017 proposed revisions at the Seventh Joint ECTRIMS–ACTRIMS Meeting.

Dr. Cohen and Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London, cochaired the International Panel on Diagnosis of MS, which drafted the new recommendations. The panel convened in November 2016 and May 2017. The meetings were organized under the International Advisory Committee on Clinical Trials in MS and supported by the US National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS). The panel’s recommendations have been submitted for publication and are in the late stages of revision, Dr. Cohen said.

Facilitate Diagnosis

New data regarding the utility of MRI, CSF, and other tests in the diagnostic process motivated neurologists to reconvene the panel. In addition, “there has been increasing recognition of the continued frequency and potential consequences of misdiagnosis of MS,” Dr. Cohen said.

“We felt that the 2010 McDonald criteria overall performed well,” he said. “We did not anticipate making major changes to the criteria. But we sought to simplify and clarify some of the components of the 2010 criteria. We wanted to facilitate the ability to make the diagnosis of MS in patients who had a high likelihood of the disease but were not currently diagnosable by the 2010 criteria. We wanted to preserve the specificity of the 2010 criteria but promote their appropriate application … to reduce the risk of misdiagnosis.” Finally, the panel “wanted to ensure that any proposed changes did not weaken the existing criteria and were supported by reasonable evidence,” he said. Dr. Cohen highlighted five of the panel’s key revisions.

Recommended Changes

First and probably most controversially, “we propose that in a patient with a typical clinically isolated syndrome, and with fulfillment by either clinical or MRI criteria for dissemination in space, that the presence of CSF-specific oligoclonal bands now allows for diagnosis of MS,” Dr. Cohen said. “It does not represent demonstration of dissemination in time per se, but it allows substitution for demonstration of dissemination in time.”

A second recommendation is that symptomatic and asymptomatic MRI lesions can be considered in the determination of dissemination in space and time. In the 2010 criteria, a symptomatic lesion in a patient with a brainstem or spinal cord syndrome could not be included as MRI evidence of dissemination in time and space.

Third, in addition to juxtacortical lesions, cortical lesions can demonstrate dissemination in space. Neurologists’ ability to detect purely cortical MRI lesions currently is relatively limited, however, Dr. Cohen noted.

Fourth, the criteria for primary progressive MS now allow the inclusion of symptomatic and cortical lesions as evidence of the disease. These criteria otherwise have not changed.

Finally, the panel recommends that neurologists determine a provisional disease course, as specified by Lublin et al, at the time of diagnosis and then periodically reevaluate the provisional course based on accumulated evidence.

Avoiding Misdiagnosis

“Much of our discussion started with the issue of misdiagnosis and differential diagnosis in MS,” Dr. Cohen said. “The potential differential diagnosis of MS is quite broad, and misdiagnosis remains an issue even today with advancements in MRI and other testing.” Solomon et al found that neuromyelitis optica spectrum disorders (NMOSDs) were the disorders most commonly misdiagnosed as MS. Physicians also misdiagnosed common conditions like migraine as MS. “Misdiagnosis may have harmful consequences, including inappropriate institution of disease therapy,” Dr. Cohen said.

Neurologists now recognize that aquaporin 4–related NMOSD is a distinct disorder from MS. “However, if you think back to the time that the 2010 criteria were developed, the relationship between NMOSD and MS was not quite as clear. Substantial data have been published since that time,” Dr. Cohen said. “We agreed that the McDonald criteria and the formal criteria for NMOSD largely distinguish the two diseases. However, there may be cases in which there is some uncertainty. Our recommendation is that … the possibility of NMOSD should be considered in all patients being evaluated for MS,” and any patient with features suggesting NMOSD should undergo aquaporin 4 testing.

In general, neurologists should recognize that the McDonald criteria originally were developed to make the diagnosis of MS in patients who have a high likelihood of the disease, not to differentiate MS from other disorders, he said. “Historical events being taken to represent a prior attack should be interpreted with caution if there is no corroborating objective evidence,” Dr. Cohen said. “In cases in which the diagnosis of MS is uncertain, further testing should be pursued. And in some cases, a clinician may want to postpone making a diagnosis pending the accumulation of sufficient data.” CSF testing and spinal MRI are not required to make the diagnosis of MS, but there should be a low threshold for obtaining them.

While data generally support the validity of the 2010 McDonald criteria in geographically diverse populations, children, and older individuals, neurologists should address potentially relevant alternative diagnoses that may be more common in these and other populations (eg, patients with comorbidities), such as infections and nutritional deficiencies.

MAGNIMS Proposal

Several proposals generated discussion during the panel meetings but were not adopted, primarily because the evidence did not justify changing the current criteria. For instance, the 2016 MAGNIMS MRI criteria propose that the number of acquired periventricular lesions be increased from one to three to provide additional specificity. “We reviewed those data … and felt that the modest increase in specificity did not justify making the change,” Dr. Cohen said. The panel also discussed incorporating optic nerve involvement into the criteria, but this proposal was not included in the update.

“The 2017 revisions further refine the well-established McDonald criteria,” Dr. Cohen said. “The appropriate application of the criteria is critical to avoid misdiagnosis. Fundamentally, MS remains a clinical diagnosis. … It requires rigorous synthesis of clinical, imaging, and laboratory data by a clinician with expertise in MS.”

Making a Diagnosis Sooner

Neurologists have been diagnosing MS in patients sooner. At the same time, misdiagnosing other conditions as MS can have profound consequences, including the potentially serious side effects of disease-modifying therapy, said Jeremy Chataway, PhD, consultant neurologist at the National Hospital for Neurology and Neurosurgery, London, in a lecture about the application of the proposed criteria. He described cases in which the 2017 proposed criteria—by allowing the inclusion of a symptomatic spinal cord lesion, or by substituting CSF-specific oligoclonal bands in place of dissemination in time—would have allowed neurologists to diagnose MS sooner. In one case, a patient might have received a diagnosis of MS about two years earlier.

Sometimes a diagnosis of MS “is obvious,” Dr. Chataway said. “Sometimes it is hard, even with advanced MRI. You can see the gradation that is required … to get us to the correct diagnosis.”

—Jake Remaly

Suggested Reading

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.

Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.

Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study. Neurology. 2016;87(13):1393-1399.

PARIS—Recommended revisions to the 2010 McDonald diagnostic criteria for multiple sclerosis (MS) include changes that are intended to enable neurologists to diagnose MS sooner in patients with a high likelihood of the disease. One addition allows the use of CSF-specific oligoclonal bands in lieu of demonstration of dissemination in time to make a diagnosis of MS in patients with a clinically isolated syndrome and demonstration of dissemination in space clinically or by MRI. Symptomatic and cortical lesions also may satisfy diagnostic criteria, according to the recommendations. In addition, the revised criteria include guidance to reduce the risk of misdiagnosing MS.

Jeffrey A. Cohen, MD, a neurologist with the Cleveland Clinic’s Mellen Center for MS Treatment and Research, presented the 2017 proposed revisions at the Seventh Joint ECTRIMS–ACTRIMS Meeting.

Dr. Cohen and Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London, cochaired the International Panel on Diagnosis of MS, which drafted the new recommendations. The panel convened in November 2016 and May 2017. The meetings were organized under the International Advisory Committee on Clinical Trials in MS and supported by the US National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS). The panel’s recommendations have been submitted for publication and are in the late stages of revision, Dr. Cohen said.

Facilitate Diagnosis

New data regarding the utility of MRI, CSF, and other tests in the diagnostic process motivated neurologists to reconvene the panel. In addition, “there has been increasing recognition of the continued frequency and potential consequences of misdiagnosis of MS,” Dr. Cohen said.

“We felt that the 2010 McDonald criteria overall performed well,” he said. “We did not anticipate making major changes to the criteria. But we sought to simplify and clarify some of the components of the 2010 criteria. We wanted to facilitate the ability to make the diagnosis of MS in patients who had a high likelihood of the disease but were not currently diagnosable by the 2010 criteria. We wanted to preserve the specificity of the 2010 criteria but promote their appropriate application … to reduce the risk of misdiagnosis.” Finally, the panel “wanted to ensure that any proposed changes did not weaken the existing criteria and were supported by reasonable evidence,” he said. Dr. Cohen highlighted five of the panel’s key revisions.

Recommended Changes

First and probably most controversially, “we propose that in a patient with a typical clinically isolated syndrome, and with fulfillment by either clinical or MRI criteria for dissemination in space, that the presence of CSF-specific oligoclonal bands now allows for diagnosis of MS,” Dr. Cohen said. “It does not represent demonstration of dissemination in time per se, but it allows substitution for demonstration of dissemination in time.”

A second recommendation is that symptomatic and asymptomatic MRI lesions can be considered in the determination of dissemination in space and time. In the 2010 criteria, a symptomatic lesion in a patient with a brainstem or spinal cord syndrome could not be included as MRI evidence of dissemination in time and space.

Third, in addition to juxtacortical lesions, cortical lesions can demonstrate dissemination in space. Neurologists’ ability to detect purely cortical MRI lesions currently is relatively limited, however, Dr. Cohen noted.

Fourth, the criteria for primary progressive MS now allow the inclusion of symptomatic and cortical lesions as evidence of the disease. These criteria otherwise have not changed.

Finally, the panel recommends that neurologists determine a provisional disease course, as specified by Lublin et al, at the time of diagnosis and then periodically reevaluate the provisional course based on accumulated evidence.

Avoiding Misdiagnosis

“Much of our discussion started with the issue of misdiagnosis and differential diagnosis in MS,” Dr. Cohen said. “The potential differential diagnosis of MS is quite broad, and misdiagnosis remains an issue even today with advancements in MRI and other testing.” Solomon et al found that neuromyelitis optica spectrum disorders (NMOSDs) were the disorders most commonly misdiagnosed as MS. Physicians also misdiagnosed common conditions like migraine as MS. “Misdiagnosis may have harmful consequences, including inappropriate institution of disease therapy,” Dr. Cohen said.

Neurologists now recognize that aquaporin 4–related NMOSD is a distinct disorder from MS. “However, if you think back to the time that the 2010 criteria were developed, the relationship between NMOSD and MS was not quite as clear. Substantial data have been published since that time,” Dr. Cohen said. “We agreed that the McDonald criteria and the formal criteria for NMOSD largely distinguish the two diseases. However, there may be cases in which there is some uncertainty. Our recommendation is that … the possibility of NMOSD should be considered in all patients being evaluated for MS,” and any patient with features suggesting NMOSD should undergo aquaporin 4 testing.

In general, neurologists should recognize that the McDonald criteria originally were developed to make the diagnosis of MS in patients who have a high likelihood of the disease, not to differentiate MS from other disorders, he said. “Historical events being taken to represent a prior attack should be interpreted with caution if there is no corroborating objective evidence,” Dr. Cohen said. “In cases in which the diagnosis of MS is uncertain, further testing should be pursued. And in some cases, a clinician may want to postpone making a diagnosis pending the accumulation of sufficient data.” CSF testing and spinal MRI are not required to make the diagnosis of MS, but there should be a low threshold for obtaining them.

While data generally support the validity of the 2010 McDonald criteria in geographically diverse populations, children, and older individuals, neurologists should address potentially relevant alternative diagnoses that may be more common in these and other populations (eg, patients with comorbidities), such as infections and nutritional deficiencies.

MAGNIMS Proposal

Several proposals generated discussion during the panel meetings but were not adopted, primarily because the evidence did not justify changing the current criteria. For instance, the 2016 MAGNIMS MRI criteria propose that the number of acquired periventricular lesions be increased from one to three to provide additional specificity. “We reviewed those data … and felt that the modest increase in specificity did not justify making the change,” Dr. Cohen said. The panel also discussed incorporating optic nerve involvement into the criteria, but this proposal was not included in the update.

“The 2017 revisions further refine the well-established McDonald criteria,” Dr. Cohen said. “The appropriate application of the criteria is critical to avoid misdiagnosis. Fundamentally, MS remains a clinical diagnosis. … It requires rigorous synthesis of clinical, imaging, and laboratory data by a clinician with expertise in MS.”

Making a Diagnosis Sooner

Neurologists have been diagnosing MS in patients sooner. At the same time, misdiagnosing other conditions as MS can have profound consequences, including the potentially serious side effects of disease-modifying therapy, said Jeremy Chataway, PhD, consultant neurologist at the National Hospital for Neurology and Neurosurgery, London, in a lecture about the application of the proposed criteria. He described cases in which the 2017 proposed criteria—by allowing the inclusion of a symptomatic spinal cord lesion, or by substituting CSF-specific oligoclonal bands in place of dissemination in time—would have allowed neurologists to diagnose MS sooner. In one case, a patient might have received a diagnosis of MS about two years earlier.

Sometimes a diagnosis of MS “is obvious,” Dr. Chataway said. “Sometimes it is hard, even with advanced MRI. You can see the gradation that is required … to get us to the correct diagnosis.”

—Jake Remaly

Suggested Reading

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.

Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.

Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study. Neurology. 2016;87(13):1393-1399.

PARIS—Recommended revisions to the 2010 McDonald diagnostic criteria for multiple sclerosis (MS) include changes that are intended to enable neurologists to diagnose MS sooner in patients with a high likelihood of the disease. One addition allows the use of CSF-specific oligoclonal bands in lieu of demonstration of dissemination in time to make a diagnosis of MS in patients with a clinically isolated syndrome and demonstration of dissemination in space clinically or by MRI. Symptomatic and cortical lesions also may satisfy diagnostic criteria, according to the recommendations. In addition, the revised criteria include guidance to reduce the risk of misdiagnosing MS.

Jeffrey A. Cohen, MD, a neurologist with the Cleveland Clinic’s Mellen Center for MS Treatment and Research, presented the 2017 proposed revisions at the Seventh Joint ECTRIMS–ACTRIMS Meeting.

Dr. Cohen and Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London, cochaired the International Panel on Diagnosis of MS, which drafted the new recommendations. The panel convened in November 2016 and May 2017. The meetings were organized under the International Advisory Committee on Clinical Trials in MS and supported by the US National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS). The panel’s recommendations have been submitted for publication and are in the late stages of revision, Dr. Cohen said.

Facilitate Diagnosis

New data regarding the utility of MRI, CSF, and other tests in the diagnostic process motivated neurologists to reconvene the panel. In addition, “there has been increasing recognition of the continued frequency and potential consequences of misdiagnosis of MS,” Dr. Cohen said.

“We felt that the 2010 McDonald criteria overall performed well,” he said. “We did not anticipate making major changes to the criteria. But we sought to simplify and clarify some of the components of the 2010 criteria. We wanted to facilitate the ability to make the diagnosis of MS in patients who had a high likelihood of the disease but were not currently diagnosable by the 2010 criteria. We wanted to preserve the specificity of the 2010 criteria but promote their appropriate application … to reduce the risk of misdiagnosis.” Finally, the panel “wanted to ensure that any proposed changes did not weaken the existing criteria and were supported by reasonable evidence,” he said. Dr. Cohen highlighted five of the panel’s key revisions.

Recommended Changes

First and probably most controversially, “we propose that in a patient with a typical clinically isolated syndrome, and with fulfillment by either clinical or MRI criteria for dissemination in space, that the presence of CSF-specific oligoclonal bands now allows for diagnosis of MS,” Dr. Cohen said. “It does not represent demonstration of dissemination in time per se, but it allows substitution for demonstration of dissemination in time.”

A second recommendation is that symptomatic and asymptomatic MRI lesions can be considered in the determination of dissemination in space and time. In the 2010 criteria, a symptomatic lesion in a patient with a brainstem or spinal cord syndrome could not be included as MRI evidence of dissemination in time and space.

Third, in addition to juxtacortical lesions, cortical lesions can demonstrate dissemination in space. Neurologists’ ability to detect purely cortical MRI lesions currently is relatively limited, however, Dr. Cohen noted.

Fourth, the criteria for primary progressive MS now allow the inclusion of symptomatic and cortical lesions as evidence of the disease. These criteria otherwise have not changed.

Finally, the panel recommends that neurologists determine a provisional disease course, as specified by Lublin et al, at the time of diagnosis and then periodically reevaluate the provisional course based on accumulated evidence.

Avoiding Misdiagnosis

“Much of our discussion started with the issue of misdiagnosis and differential diagnosis in MS,” Dr. Cohen said. “The potential differential diagnosis of MS is quite broad, and misdiagnosis remains an issue even today with advancements in MRI and other testing.” Solomon et al found that neuromyelitis optica spectrum disorders (NMOSDs) were the disorders most commonly misdiagnosed as MS. Physicians also misdiagnosed common conditions like migraine as MS. “Misdiagnosis may have harmful consequences, including inappropriate institution of disease therapy,” Dr. Cohen said.

Neurologists now recognize that aquaporin 4–related NMOSD is a distinct disorder from MS. “However, if you think back to the time that the 2010 criteria were developed, the relationship between NMOSD and MS was not quite as clear. Substantial data have been published since that time,” Dr. Cohen said. “We agreed that the McDonald criteria and the formal criteria for NMOSD largely distinguish the two diseases. However, there may be cases in which there is some uncertainty. Our recommendation is that … the possibility of NMOSD should be considered in all patients being evaluated for MS,” and any patient with features suggesting NMOSD should undergo aquaporin 4 testing.

In general, neurologists should recognize that the McDonald criteria originally were developed to make the diagnosis of MS in patients who have a high likelihood of the disease, not to differentiate MS from other disorders, he said. “Historical events being taken to represent a prior attack should be interpreted with caution if there is no corroborating objective evidence,” Dr. Cohen said. “In cases in which the diagnosis of MS is uncertain, further testing should be pursued. And in some cases, a clinician may want to postpone making a diagnosis pending the accumulation of sufficient data.” CSF testing and spinal MRI are not required to make the diagnosis of MS, but there should be a low threshold for obtaining them.

While data generally support the validity of the 2010 McDonald criteria in geographically diverse populations, children, and older individuals, neurologists should address potentially relevant alternative diagnoses that may be more common in these and other populations (eg, patients with comorbidities), such as infections and nutritional deficiencies.

MAGNIMS Proposal

Several proposals generated discussion during the panel meetings but were not adopted, primarily because the evidence did not justify changing the current criteria. For instance, the 2016 MAGNIMS MRI criteria propose that the number of acquired periventricular lesions be increased from one to three to provide additional specificity. “We reviewed those data … and felt that the modest increase in specificity did not justify making the change,” Dr. Cohen said. The panel also discussed incorporating optic nerve involvement into the criteria, but this proposal was not included in the update.

“The 2017 revisions further refine the well-established McDonald criteria,” Dr. Cohen said. “The appropriate application of the criteria is critical to avoid misdiagnosis. Fundamentally, MS remains a clinical diagnosis. … It requires rigorous synthesis of clinical, imaging, and laboratory data by a clinician with expertise in MS.”

Making a Diagnosis Sooner

Neurologists have been diagnosing MS in patients sooner. At the same time, misdiagnosing other conditions as MS can have profound consequences, including the potentially serious side effects of disease-modifying therapy, said Jeremy Chataway, PhD, consultant neurologist at the National Hospital for Neurology and Neurosurgery, London, in a lecture about the application of the proposed criteria. He described cases in which the 2017 proposed criteria—by allowing the inclusion of a symptomatic spinal cord lesion, or by substituting CSF-specific oligoclonal bands in place of dissemination in time—would have allowed neurologists to diagnose MS sooner. In one case, a patient might have received a diagnosis of MS about two years earlier.

Sometimes a diagnosis of MS “is obvious,” Dr. Chataway said. “Sometimes it is hard, even with advanced MRI. You can see the gradation that is required … to get us to the correct diagnosis.”

—Jake Remaly

Suggested Reading

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.

Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.

Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study. Neurology. 2016;87(13):1393-1399.

PARIS—Clinical efficacy of alemtuzumab was maintained for seven years in patients who had inadequate response to prior therapy, despite 47% receiving no additional treatment since the initial two courses of alemtuzumab, according to study data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. In addition, 44% of patients showed improvement in disability, researchers reported. “These findings suggest that alemtuzumab may provide a unique treatment approach for patients with relapsing-remitting multiple sclerosis (RRMS), offering durable efficacy in the absence of continuous treatment,” said Barry Singer, MD, Director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.

Alemtuzumab Treatment Then

In the CARE-MS II trial, alemtuzumab significantly improved clinical outcomes, compared with subcutaneous interferon beta-1a, over two years in patients with active RRMS and an inadequate response to prior therapy. Durable efficacy of alemtuzumab was demonstrated over six years in a completed extension study in the absence of continuous treatment. Patients in the CARE-MS II study received two courses of alemtuzumab 12 mg/day (five days of therapy at baseline and three days of therapy 12 months later). In the extension study, patients could receive as-needed alemtuzumab retreatment (12 mg/day on three consecutive days at least 12 months after a previous course for relapse or MRI activity) or other disease-modifying therapy per investigator discretion. Patients completing at least 48 months of the extension could enroll in the five-year TOPAZ study for further long-term evaluation.

Alemtuzumab Treatment Now

The goal of the TOPAZ study was to evaluate the seven-year efficacy and safety of alemtuzumab in patients with RRMS who received alemtuzumab in the CARE-MS II trial. In TOPAZ, patients could receive alemtuzumab retreatment 12 months or more after a previous course or other disease-modifying therapy at any time point (both per investigator discretion). MRI scans were performed annually. Annualized relapse rate, six-month confirmed disability worsening, six-month confirmed disability improvement, no evidence of disease activity (NEDA), and adverse events were analyzed in TOPAZ.

In total, 338 of 393 (86%) CARE-MS II patients who entered the extension remained in the study until the end of year six and then entered TOPAZ; 317 (94%) remained in the study through year seven. Annualized relapse rate remained low (0.14 at year seven), and the proportion of patients with stable or improved Expanded Disability Status Scale score remained high (73% at year seven). Through year seven, 69% of patients were free from six-month confirmed disability worsening, 44% achieved six-month confirmed disability improvement, and the majority achieved NEDA each year. These effects were achieved with 47% of patients receiving no additional treatment (alemtuzumab or other disease-modifying treatment) after their initial two courses of alemtuzumab. Incidences of overall adverse events, infusion-associated reactions, and infections decreased over time and were reduced, compared with those in the two-year core study. The incidence of thyroid adverse events incidence peaked at year three and then declined.

PARIS—Clinical efficacy of alemtuzumab was maintained for seven years in patients who had inadequate response to prior therapy, despite 47% receiving no additional treatment since the initial two courses of alemtuzumab, according to study data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. In addition, 44% of patients showed improvement in disability, researchers reported. “These findings suggest that alemtuzumab may provide a unique treatment approach for patients with relapsing-remitting multiple sclerosis (RRMS), offering durable efficacy in the absence of continuous treatment,” said Barry Singer, MD, Director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.

Alemtuzumab Treatment Then

In the CARE-MS II trial, alemtuzumab significantly improved clinical outcomes, compared with subcutaneous interferon beta-1a, over two years in patients with active RRMS and an inadequate response to prior therapy. Durable efficacy of alemtuzumab was demonstrated over six years in a completed extension study in the absence of continuous treatment. Patients in the CARE-MS II study received two courses of alemtuzumab 12 mg/day (five days of therapy at baseline and three days of therapy 12 months later). In the extension study, patients could receive as-needed alemtuzumab retreatment (12 mg/day on three consecutive days at least 12 months after a previous course for relapse or MRI activity) or other disease-modifying therapy per investigator discretion. Patients completing at least 48 months of the extension could enroll in the five-year TOPAZ study for further long-term evaluation.

Alemtuzumab Treatment Now

The goal of the TOPAZ study was to evaluate the seven-year efficacy and safety of alemtuzumab in patients with RRMS who received alemtuzumab in the CARE-MS II trial. In TOPAZ, patients could receive alemtuzumab retreatment 12 months or more after a previous course or other disease-modifying therapy at any time point (both per investigator discretion). MRI scans were performed annually. Annualized relapse rate, six-month confirmed disability worsening, six-month confirmed disability improvement, no evidence of disease activity (NEDA), and adverse events were analyzed in TOPAZ.

In total, 338 of 393 (86%) CARE-MS II patients who entered the extension remained in the study until the end of year six and then entered TOPAZ; 317 (94%) remained in the study through year seven. Annualized relapse rate remained low (0.14 at year seven), and the proportion of patients with stable or improved Expanded Disability Status Scale score remained high (73% at year seven). Through year seven, 69% of patients were free from six-month confirmed disability worsening, 44% achieved six-month confirmed disability improvement, and the majority achieved NEDA each year. These effects were achieved with 47% of patients receiving no additional treatment (alemtuzumab or other disease-modifying treatment) after their initial two courses of alemtuzumab. Incidences of overall adverse events, infusion-associated reactions, and infections decreased over time and were reduced, compared with those in the two-year core study. The incidence of thyroid adverse events incidence peaked at year three and then declined.

PARIS—Clinical efficacy of alemtuzumab was maintained for seven years in patients who had inadequate response to prior therapy, despite 47% receiving no additional treatment since the initial two courses of alemtuzumab, according to study data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. In addition, 44% of patients showed improvement in disability, researchers reported. “These findings suggest that alemtuzumab may provide a unique treatment approach for patients with relapsing-remitting multiple sclerosis (RRMS), offering durable efficacy in the absence of continuous treatment,” said Barry Singer, MD, Director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.

Alemtuzumab Treatment Then

In the CARE-MS II trial, alemtuzumab significantly improved clinical outcomes, compared with subcutaneous interferon beta-1a, over two years in patients with active RRMS and an inadequate response to prior therapy. Durable efficacy of alemtuzumab was demonstrated over six years in a completed extension study in the absence of continuous treatment. Patients in the CARE-MS II study received two courses of alemtuzumab 12 mg/day (five days of therapy at baseline and three days of therapy 12 months later). In the extension study, patients could receive as-needed alemtuzumab retreatment (12 mg/day on three consecutive days at least 12 months after a previous course for relapse or MRI activity) or other disease-modifying therapy per investigator discretion. Patients completing at least 48 months of the extension could enroll in the five-year TOPAZ study for further long-term evaluation.

Alemtuzumab Treatment Now

The goal of the TOPAZ study was to evaluate the seven-year efficacy and safety of alemtuzumab in patients with RRMS who received alemtuzumab in the CARE-MS II trial. In TOPAZ, patients could receive alemtuzumab retreatment 12 months or more after a previous course or other disease-modifying therapy at any time point (both per investigator discretion). MRI scans were performed annually. Annualized relapse rate, six-month confirmed disability worsening, six-month confirmed disability improvement, no evidence of disease activity (NEDA), and adverse events were analyzed in TOPAZ.

In total, 338 of 393 (86%) CARE-MS II patients who entered the extension remained in the study until the end of year six and then entered TOPAZ; 317 (94%) remained in the study through year seven. Annualized relapse rate remained low (0.14 at year seven), and the proportion of patients with stable or improved Expanded Disability Status Scale score remained high (73% at year seven). Through year seven, 69% of patients were free from six-month confirmed disability worsening, 44% achieved six-month confirmed disability improvement, and the majority achieved NEDA each year. These effects were achieved with 47% of patients receiving no additional treatment (alemtuzumab or other disease-modifying treatment) after their initial two courses of alemtuzumab. Incidences of overall adverse events, infusion-associated reactions, and infections decreased over time and were reduced, compared with those in the two-year core study. The incidence of thyroid adverse events incidence peaked at year three and then declined.

PARIS—Among children and adolescents with multiple sclerosis (MS), patients treated with fingolimod have a lower annualized relapse rate, compared with patients treated with interferon beta-1a, according to phase III trial results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. In addition, fingolimod results in consistently favorable MRI outcomes and may delay disability progression, compared with interferon beta-1a. Fingolimod’s safety profile in children is generally consistent with that in adults.

Between 3% and 5% of patients with MS have disease onset before age 18, but no disease-modifying therapies are FDA-approved specifically for children and adolescents with the disease. “The current treatment recommendations are based on open-label or retrospective studies,” said Tanuja Chitnis, MD, Director of the Partners Pediatric MS Center at Massachusetts General Hospital and Scientist at the Ann Romney Center for Neurological Diseases at Brigham and Women’s Hospital, in Boston.

To investigate the safety and efficacy of fingolimod versus interferon beta-1a in children and adolescents with MS, Dr. Chitnis and colleagues conducted the PARADIGMS study. “PARADIGMS is the first successfully completed global, randomized, clinical trial in pediatric MS,” said Dr. Chitnis, the principal investigator for PARADIGMS.

The PARADIGMS Study

The two-year, double-blind, double-dummy, active-controlled, parallel-group, multicenter study included children and adolescents with a confirmed diagnosis of MS. The study enrolled 215 children between the ages of 10 and 17 with an Expanded Disability Status Scale score between 0 and 5.5. The study included patients who had experienced at least one relapse in the past year or two relapses in the previous two years, or who had evidence of one or more gadolinium-enhancing lesions on MRI within six months prior to randomization.

Patients’ mean age at randomization was about 15. About two-thirds of patients were female, about two-thirds were treatment naïve, and patients were predominantly Caucasian or white. Patients had an average of 1.5 relapses in the prior 12 months and about 2.5 relapses in the prior two years.

Patients were randomized 1:1 to receive once-daily oral fingolimod (0.5 mg or 0.25 mg, dependent on patients’ body weight) or interferon beta-1a 30 μg intramuscular once weekly.

The primary end point was the frequency of relapses in patients treated up to 24 months (ie, annualized relapse rate). Secondary end points included the number of new or newly enlarged T2 lesions, gadolinium-enhancing T1 lesions, safety, and the pharmacokinetic properties of fingolimod.

Researchers conducted the study at 87 sites in more than 25 countries. Investigators designed the study with the FDA, the European Medicines Agency, and the International Pediatric MS Study Group. Basel, Switzerland-based Novartis, which markets fingolimod as Gilenya, supported the study.

Freedom From Relapse

Oral fingolimod reduced the relapse rate by 82% over a period of two years, compared with interferon beta-1a intramuscular injections, Dr. Chitnis said.

About 85% of fingolimod-treated patients were free of confirmed relapse at month 24, versus 39% of patients in the interferon beta-1a arm.

In addition, fingolimod-treated patients had a significant reduction in the number of new or newly enlarging T2 lesions and gadolinium-enhancing T1 lesions, and significantly less brain volume loss, compared with patients who received interferon beta-1a.

In a post hoc analysis, fingolimod significantly delayed confirmed disability progression, compared with interferon beta-1a.

Adverse Events

“The safety profile of fingolimod is generally consistent with that seen in the adult clinical trials,” Dr. Chitnis said. Adverse events occurred more often in the interferon beta-1a arm, whereas serious adverse events occurred more often in the fingolimod arm. The serious adverse events observed in the fingolimod arm included leukopenia in two patients, granulomatosis in one patient, hypersensitivity reaction in one patient, and four patients with seizure events, Dr. Chitnis said.

In all, 92% of fingolimod-treated patients completed the study, compared with 75% of patients in the interferon beta-1a arm. All patients had the option of transferring to an open-label fingolimod arm in an extension phase, and 171 patients entered this extension study.

—Jake Remaly

PARIS—Among children and adolescents with multiple sclerosis (MS), patients treated with fingolimod have a lower annualized relapse rate, compared with patients treated with interferon beta-1a, according to phase III trial results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. In addition, fingolimod results in consistently favorable MRI outcomes and may delay disability progression, compared with interferon beta-1a. Fingolimod’s safety profile in children is generally consistent with that in adults.

Between 3% and 5% of patients with MS have disease onset before age 18, but no disease-modifying therapies are FDA-approved specifically for children and adolescents with the disease. “The current treatment recommendations are based on open-label or retrospective studies,” said Tanuja Chitnis, MD, Director of the Partners Pediatric MS Center at Massachusetts General Hospital and Scientist at the Ann Romney Center for Neurological Diseases at Brigham and Women’s Hospital, in Boston.

To investigate the safety and efficacy of fingolimod versus interferon beta-1a in children and adolescents with MS, Dr. Chitnis and colleagues conducted the PARADIGMS study. “PARADIGMS is the first successfully completed global, randomized, clinical trial in pediatric MS,” said Dr. Chitnis, the principal investigator for PARADIGMS.

The PARADIGMS Study

The two-year, double-blind, double-dummy, active-controlled, parallel-group, multicenter study included children and adolescents with a confirmed diagnosis of MS. The study enrolled 215 children between the ages of 10 and 17 with an Expanded Disability Status Scale score between 0 and 5.5. The study included patients who had experienced at least one relapse in the past year or two relapses in the previous two years, or who had evidence of one or more gadolinium-enhancing lesions on MRI within six months prior to randomization.

Patients’ mean age at randomization was about 15. About two-thirds of patients were female, about two-thirds were treatment naïve, and patients were predominantly Caucasian or white. Patients had an average of 1.5 relapses in the prior 12 months and about 2.5 relapses in the prior two years.

Patients were randomized 1:1 to receive once-daily oral fingolimod (0.5 mg or 0.25 mg, dependent on patients’ body weight) or interferon beta-1a 30 μg intramuscular once weekly.

The primary end point was the frequency of relapses in patients treated up to 24 months (ie, annualized relapse rate). Secondary end points included the number of new or newly enlarged T2 lesions, gadolinium-enhancing T1 lesions, safety, and the pharmacokinetic properties of fingolimod.

Researchers conducted the study at 87 sites in more than 25 countries. Investigators designed the study with the FDA, the European Medicines Agency, and the International Pediatric MS Study Group. Basel, Switzerland-based Novartis, which markets fingolimod as Gilenya, supported the study.

Freedom From Relapse

Oral fingolimod reduced the relapse rate by 82% over a period of two years, compared with interferon beta-1a intramuscular injections, Dr. Chitnis said.

About 85% of fingolimod-treated patients were free of confirmed relapse at month 24, versus 39% of patients in the interferon beta-1a arm.

In addition, fingolimod-treated patients had a significant reduction in the number of new or newly enlarging T2 lesions and gadolinium-enhancing T1 lesions, and significantly less brain volume loss, compared with patients who received interferon beta-1a.

In a post hoc analysis, fingolimod significantly delayed confirmed disability progression, compared with interferon beta-1a.

Adverse Events

“The safety profile of fingolimod is generally consistent with that seen in the adult clinical trials,” Dr. Chitnis said. Adverse events occurred more often in the interferon beta-1a arm, whereas serious adverse events occurred more often in the fingolimod arm. The serious adverse events observed in the fingolimod arm included leukopenia in two patients, granulomatosis in one patient, hypersensitivity reaction in one patient, and four patients with seizure events, Dr. Chitnis said.

In all, 92% of fingolimod-treated patients completed the study, compared with 75% of patients in the interferon beta-1a arm. All patients had the option of transferring to an open-label fingolimod arm in an extension phase, and 171 patients entered this extension study.

—Jake Remaly

PARIS—Among children and adolescents with multiple sclerosis (MS), patients treated with fingolimod have a lower annualized relapse rate, compared with patients treated with interferon beta-1a, according to phase III trial results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. In addition, fingolimod results in consistently favorable MRI outcomes and may delay disability progression, compared with interferon beta-1a. Fingolimod’s safety profile in children is generally consistent with that in adults.

Between 3% and 5% of patients with MS have disease onset before age 18, but no disease-modifying therapies are FDA-approved specifically for children and adolescents with the disease. “The current treatment recommendations are based on open-label or retrospective studies,” said Tanuja Chitnis, MD, Director of the Partners Pediatric MS Center at Massachusetts General Hospital and Scientist at the Ann Romney Center for Neurological Diseases at Brigham and Women’s Hospital, in Boston.

To investigate the safety and efficacy of fingolimod versus interferon beta-1a in children and adolescents with MS, Dr. Chitnis and colleagues conducted the PARADIGMS study. “PARADIGMS is the first successfully completed global, randomized, clinical trial in pediatric MS,” said Dr. Chitnis, the principal investigator for PARADIGMS.

The PARADIGMS Study

The two-year, double-blind, double-dummy, active-controlled, parallel-group, multicenter study included children and adolescents with a confirmed diagnosis of MS. The study enrolled 215 children between the ages of 10 and 17 with an Expanded Disability Status Scale score between 0 and 5.5. The study included patients who had experienced at least one relapse in the past year or two relapses in the previous two years, or who had evidence of one or more gadolinium-enhancing lesions on MRI within six months prior to randomization.

Patients’ mean age at randomization was about 15. About two-thirds of patients were female, about two-thirds were treatment naïve, and patients were predominantly Caucasian or white. Patients had an average of 1.5 relapses in the prior 12 months and about 2.5 relapses in the prior two years.

Patients were randomized 1:1 to receive once-daily oral fingolimod (0.5 mg or 0.25 mg, dependent on patients’ body weight) or interferon beta-1a 30 μg intramuscular once weekly.

The primary end point was the frequency of relapses in patients treated up to 24 months (ie, annualized relapse rate). Secondary end points included the number of new or newly enlarged T2 lesions, gadolinium-enhancing T1 lesions, safety, and the pharmacokinetic properties of fingolimod.

Researchers conducted the study at 87 sites in more than 25 countries. Investigators designed the study with the FDA, the European Medicines Agency, and the International Pediatric MS Study Group. Basel, Switzerland-based Novartis, which markets fingolimod as Gilenya, supported the study.

Freedom From Relapse

Oral fingolimod reduced the relapse rate by 82% over a period of two years, compared with interferon beta-1a intramuscular injections, Dr. Chitnis said.

About 85% of fingolimod-treated patients were free of confirmed relapse at month 24, versus 39% of patients in the interferon beta-1a arm.

In addition, fingolimod-treated patients had a significant reduction in the number of new or newly enlarging T2 lesions and gadolinium-enhancing T1 lesions, and significantly less brain volume loss, compared with patients who received interferon beta-1a.

In a post hoc analysis, fingolimod significantly delayed confirmed disability progression, compared with interferon beta-1a.

Adverse Events

“The safety profile of fingolimod is generally consistent with that seen in the adult clinical trials,” Dr. Chitnis said. Adverse events occurred more often in the interferon beta-1a arm, whereas serious adverse events occurred more often in the fingolimod arm. The serious adverse events observed in the fingolimod arm included leukopenia in two patients, granulomatosis in one patient, hypersensitivity reaction in one patient, and four patients with seizure events, Dr. Chitnis said.

In all, 92% of fingolimod-treated patients completed the study, compared with 75% of patients in the interferon beta-1a arm. All patients had the option of transferring to an open-label fingolimod arm in an extension phase, and 171 patients entered this extension study.

—Jake Remaly

PARIS—Oligoclonal bands, together with symptomatic lesions disseminated in space, increase the risk of multiple sclerosis (MS), according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. MRI dissemination in space (DIS) at any time plus positive oligoclonal bands should be considered as an additional criterion for MS diagnosis, according to the researchers.

Previous research has suggested that the presence of oligoclonal bands in typical clinically isolated syndromes (CIS) increases the risk of a second attack independently of MRI findings. Georgina Arrambide, MD, PhD, a neurologist at Vall d’Hebron University Hospital in Barcelona, and colleagues studied an ongoing CIS cohort to explore whether oligoclonal bands would be a valuable criterion for MS diagnosis in the context of the 2010 McDonald criteria.

An Examination of MRIs

The investigators obtained MRIs at three to five months after CIS diagnosis, at one year, and at every five years. Oligoclonal bands were determined by isoelectric focusing combined with immunoblotting. Dr. Arrambide and colleagues selected 565 patients with oligoclonal band determination and sufficient data on baseline brain MRI to assess 2010 DIS and dissemination in time (DIT) considering the symptomatic lesions. They excluded 167 participants (29.6%) who already fulfilled DIS and DIT criteria and divided the remaining 398 participants into groups with no DIS and no DIT (n = 218), DIS only (n = 164), and DIT only (n = 16).

Next, the researchers performed Cox proportional hazards regression models with 2010 McDonald as the outcome, using no DIS no DIT with no lesions (n = 107) as the reference for no DIS no DIT with one or more lesion, DIS only, and DIT only. To assess performance, Dr. Arrambide’s group selected cases with a follow-up of three or more years or a second attack within three years of the CIS (n = 305). These participants were divided into groups with no DIS and no DIT (n = 165), DIS only (n = 129), and DIT only (n = 11). The investigators classified participants with no DIS and no DIT with one or more lesion (n = 93) and DIS only according to their oligoclonal band status. They assessed sensitivity, specificity, accuracy, positive predictive value, and negative predictive value with 2010 McDonald at three years as the outcome.

Oligoclonal Bands Increased Risk of Conversion to MS

The adjusted hazard ratios of second attack were 2.8 for no DIS and no DIT with one or more lesion and negative oligoclonal bands, 6.4 for no DIS and no DIT with one or more lesion and positive oligoclonal bands, 9.7 for DIS only with negative oligoclonal bands, 14.8 for DIS only with positive oligoclonal bands, and 7.9 for DIT only. Regarding performance, specificity was 77.6 for no DIS no DIT with one or more lesion and negative oligoclonal bands, 89.1 for no DIS no DIT with one or more lesion and positive oligoclonal bands, 92.5 for DIS only and negative oligoclonal bands, 88.1 for DIS only and positive oligoclonal bands, and 97.8 for DIT only. DIS only with positive oligoclonal bands had the highest sensitivity (46.2), accuracy (64.6), and positive predictive value (83.2).

PARIS—Oligoclonal bands, together with symptomatic lesions disseminated in space, increase the risk of multiple sclerosis (MS), according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. MRI dissemination in space (DIS) at any time plus positive oligoclonal bands should be considered as an additional criterion for MS diagnosis, according to the researchers.

Previous research has suggested that the presence of oligoclonal bands in typical clinically isolated syndromes (CIS) increases the risk of a second attack independently of MRI findings. Georgina Arrambide, MD, PhD, a neurologist at Vall d’Hebron University Hospital in Barcelona, and colleagues studied an ongoing CIS cohort to explore whether oligoclonal bands would be a valuable criterion for MS diagnosis in the context of the 2010 McDonald criteria.

An Examination of MRIs

The investigators obtained MRIs at three to five months after CIS diagnosis, at one year, and at every five years. Oligoclonal bands were determined by isoelectric focusing combined with immunoblotting. Dr. Arrambide and colleagues selected 565 patients with oligoclonal band determination and sufficient data on baseline brain MRI to assess 2010 DIS and dissemination in time (DIT) considering the symptomatic lesions. They excluded 167 participants (29.6%) who already fulfilled DIS and DIT criteria and divided the remaining 398 participants into groups with no DIS and no DIT (n = 218), DIS only (n = 164), and DIT only (n = 16).

Next, the researchers performed Cox proportional hazards regression models with 2010 McDonald as the outcome, using no DIS no DIT with no lesions (n = 107) as the reference for no DIS no DIT with one or more lesion, DIS only, and DIT only. To assess performance, Dr. Arrambide’s group selected cases with a follow-up of three or more years or a second attack within three years of the CIS (n = 305). These participants were divided into groups with no DIS and no DIT (n = 165), DIS only (n = 129), and DIT only (n = 11). The investigators classified participants with no DIS and no DIT with one or more lesion (n = 93) and DIS only according to their oligoclonal band status. They assessed sensitivity, specificity, accuracy, positive predictive value, and negative predictive value with 2010 McDonald at three years as the outcome.

Oligoclonal Bands Increased Risk of Conversion to MS

The adjusted hazard ratios of second attack were 2.8 for no DIS and no DIT with one or more lesion and negative oligoclonal bands, 6.4 for no DIS and no DIT with one or more lesion and positive oligoclonal bands, 9.7 for DIS only with negative oligoclonal bands, 14.8 for DIS only with positive oligoclonal bands, and 7.9 for DIT only. Regarding performance, specificity was 77.6 for no DIS no DIT with one or more lesion and negative oligoclonal bands, 89.1 for no DIS no DIT with one or more lesion and positive oligoclonal bands, 92.5 for DIS only and negative oligoclonal bands, 88.1 for DIS only and positive oligoclonal bands, and 97.8 for DIT only. DIS only with positive oligoclonal bands had the highest sensitivity (46.2), accuracy (64.6), and positive predictive value (83.2).

PARIS—Oligoclonal bands, together with symptomatic lesions disseminated in space, increase the risk of multiple sclerosis (MS), according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. MRI dissemination in space (DIS) at any time plus positive oligoclonal bands should be considered as an additional criterion for MS diagnosis, according to the researchers.

Previous research has suggested that the presence of oligoclonal bands in typical clinically isolated syndromes (CIS) increases the risk of a second attack independently of MRI findings. Georgina Arrambide, MD, PhD, a neurologist at Vall d’Hebron University Hospital in Barcelona, and colleagues studied an ongoing CIS cohort to explore whether oligoclonal bands would be a valuable criterion for MS diagnosis in the context of the 2010 McDonald criteria.

An Examination of MRIs

The investigators obtained MRIs at three to five months after CIS diagnosis, at one year, and at every five years. Oligoclonal bands were determined by isoelectric focusing combined with immunoblotting. Dr. Arrambide and colleagues selected 565 patients with oligoclonal band determination and sufficient data on baseline brain MRI to assess 2010 DIS and dissemination in time (DIT) considering the symptomatic lesions. They excluded 167 participants (29.6%) who already fulfilled DIS and DIT criteria and divided the remaining 398 participants into groups with no DIS and no DIT (n = 218), DIS only (n = 164), and DIT only (n = 16).

Next, the researchers performed Cox proportional hazards regression models with 2010 McDonald as the outcome, using no DIS no DIT with no lesions (n = 107) as the reference for no DIS no DIT with one or more lesion, DIS only, and DIT only. To assess performance, Dr. Arrambide’s group selected cases with a follow-up of three or more years or a second attack within three years of the CIS (n = 305). These participants were divided into groups with no DIS and no DIT (n = 165), DIS only (n = 129), and DIT only (n = 11). The investigators classified participants with no DIS and no DIT with one or more lesion (n = 93) and DIS only according to their oligoclonal band status. They assessed sensitivity, specificity, accuracy, positive predictive value, and negative predictive value with 2010 McDonald at three years as the outcome.

Oligoclonal Bands Increased Risk of Conversion to MS

The adjusted hazard ratios of second attack were 2.8 for no DIS and no DIT with one or more lesion and negative oligoclonal bands, 6.4 for no DIS and no DIT with one or more lesion and positive oligoclonal bands, 9.7 for DIS only with negative oligoclonal bands, 14.8 for DIS only with positive oligoclonal bands, and 7.9 for DIT only. Regarding performance, specificity was 77.6 for no DIS no DIT with one or more lesion and negative oligoclonal bands, 89.1 for no DIS no DIT with one or more lesion and positive oligoclonal bands, 92.5 for DIS only and negative oligoclonal bands, 88.1 for DIS only and positive oligoclonal bands, and 97.8 for DIT only. DIS only with positive oligoclonal bands had the highest sensitivity (46.2), accuracy (64.6), and positive predictive value (83.2).

PARIS—Head trauma in adolescence, particularly if it is repeated, is associated with an increased risk of subsequent multiple sclerosis (MS), according to data described at the Seventh Joint ECTRIMS-ACTRIMS Meeting. The increased risk may result from the initiation of an autoimmune process in the CNS. This finding underscores the importance of protecting young people from head injuries, according to the researchers.

Previous studies have suggested an association between head trauma and MS risk, but they have had methodologic limitations such as retrospective data collection and small study populations. Tomas Olsson, MD, Professor of Clinical Neuroscience and Senior Physician at Karolinska Institutet in Stockholm, and colleagues used prospectively recorded data to assess whether concussion in childhood or adolescence is associated with subsequent MS risk.

The investigators used the national Swedish Patient and MS registers to identify all diagnoses of MS up to 2012 among people born in 1964 (when the Patient Register was established) or later. They identified 7,292 patients with MS and matched each with 10 people without MS by sex, year of birth, age or vital status at MS diagnosis, and region of residence. This matching resulted in a study population of 80,212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 or from age 11 to 20. Dr. Olsson and colleagues used conditional logistic regression to examine associations between broken bones, concussions, and MS.

Concussion in adolescence was associated with an increased risk of MS, producing adjusted odds ratios of 1.22 for one diagnosis of concussion and 2.33 for more than one diagnosis of concussion, compared with none. No notable association with MS was observed for concussion in childhood, or for broken limb bones in childhood or in adolescence.

PARIS—Head trauma in adolescence, particularly if it is repeated, is associated with an increased risk of subsequent multiple sclerosis (MS), according to data described at the Seventh Joint ECTRIMS-ACTRIMS Meeting. The increased risk may result from the initiation of an autoimmune process in the CNS. This finding underscores the importance of protecting young people from head injuries, according to the researchers.

Previous studies have suggested an association between head trauma and MS risk, but they have had methodologic limitations such as retrospective data collection and small study populations. Tomas Olsson, MD, Professor of Clinical Neuroscience and Senior Physician at Karolinska Institutet in Stockholm, and colleagues used prospectively recorded data to assess whether concussion in childhood or adolescence is associated with subsequent MS risk.

The investigators used the national Swedish Patient and MS registers to identify all diagnoses of MS up to 2012 among people born in 1964 (when the Patient Register was established) or later. They identified 7,292 patients with MS and matched each with 10 people without MS by sex, year of birth, age or vital status at MS diagnosis, and region of residence. This matching resulted in a study population of 80,212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 or from age 11 to 20. Dr. Olsson and colleagues used conditional logistic regression to examine associations between broken bones, concussions, and MS.

Concussion in adolescence was associated with an increased risk of MS, producing adjusted odds ratios of 1.22 for one diagnosis of concussion and 2.33 for more than one diagnosis of concussion, compared with none. No notable association with MS was observed for concussion in childhood, or for broken limb bones in childhood or in adolescence.

PARIS—Head trauma in adolescence, particularly if it is repeated, is associated with an increased risk of subsequent multiple sclerosis (MS), according to data described at the Seventh Joint ECTRIMS-ACTRIMS Meeting. The increased risk may result from the initiation of an autoimmune process in the CNS. This finding underscores the importance of protecting young people from head injuries, according to the researchers.

Previous studies have suggested an association between head trauma and MS risk, but they have had methodologic limitations such as retrospective data collection and small study populations. Tomas Olsson, MD, Professor of Clinical Neuroscience and Senior Physician at Karolinska Institutet in Stockholm, and colleagues used prospectively recorded data to assess whether concussion in childhood or adolescence is associated with subsequent MS risk.

The investigators used the national Swedish Patient and MS registers to identify all diagnoses of MS up to 2012 among people born in 1964 (when the Patient Register was established) or later. They identified 7,292 patients with MS and matched each with 10 people without MS by sex, year of birth, age or vital status at MS diagnosis, and region of residence. This matching resulted in a study population of 80,212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 or from age 11 to 20. Dr. Olsson and colleagues used conditional logistic regression to examine associations between broken bones, concussions, and MS.

Concussion in adolescence was associated with an increased risk of MS, producing adjusted odds ratios of 1.22 for one diagnosis of concussion and 2.33 for more than one diagnosis of concussion, compared with none. No notable association with MS was observed for concussion in childhood, or for broken limb bones in childhood or in adolescence.

PARIS—Benign multiple sclerosis (MS) appears to be rare. Its estimated prevalence is less than 4%, according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting.

The existence of benign MS has been proposed, but it remains controversial. Neurologists are uncertain about the frequency and pathologic explanation for a favorable outcome in MS. Identifying and studying individuals with benign MS would have “considerable implications for patient management and for our understanding of the biology of the disease,” said Emma Tallantyre, BMBS, PhD, Clinical Senior Lecturer in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the United Kingdom, and colleagues.

Most definitions of benign MS are focused on walking ability after 10 or 15 years, despite the far wider effects of MS on ability. Dr. Tallantyre and colleagues screened a prevalent population of more than 2,000 people with MS and found 275 individuals who had unlimited walking ability after 15 or more years from onset. The investigators undertook detailed assessments of 56 of the individuals within this group (ie, those recorded to have unlimited walking ability after the longest disease durations). Assessment incorporated scores of cognition, fatigue, mood, vision, bladder symptoms, and arm and leg function.

All patients were considered to have relapsing-remitting MS, but they showed a wide range of relapse frequency and severity. In a group of 32 patients who fulfilled a contemporary definition of benign MS based on the Expanded Disability Status Scale, the researchers considered less than 25% to be truly benign, which was defined as having normal function in all domains. Patient-reported scores of MS impact correlated strongly with the outcomes of clinical assessment, but patients’ own perceptions of their condition was more benign than clinicians’ perceptions.

MR imaging was used to explore the biology underlying benign MS using a global approach and a tract-based approach. The study provides early insights into the phenotypic and imaging characteristics of benign MS and could provide information about the biologic mechanisms of a favorable outcome in MS, said Dr. Tallantyre.

PARIS—Benign multiple sclerosis (MS) appears to be rare. Its estimated prevalence is less than 4%, according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting.

The existence of benign MS has been proposed, but it remains controversial. Neurologists are uncertain about the frequency and pathologic explanation for a favorable outcome in MS. Identifying and studying individuals with benign MS would have “considerable implications for patient management and for our understanding of the biology of the disease,” said Emma Tallantyre, BMBS, PhD, Clinical Senior Lecturer in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the United Kingdom, and colleagues.

Most definitions of benign MS are focused on walking ability after 10 or 15 years, despite the far wider effects of MS on ability. Dr. Tallantyre and colleagues screened a prevalent population of more than 2,000 people with MS and found 275 individuals who had unlimited walking ability after 15 or more years from onset. The investigators undertook detailed assessments of 56 of the individuals within this group (ie, those recorded to have unlimited walking ability after the longest disease durations). Assessment incorporated scores of cognition, fatigue, mood, vision, bladder symptoms, and arm and leg function.

All patients were considered to have relapsing-remitting MS, but they showed a wide range of relapse frequency and severity. In a group of 32 patients who fulfilled a contemporary definition of benign MS based on the Expanded Disability Status Scale, the researchers considered less than 25% to be truly benign, which was defined as having normal function in all domains. Patient-reported scores of MS impact correlated strongly with the outcomes of clinical assessment, but patients’ own perceptions of their condition was more benign than clinicians’ perceptions.

MR imaging was used to explore the biology underlying benign MS using a global approach and a tract-based approach. The study provides early insights into the phenotypic and imaging characteristics of benign MS and could provide information about the biologic mechanisms of a favorable outcome in MS, said Dr. Tallantyre.

PARIS—Benign multiple sclerosis (MS) appears to be rare. Its estimated prevalence is less than 4%, according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting.

The existence of benign MS has been proposed, but it remains controversial. Neurologists are uncertain about the frequency and pathologic explanation for a favorable outcome in MS. Identifying and studying individuals with benign MS would have “considerable implications for patient management and for our understanding of the biology of the disease,” said Emma Tallantyre, BMBS, PhD, Clinical Senior Lecturer in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the United Kingdom, and colleagues.

Most definitions of benign MS are focused on walking ability after 10 or 15 years, despite the far wider effects of MS on ability. Dr. Tallantyre and colleagues screened a prevalent population of more than 2,000 people with MS and found 275 individuals who had unlimited walking ability after 15 or more years from onset. The investigators undertook detailed assessments of 56 of the individuals within this group (ie, those recorded to have unlimited walking ability after the longest disease durations). Assessment incorporated scores of cognition, fatigue, mood, vision, bladder symptoms, and arm and leg function.

All patients were considered to have relapsing-remitting MS, but they showed a wide range of relapse frequency and severity. In a group of 32 patients who fulfilled a contemporary definition of benign MS based on the Expanded Disability Status Scale, the researchers considered less than 25% to be truly benign, which was defined as having normal function in all domains. Patient-reported scores of MS impact correlated strongly with the outcomes of clinical assessment, but patients’ own perceptions of their condition was more benign than clinicians’ perceptions.

MR imaging was used to explore the biology underlying benign MS using a global approach and a tract-based approach. The study provides early insights into the phenotypic and imaging characteristics of benign MS and could provide information about the biologic mechanisms of a favorable outcome in MS, said Dr. Tallantyre.

PARIS—Interferon beta is associated with a lower risk of all-cause mortality among patients with multiple sclerosis (MS) treated in clinical practice, according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Participants in the study were observed for as long as 18 years. The findings were consistent across two geographically distinct regions (ie, Canada and France), said the investigators.

Interferon beta has benefits for patients with MS, but whether the treatment prolongs survival in this population is unclear. Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues investigated the association between interferon beta treatment and all-cause mortality in the clinical setting.

The researchers accessed prospectively collected data on patients with relapsing-remitting MS at onset, including sex, birth date, Expanded Disability Status Scale (EDSS) scores, and disease modifying treatments (DMTs), from British Columbia, Canada, and Rennes, France. Data were linked to population-based administrative databases capturing death dates in both countries. In Canada, data about drug prescriptions filled, universal health care registration, hospital admissions, and physician visits also were available. Patients were treatment-naïve at study entry, and investigators followed them from the earliest of first MS clinic visit, 18th birthday, or January 1, 1996, to the earliest of death, emigration, or December 31, 2013.

Using a nested case–control design, the researchers randomly selected as many as 20 MS controls by incidence density sampling and matched them to MS cases (ie, patients who died during follow-up) by sex, age (± 5 years), calendar year, and EDSS score at study entry. The association between all-cause mortality and interferon beta exposure (greater than six months) was estimated by conditional logistic regression, expressed as odds ratios (OR), and adjusted for glatiramer acetate (greater than six months exposure), any exposure to another DMT, age, and comorbidity burden. Analyses were stratified by sex and country. The researchers examined the association with cumulative exposure to interferon beta (up to three years or more than three years).

The cohort included 7,009 patients (75% women) with relapsing-remitting MS with a median age at study entry of 42. During follow-up (median, 12.3 years), 30% of participants were exposed to interferon beta, 11% were exposed to glatiramer acetate, and 12% were exposed to other DMTs, including MS-specific immunosuppressants. As many as 20 controls were successfully matched to each of 649 cases (mean age at death, 60). The odds of exposure to interferon beta was 32% lower among cases than controls. Stratification by sex or country did not change the interpretation of findings. Compared with no or minimal exposure, a longer cumulative time on interferon beta (ie, more than three years) was associated with increased survival (OR, 0.44), whereas exposure of less than three years was not (OR, 1.00).

PARIS—Interferon beta is associated with a lower risk of all-cause mortality among patients with multiple sclerosis (MS) treated in clinical practice, according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Participants in the study were observed for as long as 18 years. The findings were consistent across two geographically distinct regions (ie, Canada and France), said the investigators.

Interferon beta has benefits for patients with MS, but whether the treatment prolongs survival in this population is unclear. Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues investigated the association between interferon beta treatment and all-cause mortality in the clinical setting.

The researchers accessed prospectively collected data on patients with relapsing-remitting MS at onset, including sex, birth date, Expanded Disability Status Scale (EDSS) scores, and disease modifying treatments (DMTs), from British Columbia, Canada, and Rennes, France. Data were linked to population-based administrative databases capturing death dates in both countries. In Canada, data about drug prescriptions filled, universal health care registration, hospital admissions, and physician visits also were available. Patients were treatment-naïve at study entry, and investigators followed them from the earliest of first MS clinic visit, 18th birthday, or January 1, 1996, to the earliest of death, emigration, or December 31, 2013.

Using a nested case–control design, the researchers randomly selected as many as 20 MS controls by incidence density sampling and matched them to MS cases (ie, patients who died during follow-up) by sex, age (± 5 years), calendar year, and EDSS score at study entry. The association between all-cause mortality and interferon beta exposure (greater than six months) was estimated by conditional logistic regression, expressed as odds ratios (OR), and adjusted for glatiramer acetate (greater than six months exposure), any exposure to another DMT, age, and comorbidity burden. Analyses were stratified by sex and country. The researchers examined the association with cumulative exposure to interferon beta (up to three years or more than three years).

The cohort included 7,009 patients (75% women) with relapsing-remitting MS with a median age at study entry of 42. During follow-up (median, 12.3 years), 30% of participants were exposed to interferon beta, 11% were exposed to glatiramer acetate, and 12% were exposed to other DMTs, including MS-specific immunosuppressants. As many as 20 controls were successfully matched to each of 649 cases (mean age at death, 60). The odds of exposure to interferon beta was 32% lower among cases than controls. Stratification by sex or country did not change the interpretation of findings. Compared with no or minimal exposure, a longer cumulative time on interferon beta (ie, more than three years) was associated with increased survival (OR, 0.44), whereas exposure of less than three years was not (OR, 1.00).

PARIS—Interferon beta is associated with a lower risk of all-cause mortality among patients with multiple sclerosis (MS) treated in clinical practice, according to data presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Participants in the study were observed for as long as 18 years. The findings were consistent across two geographically distinct regions (ie, Canada and France), said the investigators.

Interferon beta has benefits for patients with MS, but whether the treatment prolongs survival in this population is unclear. Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues investigated the association between interferon beta treatment and all-cause mortality in the clinical setting.

The researchers accessed prospectively collected data on patients with relapsing-remitting MS at onset, including sex, birth date, Expanded Disability Status Scale (EDSS) scores, and disease modifying treatments (DMTs), from British Columbia, Canada, and Rennes, France. Data were linked to population-based administrative databases capturing death dates in both countries. In Canada, data about drug prescriptions filled, universal health care registration, hospital admissions, and physician visits also were available. Patients were treatment-naïve at study entry, and investigators followed them from the earliest of first MS clinic visit, 18th birthday, or January 1, 1996, to the earliest of death, emigration, or December 31, 2013.

Using a nested case–control design, the researchers randomly selected as many as 20 MS controls by incidence density sampling and matched them to MS cases (ie, patients who died during follow-up) by sex, age (± 5 years), calendar year, and EDSS score at study entry. The association between all-cause mortality and interferon beta exposure (greater than six months) was estimated by conditional logistic regression, expressed as odds ratios (OR), and adjusted for glatiramer acetate (greater than six months exposure), any exposure to another DMT, age, and comorbidity burden. Analyses were stratified by sex and country. The researchers examined the association with cumulative exposure to interferon beta (up to three years or more than three years).

The cohort included 7,009 patients (75% women) with relapsing-remitting MS with a median age at study entry of 42. During follow-up (median, 12.3 years), 30% of participants were exposed to interferon beta, 11% were exposed to glatiramer acetate, and 12% were exposed to other DMTs, including MS-specific immunosuppressants. As many as 20 controls were successfully matched to each of 649 cases (mean age at death, 60). The odds of exposure to interferon beta was 32% lower among cases than controls. Stratification by sex or country did not change the interpretation of findings. Compared with no or minimal exposure, a longer cumulative time on interferon beta (ie, more than three years) was associated with increased survival (OR, 0.44), whereas exposure of less than three years was not (OR, 1.00).

PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.

The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.

The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.

The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.

The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.

At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm³  in the full analysis set and −634 mm³ in the per protocol analysis set. At month 24, the differences were −778 mm³ in the full analysis set and −830 mm³ in the per protocol analysis set.

At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.

Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.

This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.

PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.

The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.

The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.

The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.

The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.

At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm³  in the full analysis set and −634 mm³ in the per protocol analysis set. At month 24, the differences were −778 mm³ in the full analysis set and −830 mm³ in the per protocol analysis set.

At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.

Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.

This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.

PARIS—Siponimod significantly reduces MRI activity and slows brain volume loss in patients with secondary progressive multiple sclerosis (MS), according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Effects are observable at month 12 and sustained at month 24. “These results, together with the clinically observed reduction in confirmed disability progression reported previously, corroborate the positive impact of treatment with siponimod in patients with secondary progressive MS,” said Robert Fox, MD, a researcher at the Mellen Center for Treatment and Research in MS in the Cleveland Clinic, and colleagues.

The EXPAND study demonstrated the benefits of siponimod, a selective modulator of sphingosine 1-phosphate receptor subtypes 1 and 5, on confirmed disability progression. Dr. Fox and colleagues examined these data to evaluate the effect of siponimod versus placebo on predefined MRI outcomes in patients with secondary progressive MS.

The researchers randomized patients 2:1 to receive siponimod or placebo. MRI scans were performed at baseline and every 12 months thereafter. Radiologists at a central reading center analyzed the scans. Key MRI outcomes included T2 lesion volume, number of new or enlarging T2 lesions, number of gadolinium-enhancing lesions, and brain volume loss assessed by percent brain volume change.

The full analysis set comprised patients who received one or more doses of study drug as per original randomization. The per-protocol analysis set consisted of all full-analysis-set patients without major protocol deviations and included efficacy data only up to discontinuation of double-blinded treatment.

The investigators randomized 1,651 patients. A total of 1,099 patients received siponimod (2 mg), and 546 received placebo. Dr. Fox and colleagues observed treatment benefits in favor of siponimod for all key outcomes and analysis sets investigated. Post-baseline MRI data were available for more than 80% of participants.

At month 12, the adjusted mean differences in the change in T2 lesion volume from baseline versus placebo were −613 mm³  in the full analysis set and −634 mm³ in the per protocol analysis set. At month 24, the differences were −778 mm³ in the full analysis set and −830 mm³ in the per protocol analysis set.

At month 12, the adjusted mean differences in percent brain volume change were 0.175 in the full analysis set and 0.221 in the per protocol analysis set. At month 24, the differences were 0.128 in the full analysis set and 0.277 in the per protocol analysis set.

Siponimod reduced the average T1 gadolinium-enhancing lesion count over months 12 and 24 by 86.6% in the full analysis set and 91.1% in the per protocol analysis set. Siponimod reduced the average count of new or enlarging T2 lesions by 80.6% in the full analysis set and 85.3% in the per protocol analysis set.

This study was funded by Novartis Pharma, which is headquartered in Basel, Switzerland.

PARIS—Tracking disease impact in patients with multiple sclerosis (MS) by predictable loss of economically important milestones trajectory, beyond what can be documented by EDSS, MRI, or apparent or reported relapse, can be accomplished by use of objective multidomain cognitive testing, according to a report presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Such a strategy can provide patient-centric information such as predicting likely loss of economically impactful abilities that are not completely dependent upon EDSS nor currently obtained in the course of traditional MS care or clinical trials. “This objective approach might provide a pathway towards actionable change by objectively monitoring disease progression in a way that EDSS and MRI are unable and that will likely impact therapy choice as well as timing of disease-modifying treatment change,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York, on behalf of his coauthors. “This approach can be incorporated into routine care and also can be utilized to easily and quantitatively track examiner independent multidomain cognitive impact longitudinally in a patient-centric manner in people with MS to perhaps improve care outcomes and reduce economic costs that accompany such increased disease burden.”

MS, which is usually characterized by relapses and progression, is traditionally measured by relapse rate reduction, changes in EDSS, and MRI findings. “EDSS change is primarily driven by physical findings or walking impairment, neither of which accounts for cognitive impact or reserve or accumulation of cognitive impairment,” Dr. Gudesblatt said. Cognitive impairment, he added, is not typically quantified or tracked in patients with MS in routine care or clinical trials. EDSS is also insensitive to the degree or types of cognitive impairment. Cognitive impairment, Dr. Gudesblatt and colleagues posit, impacts economically important abilities (eg, employment, ability to drive, and freedom from falls for both simple and complex daily activities) that are not addressed by traditional metrics.

Another layer of complexity is treatment choice. There are multiple available disease-modifying therapies of varied routes, dosing frequency, and efficacy. This makes individual treatment choice and timing of disease-modifying therapy change problematic. “A patient-centric objective analysis of disease trajectory and loss of economically important milestones relating to predictive loss of ability can supplement and perhaps improve alternative approaches to guide treatment choice, change, and timing,” Dr. Gudesblatt said.

An objective, quantitative, patient-centric, and granular EDSS-independent approach of likely disability trajectory might improve decision making regarding disease-modifying therapy choice and timing of change, offer a path to compare outcome measures across clinical trials, and possibly provide an opportunity to preempt the appearance of important disabilities that result in significantly increased cost of care and reduced quality of life. “Objective comprehensive analytics documenting unseen disease impact and change offer unique opportunities to improve care,” Dr. Gudesblatt said.

Toward this end, Dr. Gudesblatt and colleagues conducted a cross-sectional review of a prospective digital MS registry obtained in the course of routine care utilizing standardized computerized cognitive testing (NeuroTrax) to evaluate the relationship of cognitive impairment to disability. Cognitive impairment was defined as number of cognitive domains impaired (CDI) more than one standard deviation from age/education normal. Disability domains assessed were unemployment, loss of driving, and freedom from falls. Patients with an EDSS of less than 6 were included in the study cohort (ie, no one was included who was disabled to the point of requiring a cane to ambulate).

The researchers found that increasing accumulated number of CDI in patients with MS and an EDSS less than 6 is associated with likely progressive loss of:

• Employment (n = 543, CDI-0 = 61%, CDI-1 = 50%, CDI-2 = 43%, CDI-3 = 32%)
• Driving (n = 115, CDI-0 = 100%, CDI-1 = 66%, CDI-2 = 53%, CDI-3 = 21%)
• Freedom from falls (n = 159) for simple daily activities (CDI-0 = 77%, CDI-1 = 65%, CDI-2 = 37%, CDI-3 = 39%) and reduced freedom from falls for complex daily activities (CDI-0 = 72%, CDI-1 = 58%, CDI-2 = 36%, CDI-3 = 33%).

Increased risk of falls and reduced likelihood of employment and driving all represent significant impact on quality of life and result in increased economic burden and long-term costs of the disease, Dr. Gudesblatt and colleagues said.

PARIS—Tracking disease impact in patients with multiple sclerosis (MS) by predictable loss of economically important milestones trajectory, beyond what can be documented by EDSS, MRI, or apparent or reported relapse, can be accomplished by use of objective multidomain cognitive testing, according to a report presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Such a strategy can provide patient-centric information such as predicting likely loss of economically impactful abilities that are not completely dependent upon EDSS nor currently obtained in the course of traditional MS care or clinical trials. “This objective approach might provide a pathway towards actionable change by objectively monitoring disease progression in a way that EDSS and MRI are unable and that will likely impact therapy choice as well as timing of disease-modifying treatment change,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York, on behalf of his coauthors. “This approach can be incorporated into routine care and also can be utilized to easily and quantitatively track examiner independent multidomain cognitive impact longitudinally in a patient-centric manner in people with MS to perhaps improve care outcomes and reduce economic costs that accompany such increased disease burden.”

MS, which is usually characterized by relapses and progression, is traditionally measured by relapse rate reduction, changes in EDSS, and MRI findings. “EDSS change is primarily driven by physical findings or walking impairment, neither of which accounts for cognitive impact or reserve or accumulation of cognitive impairment,” Dr. Gudesblatt said. Cognitive impairment, he added, is not typically quantified or tracked in patients with MS in routine care or clinical trials. EDSS is also insensitive to the degree or types of cognitive impairment. Cognitive impairment, Dr. Gudesblatt and colleagues posit, impacts economically important abilities (eg, employment, ability to drive, and freedom from falls for both simple and complex daily activities) that are not addressed by traditional metrics.

Another layer of complexity is treatment choice. There are multiple available disease-modifying therapies of varied routes, dosing frequency, and efficacy. This makes individual treatment choice and timing of disease-modifying therapy change problematic. “A patient-centric objective analysis of disease trajectory and loss of economically important milestones relating to predictive loss of ability can supplement and perhaps improve alternative approaches to guide treatment choice, change, and timing,” Dr. Gudesblatt said.

An objective, quantitative, patient-centric, and granular EDSS-independent approach of likely disability trajectory might improve decision making regarding disease-modifying therapy choice and timing of change, offer a path to compare outcome measures across clinical trials, and possibly provide an opportunity to preempt the appearance of important disabilities that result in significantly increased cost of care and reduced quality of life. “Objective comprehensive analytics documenting unseen disease impact and change offer unique opportunities to improve care,” Dr. Gudesblatt said.

Toward this end, Dr. Gudesblatt and colleagues conducted a cross-sectional review of a prospective digital MS registry obtained in the course of routine care utilizing standardized computerized cognitive testing (NeuroTrax) to evaluate the relationship of cognitive impairment to disability. Cognitive impairment was defined as number of cognitive domains impaired (CDI) more than one standard deviation from age/education normal. Disability domains assessed were unemployment, loss of driving, and freedom from falls. Patients with an EDSS of less than 6 were included in the study cohort (ie, no one was included who was disabled to the point of requiring a cane to ambulate).

The researchers found that increasing accumulated number of CDI in patients with MS and an EDSS less than 6 is associated with likely progressive loss of:

• Employment (n = 543, CDI-0 = 61%, CDI-1 = 50%, CDI-2 = 43%, CDI-3 = 32%)
• Driving (n = 115, CDI-0 = 100%, CDI-1 = 66%, CDI-2 = 53%, CDI-3 = 21%)
• Freedom from falls (n = 159) for simple daily activities (CDI-0 = 77%, CDI-1 = 65%, CDI-2 = 37%, CDI-3 = 39%) and reduced freedom from falls for complex daily activities (CDI-0 = 72%, CDI-1 = 58%, CDI-2 = 36%, CDI-3 = 33%).

Increased risk of falls and reduced likelihood of employment and driving all represent significant impact on quality of life and result in increased economic burden and long-term costs of the disease, Dr. Gudesblatt and colleagues said.

PARIS—Tracking disease impact in patients with multiple sclerosis (MS) by predictable loss of economically important milestones trajectory, beyond what can be documented by EDSS, MRI, or apparent or reported relapse, can be accomplished by use of objective multidomain cognitive testing, according to a report presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. Such a strategy can provide patient-centric information such as predicting likely loss of economically impactful abilities that are not completely dependent upon EDSS nor currently obtained in the course of traditional MS care or clinical trials. “This objective approach might provide a pathway towards actionable change by objectively monitoring disease progression in a way that EDSS and MRI are unable and that will likely impact therapy choice as well as timing of disease-modifying treatment change,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York, on behalf of his coauthors. “This approach can be incorporated into routine care and also can be utilized to easily and quantitatively track examiner independent multidomain cognitive impact longitudinally in a patient-centric manner in people with MS to perhaps improve care outcomes and reduce economic costs that accompany such increased disease burden.”

MS, which is usually characterized by relapses and progression, is traditionally measured by relapse rate reduction, changes in EDSS, and MRI findings. “EDSS change is primarily driven by physical findings or walking impairment, neither of which accounts for cognitive impact or reserve or accumulation of cognitive impairment,” Dr. Gudesblatt said. Cognitive impairment, he added, is not typically quantified or tracked in patients with MS in routine care or clinical trials. EDSS is also insensitive to the degree or types of cognitive impairment. Cognitive impairment, Dr. Gudesblatt and colleagues posit, impacts economically important abilities (eg, employment, ability to drive, and freedom from falls for both simple and complex daily activities) that are not addressed by traditional metrics.

Another layer of complexity is treatment choice. There are multiple available disease-modifying therapies of varied routes, dosing frequency, and efficacy. This makes individual treatment choice and timing of disease-modifying therapy change problematic. “A patient-centric objective analysis of disease trajectory and loss of economically important milestones relating to predictive loss of ability can supplement and perhaps improve alternative approaches to guide treatment choice, change, and timing,” Dr. Gudesblatt said.

An objective, quantitative, patient-centric, and granular EDSS-independent approach of likely disability trajectory might improve decision making regarding disease-modifying therapy choice and timing of change, offer a path to compare outcome measures across clinical trials, and possibly provide an opportunity to preempt the appearance of important disabilities that result in significantly increased cost of care and reduced quality of life. “Objective comprehensive analytics documenting unseen disease impact and change offer unique opportunities to improve care,” Dr. Gudesblatt said.

Toward this end, Dr. Gudesblatt and colleagues conducted a cross-sectional review of a prospective digital MS registry obtained in the course of routine care utilizing standardized computerized cognitive testing (NeuroTrax) to evaluate the relationship of cognitive impairment to disability. Cognitive impairment was defined as number of cognitive domains impaired (CDI) more than one standard deviation from age/education normal. Disability domains assessed were unemployment, loss of driving, and freedom from falls. Patients with an EDSS of less than 6 were included in the study cohort (ie, no one was included who was disabled to the point of requiring a cane to ambulate).

The researchers found that increasing accumulated number of CDI in patients with MS and an EDSS less than 6 is associated with likely progressive loss of:

• Employment (n = 543, CDI-0 = 61%, CDI-1 = 50%, CDI-2 = 43%, CDI-3 = 32%)
• Driving (n = 115, CDI-0 = 100%, CDI-1 = 66%, CDI-2 = 53%, CDI-3 = 21%)
• Freedom from falls (n = 159) for simple daily activities (CDI-0 = 77%, CDI-1 = 65%, CDI-2 = 37%, CDI-3 = 39%) and reduced freedom from falls for complex daily activities (CDI-0 = 72%, CDI-1 = 58%, CDI-2 = 36%, CDI-3 = 33%).

Increased risk of falls and reduced likelihood of employment and driving all represent significant impact on quality of life and result in increased economic burden and long-term costs of the disease, Dr. Gudesblatt and colleagues said.