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Evaluation of Cortical Lesions Could Improve Diagnosis of MS
LONDON—Evaluation of cortical lesions improves the specificity of the diagnostic criteria for multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Assessment of cortical lesions, in concert with current McDonald criteria, also preserved a high level of diagnostic sensitivity and accuracy in a multicentric cohort of patients with clinically isolated syndrome, reported Paolo Preziosa, MD, Neuroimaging Research Unit at the Institute of Experimental Neurology and Division of Neuroscience at San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and his research colleagues.
Since the publication of the 2010 revised McDonald criteria, new data regarding the application of MRI for the diagnosis of MS have become available. In a single-center study, adding the assessment of cortical lesions was shown to modify the diagnostic algorithm, resulting in higher specificity.
In the present study, Dr. Preziosa and colleagues sought to test the performance of different sets of imaging criteria, including the assessment of cortical lesions, for the development of MS in a multicentric cohort of patients with clinically isolated syndrome.
The researchers analyzed brain double inversion recovery and brain and cord T2-weighted and post-contrast T1-weighted sequences acquired from 72 patients with clinically isolated syndrome from five European centers (Barcelona, Belgrade, Mainz, Milan, and Verona) within three months and after 12 months from disease onset. Patients were followed clinically for 24 or more months or until the development of clinically defined MS. Median follow-up was 24.2 months. Sensitivity, specificity, and accuracy of the different dissemination in space MRI criteria for the development of MS were tested.
At follow-up, 65 patients (90%) had clinically and/or radiologically definite MS. The sensitivity of all criteria was high (McDonald 2005, 83%; McDonald 2010, 92%; Filippi 2010, 80%). Specificity of Filippi 2010 was higher (67%), compared with the others (50% for McDonald 2005 and 2010). The accuracy of all criteria was high (McDonald 2005, 81%; McDonald 2010, 89%; Filippi 2010, 79%).
“The detection of cortical lesions in vivo using MRI should be considered in future clinical trials,” Dr. Preziosa said.
—Glenn S. Williams
Suggested Reading
Filippi M, Rocca MA, Calabrese M, et al. Intracortical lesions: relevance for new MRI diagnostic criteria for multiple sclerosis. Neurology. 2010;75(22):1988-1994.
LONDON—Evaluation of cortical lesions improves the specificity of the diagnostic criteria for multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Assessment of cortical lesions, in concert with current McDonald criteria, also preserved a high level of diagnostic sensitivity and accuracy in a multicentric cohort of patients with clinically isolated syndrome, reported Paolo Preziosa, MD, Neuroimaging Research Unit at the Institute of Experimental Neurology and Division of Neuroscience at San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and his research colleagues.
Since the publication of the 2010 revised McDonald criteria, new data regarding the application of MRI for the diagnosis of MS have become available. In a single-center study, adding the assessment of cortical lesions was shown to modify the diagnostic algorithm, resulting in higher specificity.
In the present study, Dr. Preziosa and colleagues sought to test the performance of different sets of imaging criteria, including the assessment of cortical lesions, for the development of MS in a multicentric cohort of patients with clinically isolated syndrome.
The researchers analyzed brain double inversion recovery and brain and cord T2-weighted and post-contrast T1-weighted sequences acquired from 72 patients with clinically isolated syndrome from five European centers (Barcelona, Belgrade, Mainz, Milan, and Verona) within three months and after 12 months from disease onset. Patients were followed clinically for 24 or more months or until the development of clinically defined MS. Median follow-up was 24.2 months. Sensitivity, specificity, and accuracy of the different dissemination in space MRI criteria for the development of MS were tested.
At follow-up, 65 patients (90%) had clinically and/or radiologically definite MS. The sensitivity of all criteria was high (McDonald 2005, 83%; McDonald 2010, 92%; Filippi 2010, 80%). Specificity of Filippi 2010 was higher (67%), compared with the others (50% for McDonald 2005 and 2010). The accuracy of all criteria was high (McDonald 2005, 81%; McDonald 2010, 89%; Filippi 2010, 79%).
“The detection of cortical lesions in vivo using MRI should be considered in future clinical trials,” Dr. Preziosa said.
—Glenn S. Williams
Suggested Reading
Filippi M, Rocca MA, Calabrese M, et al. Intracortical lesions: relevance for new MRI diagnostic criteria for multiple sclerosis. Neurology. 2010;75(22):1988-1994.
LONDON—Evaluation of cortical lesions improves the specificity of the diagnostic criteria for multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Assessment of cortical lesions, in concert with current McDonald criteria, also preserved a high level of diagnostic sensitivity and accuracy in a multicentric cohort of patients with clinically isolated syndrome, reported Paolo Preziosa, MD, Neuroimaging Research Unit at the Institute of Experimental Neurology and Division of Neuroscience at San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and his research colleagues.
Since the publication of the 2010 revised McDonald criteria, new data regarding the application of MRI for the diagnosis of MS have become available. In a single-center study, adding the assessment of cortical lesions was shown to modify the diagnostic algorithm, resulting in higher specificity.
In the present study, Dr. Preziosa and colleagues sought to test the performance of different sets of imaging criteria, including the assessment of cortical lesions, for the development of MS in a multicentric cohort of patients with clinically isolated syndrome.
The researchers analyzed brain double inversion recovery and brain and cord T2-weighted and post-contrast T1-weighted sequences acquired from 72 patients with clinically isolated syndrome from five European centers (Barcelona, Belgrade, Mainz, Milan, and Verona) within three months and after 12 months from disease onset. Patients were followed clinically for 24 or more months or until the development of clinically defined MS. Median follow-up was 24.2 months. Sensitivity, specificity, and accuracy of the different dissemination in space MRI criteria for the development of MS were tested.
At follow-up, 65 patients (90%) had clinically and/or radiologically definite MS. The sensitivity of all criteria was high (McDonald 2005, 83%; McDonald 2010, 92%; Filippi 2010, 80%). Specificity of Filippi 2010 was higher (67%), compared with the others (50% for McDonald 2005 and 2010). The accuracy of all criteria was high (McDonald 2005, 81%; McDonald 2010, 89%; Filippi 2010, 79%).
“The detection of cortical lesions in vivo using MRI should be considered in future clinical trials,” Dr. Preziosa said.
—Glenn S. Williams
Suggested Reading
Filippi M, Rocca MA, Calabrese M, et al. Intracortical lesions: relevance for new MRI diagnostic criteria for multiple sclerosis. Neurology. 2010;75(22):1988-1994.
Smoking, vitamin D deficiency linked to early MS disability
LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.
Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.
However, neither vitamin D deficiency nor current smoking predicted the conversion of CIS to clinically definite multiple sclerosis (CDMS), said María Zuluaga, MD, of the Centre d’Esclerosi Múltiple de Catalunya at Vall d’Hebron University Hospital in Barcelona.
Environmental factors such as vitamin D levels and smoking have been purported to play a role in the development of CIS to CDMS, Dr. Zuluaga explained at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood samples collected within 6 months of a diagnosis of CIS were examined and vitamin D deficiency defined as normal, mild, moderate, or severe based on serum 25-hydroxy vitamin D of greater than 20, 16-20, 8-15, and less that 8 ng/mL.
Levels of the nicotine metabolite cotinine in the blood were used as a proxy for current smoking. Cotinine has a half-life of around 20 hours and smokers – active or passive – have a level of 14 ng/mL or more while nonsmokers have a level of less than 14 ng/mL.
The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.
Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.
However, neither vitamin D deficiency nor current smoking predicted the conversion of CIS to clinically definite multiple sclerosis (CDMS), said María Zuluaga, MD, of the Centre d’Esclerosi Múltiple de Catalunya at Vall d’Hebron University Hospital in Barcelona.
Environmental factors such as vitamin D levels and smoking have been purported to play a role in the development of CIS to CDMS, Dr. Zuluaga explained at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood samples collected within 6 months of a diagnosis of CIS were examined and vitamin D deficiency defined as normal, mild, moderate, or severe based on serum 25-hydroxy vitamin D of greater than 20, 16-20, 8-15, and less that 8 ng/mL.
Levels of the nicotine metabolite cotinine in the blood were used as a proxy for current smoking. Cotinine has a half-life of around 20 hours and smokers – active or passive – have a level of 14 ng/mL or more while nonsmokers have a level of less than 14 ng/mL.
The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.
Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.
However, neither vitamin D deficiency nor current smoking predicted the conversion of CIS to clinically definite multiple sclerosis (CDMS), said María Zuluaga, MD, of the Centre d’Esclerosi Múltiple de Catalunya at Vall d’Hebron University Hospital in Barcelona.
Environmental factors such as vitamin D levels and smoking have been purported to play a role in the development of CIS to CDMS, Dr. Zuluaga explained at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood samples collected within 6 months of a diagnosis of CIS were examined and vitamin D deficiency defined as normal, mild, moderate, or severe based on serum 25-hydroxy vitamin D of greater than 20, 16-20, 8-15, and less that 8 ng/mL.
Levels of the nicotine metabolite cotinine in the blood were used as a proxy for current smoking. Cotinine has a half-life of around 20 hours and smokers – active or passive – have a level of 14 ng/mL or more while nonsmokers have a level of less than 14 ng/mL.
The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
Key clinical point:
Major finding: Patients with a serum 25-hydroxy vitamin D level of less than 8.0 ng/mL showed an increased risk for disability in a multivariate analysis (HR, 2.3; P = .049). Nonsmokers were significantly less likely to have disability progression (HR, 0.4; P = .002).
Data source: Barcelona CIS cohort of 1,127 individuals
Disclosures: The study received no commercial funding. Dr. Zuluaga reported having no conflict of interest related to the study.
Fluoxetine fails to slow progressive multiple sclerosis
LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.
The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.
“The progressive phase of MS remains an ill-understood part of the disease and it is a holy grail to find a drug that can stop this progression,” Dr. Cambron said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The rationale for looking at whether fluoxetine, a well-studied antidepressant drug, could be such a drug, was that it had several neuroprotective features – it has been shown to stimulate the release of brain-derived neurotrophic factor, stimulate metabolism in astrocytes, and lower glutamatergic toxicity, she said. All of these could potentially help prevent axonal degeneration.
The FLUOX-PMS (Fluoxetine in Progressive Multiple Sclerosis) trial (Trials. 2014;15:37) ran from 2012 to June 2016 and enrolled patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), as defined by the 2010 McDonald criteria. A total of 137 patients were enrolled, and 69 were randomized to treatment with fluoxetine 40 mg/day and 68 were randomized to placebo. Fluoxetine treatment was started at a dose of 20 mg and titrated to the full 40-mg dose by 12 weeks.
Patient demographics were mostly similar between the groups. Around 44% of patients in the fluoxetine and placebo groups were female; roughly 40% had PPMS and 60% had SPMS in both groups; the mean Expanded Disability Status Scale score was 5.2 in both groups; the mean age was 54 and 51 years, respectively; and the disease duration was between 18 and 20 years.
Dr. Cambron also reported that the trials’ secondary endpoints showed no advantage of using fluoxetine over placebo. The proportion of patients without sustained progression during the trial was similar among the fluoxetine- and placebo-treated patients, at a respective 69.6% and 61.8% (P = .434). The proportion of patients with a stable Hauser Ambulation Index was also similar (P = .371).
The primary and secondary endpoints were assessed every 3 months in the trial. Patients also underwent cognitive testing, completed the Beck Depression Inventory-II, and Modified Fatigue Impact Scale before treatment and at 48 and 108 weeks after treatment with fluoxetine or placebo. Brain MRI was also performed at baseline and at week 108. The results of these measurements have yet to be analyzed.
Although patients in the fluoxetine group versus the placebo arm experienced more side effects, there was no evidence of an excess of severe adverse events.
“Unfortunately, our study was inconclusive because we failed to show a statistical significant difference between the placebo arm and the fluoxetine group, although I’m convinced that there’s a trend that can certainly not be ignored,” Dr. Cambron maintained. “Probably there was not enough progression in the study and possibly the study duration was too short, she suggested, “but it remains challenging to study these patients for a long period of time, especially with a placebo-controlled design.”
The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.
The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.
“The progressive phase of MS remains an ill-understood part of the disease and it is a holy grail to find a drug that can stop this progression,” Dr. Cambron said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The rationale for looking at whether fluoxetine, a well-studied antidepressant drug, could be such a drug, was that it had several neuroprotective features – it has been shown to stimulate the release of brain-derived neurotrophic factor, stimulate metabolism in astrocytes, and lower glutamatergic toxicity, she said. All of these could potentially help prevent axonal degeneration.
The FLUOX-PMS (Fluoxetine in Progressive Multiple Sclerosis) trial (Trials. 2014;15:37) ran from 2012 to June 2016 and enrolled patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), as defined by the 2010 McDonald criteria. A total of 137 patients were enrolled, and 69 were randomized to treatment with fluoxetine 40 mg/day and 68 were randomized to placebo. Fluoxetine treatment was started at a dose of 20 mg and titrated to the full 40-mg dose by 12 weeks.
Patient demographics were mostly similar between the groups. Around 44% of patients in the fluoxetine and placebo groups were female; roughly 40% had PPMS and 60% had SPMS in both groups; the mean Expanded Disability Status Scale score was 5.2 in both groups; the mean age was 54 and 51 years, respectively; and the disease duration was between 18 and 20 years.
Dr. Cambron also reported that the trials’ secondary endpoints showed no advantage of using fluoxetine over placebo. The proportion of patients without sustained progression during the trial was similar among the fluoxetine- and placebo-treated patients, at a respective 69.6% and 61.8% (P = .434). The proportion of patients with a stable Hauser Ambulation Index was also similar (P = .371).
The primary and secondary endpoints were assessed every 3 months in the trial. Patients also underwent cognitive testing, completed the Beck Depression Inventory-II, and Modified Fatigue Impact Scale before treatment and at 48 and 108 weeks after treatment with fluoxetine or placebo. Brain MRI was also performed at baseline and at week 108. The results of these measurements have yet to be analyzed.
Although patients in the fluoxetine group versus the placebo arm experienced more side effects, there was no evidence of an excess of severe adverse events.
“Unfortunately, our study was inconclusive because we failed to show a statistical significant difference between the placebo arm and the fluoxetine group, although I’m convinced that there’s a trend that can certainly not be ignored,” Dr. Cambron maintained. “Probably there was not enough progression in the study and possibly the study duration was too short, she suggested, “but it remains challenging to study these patients for a long period of time, especially with a placebo-controlled design.”
The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.
The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.
“The progressive phase of MS remains an ill-understood part of the disease and it is a holy grail to find a drug that can stop this progression,” Dr. Cambron said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The rationale for looking at whether fluoxetine, a well-studied antidepressant drug, could be such a drug, was that it had several neuroprotective features – it has been shown to stimulate the release of brain-derived neurotrophic factor, stimulate metabolism in astrocytes, and lower glutamatergic toxicity, she said. All of these could potentially help prevent axonal degeneration.
The FLUOX-PMS (Fluoxetine in Progressive Multiple Sclerosis) trial (Trials. 2014;15:37) ran from 2012 to June 2016 and enrolled patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), as defined by the 2010 McDonald criteria. A total of 137 patients were enrolled, and 69 were randomized to treatment with fluoxetine 40 mg/day and 68 were randomized to placebo. Fluoxetine treatment was started at a dose of 20 mg and titrated to the full 40-mg dose by 12 weeks.
Patient demographics were mostly similar between the groups. Around 44% of patients in the fluoxetine and placebo groups were female; roughly 40% had PPMS and 60% had SPMS in both groups; the mean Expanded Disability Status Scale score was 5.2 in both groups; the mean age was 54 and 51 years, respectively; and the disease duration was between 18 and 20 years.
Dr. Cambron also reported that the trials’ secondary endpoints showed no advantage of using fluoxetine over placebo. The proportion of patients without sustained progression during the trial was similar among the fluoxetine- and placebo-treated patients, at a respective 69.6% and 61.8% (P = .434). The proportion of patients with a stable Hauser Ambulation Index was also similar (P = .371).
The primary and secondary endpoints were assessed every 3 months in the trial. Patients also underwent cognitive testing, completed the Beck Depression Inventory-II, and Modified Fatigue Impact Scale before treatment and at 48 and 108 weeks after treatment with fluoxetine or placebo. Brain MRI was also performed at baseline and at week 108. The results of these measurements have yet to be analyzed.
Although patients in the fluoxetine group versus the placebo arm experienced more side effects, there was no evidence of an excess of severe adverse events.
“Unfortunately, our study was inconclusive because we failed to show a statistical significant difference between the placebo arm and the fluoxetine group, although I’m convinced that there’s a trend that can certainly not be ignored,” Dr. Cambron maintained. “Probably there was not enough progression in the study and possibly the study duration was too short, she suggested, “but it remains challenging to study these patients for a long period of time, especially with a placebo-controlled design.”
The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
Key clinical point:
Major finding: There was no difference in the time to confirmed disease progression between fluoxetine- and placebo-treated patients (P = .07).
Data source: FLUOX-PMS, a multicenter, randomized, double-blind, placebo-controlled clinical study of 137 patients with primary or secondary progressive multiple sclerosis treated with fluoxetine or placebo.
Disclosures: The trial was funded by IWT, the Government Agency for Innovation by Science and Technology in Flanders (Belgium). Dr. Cambron had no relevant financial disclosures.
Neuronal protein could be multiple sclerosis blood biomarker
LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.
“These findings support a role for neurofilament light chain (NfL) as a peripheral biomarker for MS,” said the reporting investigator Jens Kuhle, MD, of University Hospital Basel (Switzerland).
“There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials,” Dr. Kuhle said.
He added: “NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF [cerebral spinal fluid], and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that using an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623365).
In the current study, a Single Molecule Array Immunoassay (Quanterix) was used. This is based on an enzyme-linked immunoassay with more than 280,000 wells and developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood” when compared with conventional ELISA or electrochemiluminescence (Clin Chem Lab Med. 2016;54[10]:1655-61).
Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and these were compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.
Patients with two or more relapses in the past 24 months had significantly higher NfL levels than did those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.
Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at 6 months being highly predictive of brain volume changes at 24 months (P less than .0001).
And, in this preliminary dataset, patients who had been treated with fingolimod (Gilenya) versus placebo in the FREEDOMS trial had lower NfL levels at 6, 12, and 24 months.
Dr. Kuhle observed that the findings of this study were corroborated by other study data presented during the poster sessions at the ECTRIMS 2016 meeting.
The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.
“These findings support a role for neurofilament light chain (NfL) as a peripheral biomarker for MS,” said the reporting investigator Jens Kuhle, MD, of University Hospital Basel (Switzerland).
“There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials,” Dr. Kuhle said.
He added: “NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF [cerebral spinal fluid], and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that using an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623365).
In the current study, a Single Molecule Array Immunoassay (Quanterix) was used. This is based on an enzyme-linked immunoassay with more than 280,000 wells and developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood” when compared with conventional ELISA or electrochemiluminescence (Clin Chem Lab Med. 2016;54[10]:1655-61).
Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and these were compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.
Patients with two or more relapses in the past 24 months had significantly higher NfL levels than did those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.
Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at 6 months being highly predictive of brain volume changes at 24 months (P less than .0001).
And, in this preliminary dataset, patients who had been treated with fingolimod (Gilenya) versus placebo in the FREEDOMS trial had lower NfL levels at 6, 12, and 24 months.
Dr. Kuhle observed that the findings of this study were corroborated by other study data presented during the poster sessions at the ECTRIMS 2016 meeting.
The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.
“These findings support a role for neurofilament light chain (NfL) as a peripheral biomarker for MS,” said the reporting investigator Jens Kuhle, MD, of University Hospital Basel (Switzerland).
“There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials,” Dr. Kuhle said.
He added: “NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF [cerebral spinal fluid], and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis.
Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that using an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity (Mult Scler. 2016 Jan 11. doi: 10.1177/1352458515623365).
In the current study, a Single Molecule Array Immunoassay (Quanterix) was used. This is based on an enzyme-linked immunoassay with more than 280,000 wells and developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood” when compared with conventional ELISA or electrochemiluminescence (Clin Chem Lab Med. 2016;54[10]:1655-61).
Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and these were compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.
Patients with two or more relapses in the past 24 months had significantly higher NfL levels than did those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.
Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at 6 months being highly predictive of brain volume changes at 24 months (P less than .0001).
And, in this preliminary dataset, patients who had been treated with fingolimod (Gilenya) versus placebo in the FREEDOMS trial had lower NfL levels at 6, 12, and 24 months.
Dr. Kuhle observed that the findings of this study were corroborated by other study data presented during the poster sessions at the ECTRIMS 2016 meeting.
The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
Key clinical point:
Major finding: Blood NfL levels were significantly higher in MS patients than in healthy individuals (28.1 vs. 12.5 pg/mL; P less than .0001); NfL levels were also increased in patients with greater disease activity seen on MRI.
Data source: Proof-of-concept study involving blood samples taken from 149 patients with relapsing-remitting MS (RRMS) participating in the phase III FREEDOMS trial and 29 healthy individuals without MS from a separate biobank.
Disclosures: The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle disclosed receiving research support and consulting fees from Biogen, Novartis, and Protagen AG. He has also received speaker fees and travel expenses from Novartis and several other companies, and several of his coinvestigators were employees of Novartis.
Retinal Measurements Predict 10-Year Disability in MS
LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.
Measures of retinal layer thickness obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thickness, as assessed by OCT, predicts disability in MS 10 years later.
A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007. During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thickness at baseline predict EDSS score after 10 years.
The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean difference = 21.5 years and 11.7 years, respectively) and that patients with SPMS had a longer disease duration than patients with RRMS and PPMS (mean difference = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts. Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm3 lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.
—Glenn S. Williams
LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.
Measures of retinal layer thickness obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thickness, as assessed by OCT, predicts disability in MS 10 years later.
A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007. During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thickness at baseline predict EDSS score after 10 years.
The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean difference = 21.5 years and 11.7 years, respectively) and that patients with SPMS had a longer disease duration than patients with RRMS and PPMS (mean difference = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts. Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm3 lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.
—Glenn S. Williams
LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.
Measures of retinal layer thickness obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thickness, as assessed by OCT, predicts disability in MS 10 years later.
A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007. During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thickness at baseline predict EDSS score after 10 years.
The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean difference = 21.5 years and 11.7 years, respectively) and that patients with SPMS had a longer disease duration than patients with RRMS and PPMS (mean difference = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts. Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm3 lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.
—Glenn S. Williams
Can Neurologists Predict Long-Term Disability Trajectories in Primary Progressive MS?
LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.
Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.
Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.
A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS score of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS score of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS score of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).
“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”
LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.
Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.
Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.
A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS score of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS score of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS score of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).
“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”
LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.
Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.
Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.
A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS score of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS score of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS score of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).
“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”
Clinical Considerations of New and Pending MS Treatments
HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.
In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.
Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.
“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”
“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”
Daclizumab
Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.
The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.
In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.
In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.
Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.
Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”
Ocrelizumab
Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.
Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.
In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.
The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.
Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.
In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.
The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.
—Jake Remaly
HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.
In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.
Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.
“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”
“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”
Daclizumab
Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.
The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.
In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.
In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.
Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.
Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”
Ocrelizumab
Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.
Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.
In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.
The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.
Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.
In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.
The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.
—Jake Remaly
HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.
In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.
Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.
“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”
“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”
Daclizumab
Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.
The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.
In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.
In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.
Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.
Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”
Ocrelizumab
Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.
Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.
In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.
The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.
Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.
In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.
The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.
—Jake Remaly
What Distinguishes MS From Its Mimics?
HILTON HEAD—Multiple sclerosis (MS) is the most common demyelinating disease, and its mimics are rare, according to an overview provided at the 39th Annual Contemporary Clinical Neurology Symposium. Given that the treatments and outcomes for MS and its mimics are so different, neurologists should take care to establish a diagnosis early, said Sid Pawate, MD, Assistant Professor of Neurology at Vanderbilt University School of Medicine in Nashville.
Because of the varied clinical presentation of MS, a wide variety of conditions enter the differential diagnosis. Because of the central role that MRI plays in MS diagnosis, imaging mimics that cause white matter lesions also need to be considered, said Dr. Pawate. Typically, the white matter lesions seen in MS are periventricular, juxtacortical, and callososeptal in location. Infratentorially, cerebellar peduncles are a common site. The lesions tend to be ovoid, are 3 mm to 5 mm or larger, and appear hyperintense on T2 and FLAIR sequences. Acute lesions may show restricted diffusion or enhancement after the administration of gadolinium contrast.
Typical Presentations of MS
The three most common presentations of MS are transverse myelitis, optic neuritis, and brainstem–cerebellar dysfunction. Acute partial transverse myelitis is “the most classic” form of transverse myelitis among patients with MS, said Dr. Pawate. Acute complete transverse myelitis, on the other hand, may be postinfectious or idiopathic, or seen as part of acute disseminated encephalomyelitis (ADEM). Similarly, longitudinally extensive transverse myelitis is more suggestive of neuromyelitis optica spectrum disorders (NMOSD) than MS.
The most typical presentation of MS optic neuritis is unilateral and has acute or subacute onset. Patients often have retrobulbar, “gritty” pain when they move their eye. Complete blindness is unusual, and complete recovery occurs in nearly all patients. Hyperacute onset suggests a vascular process rather than optic neuritis, said Dr. Pawate. Slow, insidious onset may indicate an infiltrative process such as neoplasm or sarcoidosis. Painless vision loss may indicate ischemic optic neuropathy, and severe blindness without recovery may result from NMOSD.
The most pathognomonic brainstem dysfunction in MS is intranuclear ophthalmoplegia (INO), especially when it is bilateral. Other brainstem symptoms typical of MS include ataxia, painless diplopia, facial numbness, and trigeminal neuralgia in a young patient. Hyperacute or insidious onset of brainstem symptoms is unlikely to indicate MS. Symptoms that localize to a vascular territory usually result from a stroke. In addition, multiple cranial neuropathy is more suggestive of infections such as Lyme disease, sarcoidosis, or carcinomic ulcers.
Unusual Presentations of MS
Certain variants of MS do not present with the typical periventricular ovoid lesions. Tumefactive MS often presents with a large (ie, larger than 2 cm), solitary demyelinating lesion. These lesions usually are biopsied. Treatment with steroids usually brings improvement. After this first manifestation, the patient’s course is typical of relapsing-remitting MS. “Rarely do patients have tumefactive lesions in the middle of their MS course,” said Dr. Pawate.
Another unusual presentation is concentric rings of demyelination, sometimes with mass effect. This variant is called Balo’s concentric sclerosis, and the patient may have typical MS lesions in addition to the rings. “Historically, Balo’s concentric sclerosis was thought to be a severe disease with a poor prognosis,” said Dr. Pawate. “With the advent of MRI, we know that these [rings] are more common than we initially thought, and more benign—not much different from any other MS lesions.”
Patients also may present with multiple large lesions and aggressive disease onset. Such patients need early treatment. “When I see something like this, I treat aggressively using plasma exchange and IV steroids,” said Dr. Pawate. This treatment may be followed by natalizumab infusions, and the patients may make a good recovery. “Historically, this aggressive MS onset was called Marburg variant and was fatal,” said Dr. Pawate.
MS Mimics
ADEM is more common in children than in adults, and imaging can distinguish it from MS. One distinguishing feature of ADEM is that the patient has many lesions that appear to be of the same age. Lesions may appear on the basal ganglia and the thalamus, which is atypical for MS. Spinal cord lesions tend to be longer in ADEM, compared with those in MS. ADEM tends to have a monophasic course, and patients usually present with encephalopathy, headaches, and vomiting. Patients often have a history of preceding vaccination or infection.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) also can mimic MS on MRI. What distinguishes it from MS are lacunar infarcts, involvement in sites like the thalamus and basal ganglia, and gray matter involvement. CADASIL affects middle-aged adults and leads to disability and dementia.
If a patient referred for suspected MS has bilaterally symmetric confluent lesions, “think more in terms of leukodystrophies,” said Dr. Pawate. The absence of gadolinium enhancement is typical in leukodystrophies. The disorders may involve the U-fibers, the brainstem, or the cerebellum, and patients may present with cognitive decline.
Susac’s syndrome is a triad of branch retinal artery occlusion, sensorineural hearing loss, and encephalopathy. The syndrome is associated with a characteristic MRI that includes “spokes” (ie, linear lesions) and “snowballs” (ie, globular lesions) in the corpus callosum, as well as a “string of pearls” (ie, microinfarcts) in the internal capsule. In the eye, the most pathognomonic finding is hyperfluorescence of the arterial wall on fluorescein angiogram. Early treatment can produce good outcomes, but missing the diagnosis may quickly result in dementia, vision loss, and hearing loss.
Lupus can cause CNS manifestations, including cerebritis, vasculitis, and myelitis. “Primary CNS vasculitis can mimic MS on MRI sometimes, but the red flags are that the patient may have headache and infarcts on MRI, which are not seen in MS,” said Dr. Pawate. The white matter lesions in neurosarcoidosis can be similar to those in MS, but neurosarcoidosis also causes leptomeningeal enhancement and cranial nerve enhancement, which are not seen in MS.
—Erik Greb
Suggested Reading
Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15(6):319-328.
Kleinfeld K, Mobley B, Hedera P, et al. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013;260(2):558-571.
Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac’s syndrome. Neurol Sci. 2009;30(1):59-64.
HILTON HEAD—Multiple sclerosis (MS) is the most common demyelinating disease, and its mimics are rare, according to an overview provided at the 39th Annual Contemporary Clinical Neurology Symposium. Given that the treatments and outcomes for MS and its mimics are so different, neurologists should take care to establish a diagnosis early, said Sid Pawate, MD, Assistant Professor of Neurology at Vanderbilt University School of Medicine in Nashville.
Because of the varied clinical presentation of MS, a wide variety of conditions enter the differential diagnosis. Because of the central role that MRI plays in MS diagnosis, imaging mimics that cause white matter lesions also need to be considered, said Dr. Pawate. Typically, the white matter lesions seen in MS are periventricular, juxtacortical, and callososeptal in location. Infratentorially, cerebellar peduncles are a common site. The lesions tend to be ovoid, are 3 mm to 5 mm or larger, and appear hyperintense on T2 and FLAIR sequences. Acute lesions may show restricted diffusion or enhancement after the administration of gadolinium contrast.
Typical Presentations of MS
The three most common presentations of MS are transverse myelitis, optic neuritis, and brainstem–cerebellar dysfunction. Acute partial transverse myelitis is “the most classic” form of transverse myelitis among patients with MS, said Dr. Pawate. Acute complete transverse myelitis, on the other hand, may be postinfectious or idiopathic, or seen as part of acute disseminated encephalomyelitis (ADEM). Similarly, longitudinally extensive transverse myelitis is more suggestive of neuromyelitis optica spectrum disorders (NMOSD) than MS.
The most typical presentation of MS optic neuritis is unilateral and has acute or subacute onset. Patients often have retrobulbar, “gritty” pain when they move their eye. Complete blindness is unusual, and complete recovery occurs in nearly all patients. Hyperacute onset suggests a vascular process rather than optic neuritis, said Dr. Pawate. Slow, insidious onset may indicate an infiltrative process such as neoplasm or sarcoidosis. Painless vision loss may indicate ischemic optic neuropathy, and severe blindness without recovery may result from NMOSD.
The most pathognomonic brainstem dysfunction in MS is intranuclear ophthalmoplegia (INO), especially when it is bilateral. Other brainstem symptoms typical of MS include ataxia, painless diplopia, facial numbness, and trigeminal neuralgia in a young patient. Hyperacute or insidious onset of brainstem symptoms is unlikely to indicate MS. Symptoms that localize to a vascular territory usually result from a stroke. In addition, multiple cranial neuropathy is more suggestive of infections such as Lyme disease, sarcoidosis, or carcinomic ulcers.
Unusual Presentations of MS
Certain variants of MS do not present with the typical periventricular ovoid lesions. Tumefactive MS often presents with a large (ie, larger than 2 cm), solitary demyelinating lesion. These lesions usually are biopsied. Treatment with steroids usually brings improvement. After this first manifestation, the patient’s course is typical of relapsing-remitting MS. “Rarely do patients have tumefactive lesions in the middle of their MS course,” said Dr. Pawate.
Another unusual presentation is concentric rings of demyelination, sometimes with mass effect. This variant is called Balo’s concentric sclerosis, and the patient may have typical MS lesions in addition to the rings. “Historically, Balo’s concentric sclerosis was thought to be a severe disease with a poor prognosis,” said Dr. Pawate. “With the advent of MRI, we know that these [rings] are more common than we initially thought, and more benign—not much different from any other MS lesions.”
Patients also may present with multiple large lesions and aggressive disease onset. Such patients need early treatment. “When I see something like this, I treat aggressively using plasma exchange and IV steroids,” said Dr. Pawate. This treatment may be followed by natalizumab infusions, and the patients may make a good recovery. “Historically, this aggressive MS onset was called Marburg variant and was fatal,” said Dr. Pawate.
MS Mimics
ADEM is more common in children than in adults, and imaging can distinguish it from MS. One distinguishing feature of ADEM is that the patient has many lesions that appear to be of the same age. Lesions may appear on the basal ganglia and the thalamus, which is atypical for MS. Spinal cord lesions tend to be longer in ADEM, compared with those in MS. ADEM tends to have a monophasic course, and patients usually present with encephalopathy, headaches, and vomiting. Patients often have a history of preceding vaccination or infection.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) also can mimic MS on MRI. What distinguishes it from MS are lacunar infarcts, involvement in sites like the thalamus and basal ganglia, and gray matter involvement. CADASIL affects middle-aged adults and leads to disability and dementia.
If a patient referred for suspected MS has bilaterally symmetric confluent lesions, “think more in terms of leukodystrophies,” said Dr. Pawate. The absence of gadolinium enhancement is typical in leukodystrophies. The disorders may involve the U-fibers, the brainstem, or the cerebellum, and patients may present with cognitive decline.
Susac’s syndrome is a triad of branch retinal artery occlusion, sensorineural hearing loss, and encephalopathy. The syndrome is associated with a characteristic MRI that includes “spokes” (ie, linear lesions) and “snowballs” (ie, globular lesions) in the corpus callosum, as well as a “string of pearls” (ie, microinfarcts) in the internal capsule. In the eye, the most pathognomonic finding is hyperfluorescence of the arterial wall on fluorescein angiogram. Early treatment can produce good outcomes, but missing the diagnosis may quickly result in dementia, vision loss, and hearing loss.
Lupus can cause CNS manifestations, including cerebritis, vasculitis, and myelitis. “Primary CNS vasculitis can mimic MS on MRI sometimes, but the red flags are that the patient may have headache and infarcts on MRI, which are not seen in MS,” said Dr. Pawate. The white matter lesions in neurosarcoidosis can be similar to those in MS, but neurosarcoidosis also causes leptomeningeal enhancement and cranial nerve enhancement, which are not seen in MS.
—Erik Greb
Suggested Reading
Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15(6):319-328.
Kleinfeld K, Mobley B, Hedera P, et al. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013;260(2):558-571.
Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac’s syndrome. Neurol Sci. 2009;30(1):59-64.
HILTON HEAD—Multiple sclerosis (MS) is the most common demyelinating disease, and its mimics are rare, according to an overview provided at the 39th Annual Contemporary Clinical Neurology Symposium. Given that the treatments and outcomes for MS and its mimics are so different, neurologists should take care to establish a diagnosis early, said Sid Pawate, MD, Assistant Professor of Neurology at Vanderbilt University School of Medicine in Nashville.
Because of the varied clinical presentation of MS, a wide variety of conditions enter the differential diagnosis. Because of the central role that MRI plays in MS diagnosis, imaging mimics that cause white matter lesions also need to be considered, said Dr. Pawate. Typically, the white matter lesions seen in MS are periventricular, juxtacortical, and callososeptal in location. Infratentorially, cerebellar peduncles are a common site. The lesions tend to be ovoid, are 3 mm to 5 mm or larger, and appear hyperintense on T2 and FLAIR sequences. Acute lesions may show restricted diffusion or enhancement after the administration of gadolinium contrast.
Typical Presentations of MS
The three most common presentations of MS are transverse myelitis, optic neuritis, and brainstem–cerebellar dysfunction. Acute partial transverse myelitis is “the most classic” form of transverse myelitis among patients with MS, said Dr. Pawate. Acute complete transverse myelitis, on the other hand, may be postinfectious or idiopathic, or seen as part of acute disseminated encephalomyelitis (ADEM). Similarly, longitudinally extensive transverse myelitis is more suggestive of neuromyelitis optica spectrum disorders (NMOSD) than MS.
The most typical presentation of MS optic neuritis is unilateral and has acute or subacute onset. Patients often have retrobulbar, “gritty” pain when they move their eye. Complete blindness is unusual, and complete recovery occurs in nearly all patients. Hyperacute onset suggests a vascular process rather than optic neuritis, said Dr. Pawate. Slow, insidious onset may indicate an infiltrative process such as neoplasm or sarcoidosis. Painless vision loss may indicate ischemic optic neuropathy, and severe blindness without recovery may result from NMOSD.
The most pathognomonic brainstem dysfunction in MS is intranuclear ophthalmoplegia (INO), especially when it is bilateral. Other brainstem symptoms typical of MS include ataxia, painless diplopia, facial numbness, and trigeminal neuralgia in a young patient. Hyperacute or insidious onset of brainstem symptoms is unlikely to indicate MS. Symptoms that localize to a vascular territory usually result from a stroke. In addition, multiple cranial neuropathy is more suggestive of infections such as Lyme disease, sarcoidosis, or carcinomic ulcers.
Unusual Presentations of MS
Certain variants of MS do not present with the typical periventricular ovoid lesions. Tumefactive MS often presents with a large (ie, larger than 2 cm), solitary demyelinating lesion. These lesions usually are biopsied. Treatment with steroids usually brings improvement. After this first manifestation, the patient’s course is typical of relapsing-remitting MS. “Rarely do patients have tumefactive lesions in the middle of their MS course,” said Dr. Pawate.
Another unusual presentation is concentric rings of demyelination, sometimes with mass effect. This variant is called Balo’s concentric sclerosis, and the patient may have typical MS lesions in addition to the rings. “Historically, Balo’s concentric sclerosis was thought to be a severe disease with a poor prognosis,” said Dr. Pawate. “With the advent of MRI, we know that these [rings] are more common than we initially thought, and more benign—not much different from any other MS lesions.”
Patients also may present with multiple large lesions and aggressive disease onset. Such patients need early treatment. “When I see something like this, I treat aggressively using plasma exchange and IV steroids,” said Dr. Pawate. This treatment may be followed by natalizumab infusions, and the patients may make a good recovery. “Historically, this aggressive MS onset was called Marburg variant and was fatal,” said Dr. Pawate.
MS Mimics
ADEM is more common in children than in adults, and imaging can distinguish it from MS. One distinguishing feature of ADEM is that the patient has many lesions that appear to be of the same age. Lesions may appear on the basal ganglia and the thalamus, which is atypical for MS. Spinal cord lesions tend to be longer in ADEM, compared with those in MS. ADEM tends to have a monophasic course, and patients usually present with encephalopathy, headaches, and vomiting. Patients often have a history of preceding vaccination or infection.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) also can mimic MS on MRI. What distinguishes it from MS are lacunar infarcts, involvement in sites like the thalamus and basal ganglia, and gray matter involvement. CADASIL affects middle-aged adults and leads to disability and dementia.
If a patient referred for suspected MS has bilaterally symmetric confluent lesions, “think more in terms of leukodystrophies,” said Dr. Pawate. The absence of gadolinium enhancement is typical in leukodystrophies. The disorders may involve the U-fibers, the brainstem, or the cerebellum, and patients may present with cognitive decline.
Susac’s syndrome is a triad of branch retinal artery occlusion, sensorineural hearing loss, and encephalopathy. The syndrome is associated with a characteristic MRI that includes “spokes” (ie, linear lesions) and “snowballs” (ie, globular lesions) in the corpus callosum, as well as a “string of pearls” (ie, microinfarcts) in the internal capsule. In the eye, the most pathognomonic finding is hyperfluorescence of the arterial wall on fluorescein angiogram. Early treatment can produce good outcomes, but missing the diagnosis may quickly result in dementia, vision loss, and hearing loss.
Lupus can cause CNS manifestations, including cerebritis, vasculitis, and myelitis. “Primary CNS vasculitis can mimic MS on MRI sometimes, but the red flags are that the patient may have headache and infarcts on MRI, which are not seen in MS,” said Dr. Pawate. The white matter lesions in neurosarcoidosis can be similar to those in MS, but neurosarcoidosis also causes leptomeningeal enhancement and cranial nerve enhancement, which are not seen in MS.
—Erik Greb
Suggested Reading
Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15(6):319-328.
Kleinfeld K, Mobley B, Hedera P, et al. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013;260(2):558-571.
Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac’s syndrome. Neurol Sci. 2009;30(1):59-64.
Alemtuzumab, natalizumab found equally effective for relapsing-remitting MS
LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.
“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.
Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.
Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.
Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.
Versus interferon beta-1a
The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.
In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.
Versus fingolimod
The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.
“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.
Versus natalizumab
The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.
Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.
A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.
Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.
Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.
“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.
Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.
Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.
Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.
Versus interferon beta-1a
The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.
In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.
Versus fingolimod
The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.
“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.
Versus natalizumab
The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.
Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.
A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.
Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.
Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.
“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.
Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.
Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.
Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.
Versus interferon beta-1a
The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.
In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.
Versus fingolimod
The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.
“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.
Versus natalizumab
The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.
Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.
A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.
Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.
Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
AT ECTRIMS 2016
Key clinical point:Alemtuzumab and natalizumab are similarly effective at preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.
Major finding: The annualized relapse rates comparing alemtuzumab with natalizumab, interferon beta-1a, and fingolimod were 0.2 and 0.2 (P = .8), 0.2 and 0.5 (P less than .001), and 0.15 and 0.30 (P less than .001).
Data source: Retrospective, propensity-matched analysis of prospectively collected observational data of more than 4,000 patients with RRMS treated with alemtuzumab (n = 189), natalizumab (n = 1,160), interferon beta-1a (n = 2,155), or fingolimod (n = 828).
Disclosures: Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.
Ocrelizumab Increases Likelihood of No Evidence of Disease Progression
Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.
Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20+ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.
Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.
In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.
Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.
The study was sponsored by F. Hoffmann-La Roche.
Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.
Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20+ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.
Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.
In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.
Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.
The study was sponsored by F. Hoffmann-La Roche.
Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.
Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20+ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.
Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.
In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.
Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.
The study was sponsored by F. Hoffmann-La Roche.