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Average daily step count reflects disability in MS
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.
Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.
The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.
In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.
Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).
As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.
Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.
Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.
SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.
Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.
The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.
In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.
Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).
As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.
Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.
Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.
SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.
Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.
The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.
In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.
Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).
As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.
Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.
Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.
SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.
REPORTING FROM ECTRIMS 2019
In highly active MS, is skipping gadolinium an option?
STOCKHOLM – Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.
“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.
The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.
For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.
The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.
The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.
In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.
Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”
In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.
The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.
Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.
Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.
SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.
STOCKHOLM – Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.
“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.
The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.
For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.
The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.
The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.
In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.
Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”
In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.
The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.
Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.
Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.
SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.
STOCKHOLM – Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.
“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.
The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.
For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.
The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.
The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.
In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.
Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”
In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.
The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.
Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.
Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.
SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.
REPORTING FROM ECTRIMS 2019
Most patients with RIS develop MS within 10 years
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
STOCKHOLM – Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.
The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.
Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).
The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).
Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.
RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.
Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.
The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.
Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.
“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.
Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.
REPORTING FROM ECTRIMS 2019
In MS, iron-ringed lesions may add to imaging toolkit
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.
“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”
Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”
It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.
The cross-sectional, single-center study enrolled patients with clinically isolated syndrome (CIS), MS, and conditions which can mimic MS on MRI. Dr. Clarke and her coinvestigators looked at the frequency of lesions with the central vein sign, and with iron rings, in all patients.
An additional aim of the study was to compare how experienced and inexperienced raters fared in their identification of both central veins and iron rings in 25 scans randomly chosen from within the study population. Inter-rater reliability between experienced and inexperienced raters was assessed as good, with little difference between experience levels in detecting iron rings and central veins, said Dr. Clarke.
Criteria used for central vein determination were those established by the North American Imaging in MS initiative, said Dr. Clarke: The vein needs to be seen entering and/or exiting the lesion, and the vein must course through the lesion’s center. If lesions are confluent, each of the larger lesion’s “fingers” must be assessed individually.
Iron rings appear as a hypointense area rimming the lesion’s edge; for the study, an iron ring was considered present if it could be seen fully or partially encircling a lesion, and if the ring was visible on at least two slices.
The study enrolled 103 patients with relapsing-remitting MS, 49 with progressive MS, 112 with CIS, and 35 non-MS patients; about 60% of this latter group had either autoimmune or vascular disease.
The fewest white matter lesions – a median of 4 per patient - were seen in the CIS group, while the progressive MS and non-MS group each had a median of 7 lesions, and the relapsing-remitting MS group had a median of 10 lesions.
In all, 2,617 lesions were analyzed, and 1,352 were assessed as having the central vein sign. Patients with MS or CIS had central vein sign in more than 50% of their lesions, while the non-MS patients had fewer than 20% central vein–positive lesions. In CIS and MS patients, central vein–positive lesions occurred more frequently in the periventricular and subcortical regions, compared with other brain regions (P less than .001).
Iron rings were detected in 392 lesions; none of the non-MS patients had iron ring–positive lesions. In terms of the brain regions where iron rings were most likely to be seen, said Dr. Clarke, “Over half of all iron ring-positive lesions were periventricular.” This finding was statistically significant as well (P less than .001). At least one lesion with an iron ring was seen in 59% of relapsing-remitting MS patients, 39% of progressive MS patients, and 48% of CIS patients.
In terms of patient characteristics, men were 40% more likely to have iron ring–positive lesions, and patients with relapsing-remitting MS were 50% more likely than were patients with CIS to have iron rings. Iron rings became 3% less likely for each additional year of age, as well (P less than .01 for all comparisons).
“Our results show that iron ring numbers peak in relapsing-remitting MS and decrease with longer disease duration,” Dr. Clarke and colleagues reported.
Dr. Clarke acknowledged several limitations of the study, including its single-center and retrospective nature, as well as the relatively low numbers of non-MS patients and patients with progressive MS. She and her colleagues are planning larger studies using 5-year follow-up data, she said.
Dr. Clarke is an ECTRIMS-MAGNIMS fellow and reported a speaker honorarium from Novartis.
SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.
“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”
Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”
It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.
The cross-sectional, single-center study enrolled patients with clinically isolated syndrome (CIS), MS, and conditions which can mimic MS on MRI. Dr. Clarke and her coinvestigators looked at the frequency of lesions with the central vein sign, and with iron rings, in all patients.
An additional aim of the study was to compare how experienced and inexperienced raters fared in their identification of both central veins and iron rings in 25 scans randomly chosen from within the study population. Inter-rater reliability between experienced and inexperienced raters was assessed as good, with little difference between experience levels in detecting iron rings and central veins, said Dr. Clarke.
Criteria used for central vein determination were those established by the North American Imaging in MS initiative, said Dr. Clarke: The vein needs to be seen entering and/or exiting the lesion, and the vein must course through the lesion’s center. If lesions are confluent, each of the larger lesion’s “fingers” must be assessed individually.
Iron rings appear as a hypointense area rimming the lesion’s edge; for the study, an iron ring was considered present if it could be seen fully or partially encircling a lesion, and if the ring was visible on at least two slices.
The study enrolled 103 patients with relapsing-remitting MS, 49 with progressive MS, 112 with CIS, and 35 non-MS patients; about 60% of this latter group had either autoimmune or vascular disease.
The fewest white matter lesions – a median of 4 per patient - were seen in the CIS group, while the progressive MS and non-MS group each had a median of 7 lesions, and the relapsing-remitting MS group had a median of 10 lesions.
In all, 2,617 lesions were analyzed, and 1,352 were assessed as having the central vein sign. Patients with MS or CIS had central vein sign in more than 50% of their lesions, while the non-MS patients had fewer than 20% central vein–positive lesions. In CIS and MS patients, central vein–positive lesions occurred more frequently in the periventricular and subcortical regions, compared with other brain regions (P less than .001).
Iron rings were detected in 392 lesions; none of the non-MS patients had iron ring–positive lesions. In terms of the brain regions where iron rings were most likely to be seen, said Dr. Clarke, “Over half of all iron ring-positive lesions were periventricular.” This finding was statistically significant as well (P less than .001). At least one lesion with an iron ring was seen in 59% of relapsing-remitting MS patients, 39% of progressive MS patients, and 48% of CIS patients.
In terms of patient characteristics, men were 40% more likely to have iron ring–positive lesions, and patients with relapsing-remitting MS were 50% more likely than were patients with CIS to have iron rings. Iron rings became 3% less likely for each additional year of age, as well (P less than .01 for all comparisons).
“Our results show that iron ring numbers peak in relapsing-remitting MS and decrease with longer disease duration,” Dr. Clarke and colleagues reported.
Dr. Clarke acknowledged several limitations of the study, including its single-center and retrospective nature, as well as the relatively low numbers of non-MS patients and patients with progressive MS. She and her colleagues are planning larger studies using 5-year follow-up data, she said.
Dr. Clarke is an ECTRIMS-MAGNIMS fellow and reported a speaker honorarium from Novartis.
SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.
“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”
Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”
It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.
The cross-sectional, single-center study enrolled patients with clinically isolated syndrome (CIS), MS, and conditions which can mimic MS on MRI. Dr. Clarke and her coinvestigators looked at the frequency of lesions with the central vein sign, and with iron rings, in all patients.
An additional aim of the study was to compare how experienced and inexperienced raters fared in their identification of both central veins and iron rings in 25 scans randomly chosen from within the study population. Inter-rater reliability between experienced and inexperienced raters was assessed as good, with little difference between experience levels in detecting iron rings and central veins, said Dr. Clarke.
Criteria used for central vein determination were those established by the North American Imaging in MS initiative, said Dr. Clarke: The vein needs to be seen entering and/or exiting the lesion, and the vein must course through the lesion’s center. If lesions are confluent, each of the larger lesion’s “fingers” must be assessed individually.
Iron rings appear as a hypointense area rimming the lesion’s edge; for the study, an iron ring was considered present if it could be seen fully or partially encircling a lesion, and if the ring was visible on at least two slices.
The study enrolled 103 patients with relapsing-remitting MS, 49 with progressive MS, 112 with CIS, and 35 non-MS patients; about 60% of this latter group had either autoimmune or vascular disease.
The fewest white matter lesions – a median of 4 per patient - were seen in the CIS group, while the progressive MS and non-MS group each had a median of 7 lesions, and the relapsing-remitting MS group had a median of 10 lesions.
In all, 2,617 lesions were analyzed, and 1,352 were assessed as having the central vein sign. Patients with MS or CIS had central vein sign in more than 50% of their lesions, while the non-MS patients had fewer than 20% central vein–positive lesions. In CIS and MS patients, central vein–positive lesions occurred more frequently in the periventricular and subcortical regions, compared with other brain regions (P less than .001).
Iron rings were detected in 392 lesions; none of the non-MS patients had iron ring–positive lesions. In terms of the brain regions where iron rings were most likely to be seen, said Dr. Clarke, “Over half of all iron ring-positive lesions were periventricular.” This finding was statistically significant as well (P less than .001). At least one lesion with an iron ring was seen in 59% of relapsing-remitting MS patients, 39% of progressive MS patients, and 48% of CIS patients.
In terms of patient characteristics, men were 40% more likely to have iron ring–positive lesions, and patients with relapsing-remitting MS were 50% more likely than were patients with CIS to have iron rings. Iron rings became 3% less likely for each additional year of age, as well (P less than .01 for all comparisons).
“Our results show that iron ring numbers peak in relapsing-remitting MS and decrease with longer disease duration,” Dr. Clarke and colleagues reported.
Dr. Clarke acknowledged several limitations of the study, including its single-center and retrospective nature, as well as the relatively low numbers of non-MS patients and patients with progressive MS. She and her colleagues are planning larger studies using 5-year follow-up data, she said.
Dr. Clarke is an ECTRIMS-MAGNIMS fellow and reported a speaker honorarium from Novartis.
SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.
REPORTING FROM ECTRIMS 2019
Ponesimod reduces annualized relapse rate, compared with teriflunomide
STOCKHOLM – according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.
Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.
Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.
The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.
Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.
At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.
The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.
This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.
The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.
SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.
STOCKHOLM – according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.
Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.
Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.
The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.
Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.
At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.
The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.
This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.
The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.
SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.
STOCKHOLM – according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.
Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.
Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.
The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.
Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.
At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.
The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.
This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.
The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.
SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.
REPORTING FROM ECTRIMS 2019
Key clinical point: Ponesimod reduces the number of confirmed MS relapses, compared with teriflunomide.
Major finding: Annualized relapse rate was 30.5% lower with ponesimod, compared with teriflunomide.
Study details: A randomized, double-blind, superiority study of 1,133 patients with relapsing-remitting MS.
Disclosures: Actelion Pharmaceuticals sponsored the study.
Source: Kappos L et al. ECTRIMS 2019, Abstract 93.
Continuous treatment reduces risk of confirmed disability progression in MS
STOCKHOLM – (CDP), according to an investigation presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using several confirmation points for Expanded Disability Status Scale (EDSS) progression (e.g., 12 months and 24 months), researchers detected a clear gradient of treatment effect. Identification of the most reliable outcome definitions will require further investigations, they said.
“The ultimate goal of MS treatment is the prevention of long-term disability accumulation,” said Giuseppe Lucisano, a biostatistician at the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy. “Continuous DMT exposure can impact long-term disability accumulation in MS, but it has not been definitively demonstrated yet.”
Registries and clinical databases provide the opportunity to collect longitudinal data for treated and untreated patients as a means of investigating questions such as this one, the researchers said. The Danish, Italian, and Swedish national MS registries, MSBase, and the Observatoire of MS (OFSEP) merged their data in the Big Multiple Sclerosis Data (BMSD) Network, which includes approximately 150,000 patients and more than 470,000 EDSS evaluations. The result is a large dataset suitable for long-term longitudinal studies.
Mr. Lucisano and colleagues sought to examine the long-term effect of DMTs on CDP and irreversible disability milestones (i.e., EDSS scores of 4 and 6) in relapsing-remitting MS. The researchers used marginal structural proportional models, a novel technique that enables them to correct modeling for confounders that vary with time in longitudinal observational studies. Such confounders include treatment switches, on-treatment relapses, and treatment gaps.
The investigators selected patients with 10 or more years’ follow-up and one or more EDSS score evaluations per year from the BMSD pooled cohort. Using marginal structural proportional models, the investigators evaluated cumulative hazards of 3-, 12- and 24-month CDP (i.e., CDP3, CDP12, CDP24) events in 6-month periods. They created stabilized inverse probability of treatment weights (IPTWs) at each 6-month period using survival models according to treatment status (i.e., treated versus untreated). Treatment status was assigned for each patient according to the percentage of time that he or she spent receiving DMT in each 6-month period. A patient who received treatment for 70% or more of the period studied was considered treated; patients who did not meet this threshold were considered untreated. The weights were calculated on the basis of sex, age, occurrence of relapse, EDSS score, and registry source. Finally, the researchers used Cox regression models estimating the effect of DMTs on the risk of reaching CDP3, CDP12, and CDP24, adjusted by the IPTWs, to compare cohorts that remained treated or untreated throughout follow-up.
The investigators identified a cohort of 15,602 patients with relapsing-remitting MS, and this group had 312,040 EDSS score evaluations. Approximately 28% of patients were male. Median age at disease onset was 28.3 years, and median disease duration was 18.7 years. Median follow-up duration was 13.8 years.
During follow-up, 43.3% of patients had CDP3, 27.7% had CDP12, and 14.4% had CDP24 events. In addition, 23.6% of patients reached an EDSS score of 4, and 11.2% reached an EDSS score of 6.
Cox models adjusted by IPTW demonstrated increasing positive evidence of the effect of cumulative treatment exposure, compared with cumulative untreated epochs, according to the length of confirmation time used for defining the CDP. The investigators did not observe an effect of treatment on the probability of reaching CDP3 (hazard ratio [HR], 1.02), but treatment had a protective effect on CDP12 (HR, 0.90) and CDP24 (HR, 0.65) endpoints. During treated epochs, the HR of EDSS 4 was 0.89, and the HR of EDSS 6 was 0.86. Sensitivity analyses largely confirmed the results of the main analysis.
Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
STOCKHOLM – (CDP), according to an investigation presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using several confirmation points for Expanded Disability Status Scale (EDSS) progression (e.g., 12 months and 24 months), researchers detected a clear gradient of treatment effect. Identification of the most reliable outcome definitions will require further investigations, they said.
“The ultimate goal of MS treatment is the prevention of long-term disability accumulation,” said Giuseppe Lucisano, a biostatistician at the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy. “Continuous DMT exposure can impact long-term disability accumulation in MS, but it has not been definitively demonstrated yet.”
Registries and clinical databases provide the opportunity to collect longitudinal data for treated and untreated patients as a means of investigating questions such as this one, the researchers said. The Danish, Italian, and Swedish national MS registries, MSBase, and the Observatoire of MS (OFSEP) merged their data in the Big Multiple Sclerosis Data (BMSD) Network, which includes approximately 150,000 patients and more than 470,000 EDSS evaluations. The result is a large dataset suitable for long-term longitudinal studies.
Mr. Lucisano and colleagues sought to examine the long-term effect of DMTs on CDP and irreversible disability milestones (i.e., EDSS scores of 4 and 6) in relapsing-remitting MS. The researchers used marginal structural proportional models, a novel technique that enables them to correct modeling for confounders that vary with time in longitudinal observational studies. Such confounders include treatment switches, on-treatment relapses, and treatment gaps.
The investigators selected patients with 10 or more years’ follow-up and one or more EDSS score evaluations per year from the BMSD pooled cohort. Using marginal structural proportional models, the investigators evaluated cumulative hazards of 3-, 12- and 24-month CDP (i.e., CDP3, CDP12, CDP24) events in 6-month periods. They created stabilized inverse probability of treatment weights (IPTWs) at each 6-month period using survival models according to treatment status (i.e., treated versus untreated). Treatment status was assigned for each patient according to the percentage of time that he or she spent receiving DMT in each 6-month period. A patient who received treatment for 70% or more of the period studied was considered treated; patients who did not meet this threshold were considered untreated. The weights were calculated on the basis of sex, age, occurrence of relapse, EDSS score, and registry source. Finally, the researchers used Cox regression models estimating the effect of DMTs on the risk of reaching CDP3, CDP12, and CDP24, adjusted by the IPTWs, to compare cohorts that remained treated or untreated throughout follow-up.
The investigators identified a cohort of 15,602 patients with relapsing-remitting MS, and this group had 312,040 EDSS score evaluations. Approximately 28% of patients were male. Median age at disease onset was 28.3 years, and median disease duration was 18.7 years. Median follow-up duration was 13.8 years.
During follow-up, 43.3% of patients had CDP3, 27.7% had CDP12, and 14.4% had CDP24 events. In addition, 23.6% of patients reached an EDSS score of 4, and 11.2% reached an EDSS score of 6.
Cox models adjusted by IPTW demonstrated increasing positive evidence of the effect of cumulative treatment exposure, compared with cumulative untreated epochs, according to the length of confirmation time used for defining the CDP. The investigators did not observe an effect of treatment on the probability of reaching CDP3 (hazard ratio [HR], 1.02), but treatment had a protective effect on CDP12 (HR, 0.90) and CDP24 (HR, 0.65) endpoints. During treated epochs, the HR of EDSS 4 was 0.89, and the HR of EDSS 6 was 0.86. Sensitivity analyses largely confirmed the results of the main analysis.
Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
STOCKHOLM – (CDP), according to an investigation presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Using several confirmation points for Expanded Disability Status Scale (EDSS) progression (e.g., 12 months and 24 months), researchers detected a clear gradient of treatment effect. Identification of the most reliable outcome definitions will require further investigations, they said.
“The ultimate goal of MS treatment is the prevention of long-term disability accumulation,” said Giuseppe Lucisano, a biostatistician at the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy. “Continuous DMT exposure can impact long-term disability accumulation in MS, but it has not been definitively demonstrated yet.”
Registries and clinical databases provide the opportunity to collect longitudinal data for treated and untreated patients as a means of investigating questions such as this one, the researchers said. The Danish, Italian, and Swedish national MS registries, MSBase, and the Observatoire of MS (OFSEP) merged their data in the Big Multiple Sclerosis Data (BMSD) Network, which includes approximately 150,000 patients and more than 470,000 EDSS evaluations. The result is a large dataset suitable for long-term longitudinal studies.
Mr. Lucisano and colleagues sought to examine the long-term effect of DMTs on CDP and irreversible disability milestones (i.e., EDSS scores of 4 and 6) in relapsing-remitting MS. The researchers used marginal structural proportional models, a novel technique that enables them to correct modeling for confounders that vary with time in longitudinal observational studies. Such confounders include treatment switches, on-treatment relapses, and treatment gaps.
The investigators selected patients with 10 or more years’ follow-up and one or more EDSS score evaluations per year from the BMSD pooled cohort. Using marginal structural proportional models, the investigators evaluated cumulative hazards of 3-, 12- and 24-month CDP (i.e., CDP3, CDP12, CDP24) events in 6-month periods. They created stabilized inverse probability of treatment weights (IPTWs) at each 6-month period using survival models according to treatment status (i.e., treated versus untreated). Treatment status was assigned for each patient according to the percentage of time that he or she spent receiving DMT in each 6-month period. A patient who received treatment for 70% or more of the period studied was considered treated; patients who did not meet this threshold were considered untreated. The weights were calculated on the basis of sex, age, occurrence of relapse, EDSS score, and registry source. Finally, the researchers used Cox regression models estimating the effect of DMTs on the risk of reaching CDP3, CDP12, and CDP24, adjusted by the IPTWs, to compare cohorts that remained treated or untreated throughout follow-up.
The investigators identified a cohort of 15,602 patients with relapsing-remitting MS, and this group had 312,040 EDSS score evaluations. Approximately 28% of patients were male. Median age at disease onset was 28.3 years, and median disease duration was 18.7 years. Median follow-up duration was 13.8 years.
During follow-up, 43.3% of patients had CDP3, 27.7% had CDP12, and 14.4% had CDP24 events. In addition, 23.6% of patients reached an EDSS score of 4, and 11.2% reached an EDSS score of 6.
Cox models adjusted by IPTW demonstrated increasing positive evidence of the effect of cumulative treatment exposure, compared with cumulative untreated epochs, according to the length of confirmation time used for defining the CDP. The investigators did not observe an effect of treatment on the probability of reaching CDP3 (hazard ratio [HR], 1.02), but treatment had a protective effect on CDP12 (HR, 0.90) and CDP24 (HR, 0.65) endpoints. During treated epochs, the HR of EDSS 4 was 0.89, and the HR of EDSS 6 was 0.86. Sensitivity analyses largely confirmed the results of the main analysis.
Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
REPORTING FROM ECTRIMS 2019
Which Interventions Can Treat Cognitive Fatigue?
Key clinical point: Only one intervention – transcranial direct current stimulation (tDCS) – has been found to counteract cognitive fatigability in a trial with objective outcome measures.
Major finding: Compared with sham stimulation, anodal tDCS increased P300 amplitude and reduced fatigue-related decrements in reaction time in a preliminary study.
Study details: A systematic review of intervention studies that objectively measured cognitive fatigability in adults with neurologic disorders.
Disclosures: The authors had no disclosures.
Citation: Lindsay-Brown A et al. CMSC 2019, Abstract NNN10.
Key clinical point: Only one intervention – transcranial direct current stimulation (tDCS) – has been found to counteract cognitive fatigability in a trial with objective outcome measures.
Major finding: Compared with sham stimulation, anodal tDCS increased P300 amplitude and reduced fatigue-related decrements in reaction time in a preliminary study.
Study details: A systematic review of intervention studies that objectively measured cognitive fatigability in adults with neurologic disorders.
Disclosures: The authors had no disclosures.
Citation: Lindsay-Brown A et al. CMSC 2019, Abstract NNN10.
Key clinical point: Only one intervention – transcranial direct current stimulation (tDCS) – has been found to counteract cognitive fatigability in a trial with objective outcome measures.
Major finding: Compared with sham stimulation, anodal tDCS increased P300 amplitude and reduced fatigue-related decrements in reaction time in a preliminary study.
Study details: A systematic review of intervention studies that objectively measured cognitive fatigability in adults with neurologic disorders.
Disclosures: The authors had no disclosures.
Citation: Lindsay-Brown A et al. CMSC 2019, Abstract NNN10.
Out-of-Pocket Costs for MS Drugs Rose Significantly
Key clinical point: Prices of self-administered disease-modifying therapies for multiple sclerosis increased significantly from 2006 to 2016.
Major finding: Patients’ out-of-pocket costs increased by a factor of 7.2 during this period.
Study details: A cohort study of Medicare claims data from 2006 to 2016.
Disclosures: The Myers Family Foundation and the National Heart, Lung, and Blood Institute funded this research. Several authors are employees of health insurance companies such as the UPMC Health Plan Insurance Services Division and Humana. One author received personal fees from Pfizer that were unrelated to this study.
Citation: San-Juan-Rodriguez A et al. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2711; Hartung DM and Bourdette D. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2445.
Key clinical point: Prices of self-administered disease-modifying therapies for multiple sclerosis increased significantly from 2006 to 2016.
Major finding: Patients’ out-of-pocket costs increased by a factor of 7.2 during this period.
Study details: A cohort study of Medicare claims data from 2006 to 2016.
Disclosures: The Myers Family Foundation and the National Heart, Lung, and Blood Institute funded this research. Several authors are employees of health insurance companies such as the UPMC Health Plan Insurance Services Division and Humana. One author received personal fees from Pfizer that were unrelated to this study.
Citation: San-Juan-Rodriguez A et al. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2711; Hartung DM and Bourdette D. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2445.
Key clinical point: Prices of self-administered disease-modifying therapies for multiple sclerosis increased significantly from 2006 to 2016.
Major finding: Patients’ out-of-pocket costs increased by a factor of 7.2 during this period.
Study details: A cohort study of Medicare claims data from 2006 to 2016.
Disclosures: The Myers Family Foundation and the National Heart, Lung, and Blood Institute funded this research. Several authors are employees of health insurance companies such as the UPMC Health Plan Insurance Services Division and Humana. One author received personal fees from Pfizer that were unrelated to this study.
Citation: San-Juan-Rodriguez A et al. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2711; Hartung DM and Bourdette D. JAMA Neurol. 2019 Aug 26. doi: 10.1001/jamaneurol.2019.2445.
Neurologists need not discourage breastfeeding in women with MS
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
STOCKHOLM – Most neurologists are overly conservative when it comes to advising women with multiple sclerosis (MS) about breastfeeding, discouraging this broadly beneficial practice in favor of early resumption of treatment post pregnancy, Kerstin Hellwig, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We should change our behavior, and I predict we will change it so that more women are breastfeeding while under MS medication within the next couple years. ,” said Dr. Hellwig, senior consultant and MS specialist in the department of neurology at St. Josef Hospital/Ruhr University in Bochum, Germany.
She was a coauthor of a groundbreaking 2012 meta-analysis that concluded that breastfeeding by MS patients is not harmful (J Neurol. 2012 Oct;259[10]:2246-8), a finding since confirmed in multiple additional studies.
“Women with MS who want to breastfeed should be supported in doing so,” Dr. Hellwig said.
In this regard, many neurologists are out of step with their colleagues in rheumatology and gastroenterology, who commonly endorse breastfeeding by their patients while on monoclonal antibodies for other autoimmune diseases, according to Dr. Hellwig.
It is important to recognize that most women of reproductive age with MS have milder forms of the disease, she said. They can safely breastfeed without being on any MS medications at all for the duration.
For women who want to breastfeed and have more-active disease where early treatment resumption is warranted, the key is to select a breastfeeding-compatible medication. The main determinant of whether a drug will enter the mother’s breast milk is the size of the drug molecule, with large molecules being unlikely to make their way into breast milk in anything approaching clinically meaningful amounts. The injectable first-line disease-modifying drugs are good options: For example, interferon-beta is a very large molecule which has been detected in breast milk at 0.0006% of the relative infant dose. That’s reassuring, Dr. Hellwig said, since anything less than a relative infant dose of 10% is generally considered to be safe for a baby. And while glatiramer acetate, another injectable, has not been tested, it is metabolized so rapidly that it is unlikely to be detectable in breast milk, according to Dr. Hellwig.
Monoclonal antibodies are also compatible with breastfeeding. Rituximab has been detected in breast milk at 1/240th of the maternal serum level, and natalizumab at less than 1/200th. These are large molecules with a low likelihood of infant absorption, since they are probably destroyed in the child’s gastrointestinal tract. Ocrelizumab has not been studied in breast milk, but it is an IgG1 monoclonal antibody, as is rituximab, and so should likewise pose “exceedingly low risk,” Dr. Hellwig said.
At last year’s ECTRIMS conference, she presented reassuring 1-year follow-up data on a cohort of infants breastfed by mothers with MS while on interferon-beta. “We do not see any growth disturbances, any severe infections, hospitalizations, excess antibiotic use, or postponed reaching of developmental milestones in babies being breastfed under the injectables,” she said.
Dr. Hellwig has served on scientific advisory board for Bayer, Biogen, Genzyme Sanofi, Teva, Roche, Novartis, and Merck. She has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, SanofiGenzyme, and Teva, and has received support for congress participation from Bayer, Biogen, Genzyme, Teva, Roche, and Merck.
EXPERT ANALYSIS FROM ECTRIMS 2019
Interview with Andrew Solomon, MD, on diagnosing multiple sclerosis
Andrew Solomon, MD, is a neurologist and Associate Professor in the Department of Neurological Sciences and Division Chief of Multiple Sclerosis at The University of Vermont. We sat down to talk with Dr. Solomon about his experience with multiple sclerosis (MS) misdiagnosis and what can be done to improve MS diagnosis going forward.
How prevalent is the misdiagnosis of MS and what are the effects that it has on patients?
The first thing to clarify is what we mean by MS misdiagnosis. In this case, we’re talking about patients who are incorrectly assigned a diagnosis of MS. MS is hard to diagnose. Sometimes we take too long to diagnose people who have MS, sometimes we incorrectly diagnose MS in people who don’t have it.
We don’t have very good data in terms of how frequent misdiagnosis is, but we have some. The earliest data we have is from the 1980s. In 1988 there was a study published involving approximately 500 patients who had been diagnosed with MS in life and subsequently died between the 1960s and the 1980s and had a postmortem exam. 6% of those people who had a diagnosis of MS during their lifetime didn’t actually have MS.1
In 2012, we did a survey of 122 MS specialists.2 We asked them if they had encountered patients incorrectly assigned a diagnosis of MS in the past year, and 95% of them had seen such a patient. This was not the most scientific study because it was just a survey and subject to recall bias. Still, many of these MS providers recalled having seen three to ten such patients in the last year where they strongly felt that a pre-existing MS diagnosis made by another provider was incorrect.
Another study was recently published by Dr. Kaisey.3 She looked at referrals to two academic MS centers on the West Coast, and specifically new patient referrals over 12 months to those two MS centers. She found that out of 241 patients referred to the two MS centers, almost one in five who was referred with a pre-existing diagnosis of MS who came to these MS centers was subsequently found not have MS. This included 17% of patients at Cedars Sinai and 19% at UCLA. That’s an alarmingly high number of patients. And that’s the best data we have right now.
We don’t know how representative that number is of other MS centers and clinical practice nationally, but the bottom line is that misdiagnosis of MS is, unfortunately, fairly common and there’s a lot of risks to patients associated with misdiagnosis, as well as costs to our health care system.
Can you elaborate on the risks to patients?
We published a study where we looked at records from 110 patients who had been incorrectly assigned a diagnosis of MS. Twenty-three MS specialists from 4 different MS centers participated in this study that was published in Neurology in 2016.4
70% of these patients had been receiving disease modifying therapy for MS, which certainly has risks and side effects associated with it. 24% received disease modifying therapy with a known risk of PML, which is a frequently fatal brain infection associated with these therapies. Approximately 30% of these patients who did not have MS were on disease modifying therapy for in 3 to 9 years and 30% were on disease modifying therapy for 10 years or more.
Dr. Kaisey’s study also supports our findings. She found approximately 110 patient-years of exposure to unnecessary disease modifying therapy in the misdiagnosed patients in her study.3 Patients suffer side effects in addition to unnecessary risk related to these therapies.
It’s also important to emphasize that many of these patients also received inadequate treatment for their correct diagnoses.
How did the 2017 revision to the McDonald criteria address the challenge of MS diagnosis?
The problem of MS misdiagnosis is prominently discussed in the 2017 McDonald criteria.5 Unfortunately, one of the likely causes of misdiagnosis is that many clinicians may not read the full manuscript of the McDonald criteria itself. They instead rely on summary cards or reproductions—condensed versions of how to diagnose MS—which often don’t really provide the full context that would allow physicians to think critically and avoid a misdiagnosis.
MS is still a clinical diagnosis, which means we’re reliant on physician decision-making to confirm a diagnosis of MS. There are multiple steps to it.
First, we must determine if somebody has a syndrome typical for MS and they have objective evidence of a CNS lesion. After that the McDonald criteria can be applied to determine if they meet dissemination in time, dissemination in space, and have no other explanation for this syndrome before making a diagnosis of MS. Each one of those steps is reliant on thoughtful clinical decision-making and may be prone to potential error.
Knowing the ins and outs and the details of each of those steps is important. Reading the diagnostic criteria is probably the first step in becoming skilled at MS diagnosis. It’s important to know the criteria were not developed as a screening tool. The neurologist is essentially the screening tool. The diagnostic criteria can’t be used until a MS-typical syndrome with objective evidence of a CNS lesion is confirmed.
In what way was the previous criteria flawed?
I wouldn’t say any of the MS diagnostic criteria were flawed; they have evolved along with data in our field that has helped us make diagnosis of MS earlier in many patients. When using the criteria, it’s important to understand the types of patients in the cohorts used to validate our diagnostic criteria. They were primarily younger than 50, and usually Caucasian. They had only syndromes typical for MS with objective evidence of CNS damage corroborating these syndromes. Using the criteria more broadly in patients who do not fit this profile can reduce its specificity and lead to misdiagnosis.
For determination of MRI dissemination in time and dissemination space, there are also some misconceptions that frequently lead to misdiagnosis. Knowing which areas are required for dissemination in space in crucial. For example, the optic nerve currently is not an area that can be used to fulfill dissemination in space, which is a mistake people frequently make. Knowing that the terms “juxtacortical” and “periventricular” means touching the ventricle and touching the cortex is very important. This is a mistake that’s often made as well, and many disorders present with MRI lesions near but not touching the cortex or ventricle. Knowing each element of our diagnostic criteria and what those terms specifically mean is important. In the 2017 McDonald criteria there’s an excellent glossary that helps clinicians understand these terms and how to use them appropriately.5
What more needs to be done to prevent MS misdiagnosis?
First, we need to figure out how to better educate clinicians on how to use our diagnostic criteria appropriately.
We recently completed a study that suggests that residents in training, and even MS specialists, have trouble using the diagnostic criteria. This study was presented at the American Academy of Neurology Annual meeting but has not been published yet. Education on how to use the diagnostic criteria, and in which patients to use the criteria (and in which patients the criteria do not apply) is important, particularly when new revisions to the diagnostic criteria are published.
We published a paper recently that provided guidance on how to avoid misdiagnosis using the 2017 McDonald criteria, and how to approach patients where the diagnostic criteria didn’t apply.6 Sometimes additional clinical, laboratory, or MRI evaluation and monitoring is required in such patients to either confirm a diagnosis of MS, or determine that a patient does not have MS.
We also desperately need biomarkers that may help us diagnose MS more accurately in patients who have neurological symptoms and an abnormal MRI and are seeing a neurologist for the first time. There’s research going on now to find relevant biomarkers in the form of blood tests, as well as MRI assessments. In particular, ongoing research focused on the MRI finding we have termed the “central vein sign” suggests this approach may be helpful as a MRI-specific biomarker for MS.7,8 We need multicenter studies evaluating this and other biomarkers in patients who come to our clinics for a new evaluation for MS, to confirm that they are accurate. We need more researchers working on how to improve diagnosis of MS.
References:
1. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
2. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.
4. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.
5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173..
6. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.
7. Sati P, Oh J, Constable RT, et al; NAIMS Cooperative. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
8. Sinnecker T, Clarke MA, Meier D, et al. Evaluation of the central vein sign as a diagnostic imaging biomarker in multiple sclerosis [published online ahead of print August 19, 2019]. JAMA Neurology. 2019: doi: 10.1001/jamaneurol.2019.2478.
Andrew Solomon, MD, is a neurologist and Associate Professor in the Department of Neurological Sciences and Division Chief of Multiple Sclerosis at The University of Vermont. We sat down to talk with Dr. Solomon about his experience with multiple sclerosis (MS) misdiagnosis and what can be done to improve MS diagnosis going forward.
How prevalent is the misdiagnosis of MS and what are the effects that it has on patients?
The first thing to clarify is what we mean by MS misdiagnosis. In this case, we’re talking about patients who are incorrectly assigned a diagnosis of MS. MS is hard to diagnose. Sometimes we take too long to diagnose people who have MS, sometimes we incorrectly diagnose MS in people who don’t have it.
We don’t have very good data in terms of how frequent misdiagnosis is, but we have some. The earliest data we have is from the 1980s. In 1988 there was a study published involving approximately 500 patients who had been diagnosed with MS in life and subsequently died between the 1960s and the 1980s and had a postmortem exam. 6% of those people who had a diagnosis of MS during their lifetime didn’t actually have MS.1
In 2012, we did a survey of 122 MS specialists.2 We asked them if they had encountered patients incorrectly assigned a diagnosis of MS in the past year, and 95% of them had seen such a patient. This was not the most scientific study because it was just a survey and subject to recall bias. Still, many of these MS providers recalled having seen three to ten such patients in the last year where they strongly felt that a pre-existing MS diagnosis made by another provider was incorrect.
Another study was recently published by Dr. Kaisey.3 She looked at referrals to two academic MS centers on the West Coast, and specifically new patient referrals over 12 months to those two MS centers. She found that out of 241 patients referred to the two MS centers, almost one in five who was referred with a pre-existing diagnosis of MS who came to these MS centers was subsequently found not have MS. This included 17% of patients at Cedars Sinai and 19% at UCLA. That’s an alarmingly high number of patients. And that’s the best data we have right now.
We don’t know how representative that number is of other MS centers and clinical practice nationally, but the bottom line is that misdiagnosis of MS is, unfortunately, fairly common and there’s a lot of risks to patients associated with misdiagnosis, as well as costs to our health care system.
Can you elaborate on the risks to patients?
We published a study where we looked at records from 110 patients who had been incorrectly assigned a diagnosis of MS. Twenty-three MS specialists from 4 different MS centers participated in this study that was published in Neurology in 2016.4
70% of these patients had been receiving disease modifying therapy for MS, which certainly has risks and side effects associated with it. 24% received disease modifying therapy with a known risk of PML, which is a frequently fatal brain infection associated with these therapies. Approximately 30% of these patients who did not have MS were on disease modifying therapy for in 3 to 9 years and 30% were on disease modifying therapy for 10 years or more.
Dr. Kaisey’s study also supports our findings. She found approximately 110 patient-years of exposure to unnecessary disease modifying therapy in the misdiagnosed patients in her study.3 Patients suffer side effects in addition to unnecessary risk related to these therapies.
It’s also important to emphasize that many of these patients also received inadequate treatment for their correct diagnoses.
How did the 2017 revision to the McDonald criteria address the challenge of MS diagnosis?
The problem of MS misdiagnosis is prominently discussed in the 2017 McDonald criteria.5 Unfortunately, one of the likely causes of misdiagnosis is that many clinicians may not read the full manuscript of the McDonald criteria itself. They instead rely on summary cards or reproductions—condensed versions of how to diagnose MS—which often don’t really provide the full context that would allow physicians to think critically and avoid a misdiagnosis.
MS is still a clinical diagnosis, which means we’re reliant on physician decision-making to confirm a diagnosis of MS. There are multiple steps to it.
First, we must determine if somebody has a syndrome typical for MS and they have objective evidence of a CNS lesion. After that the McDonald criteria can be applied to determine if they meet dissemination in time, dissemination in space, and have no other explanation for this syndrome before making a diagnosis of MS. Each one of those steps is reliant on thoughtful clinical decision-making and may be prone to potential error.
Knowing the ins and outs and the details of each of those steps is important. Reading the diagnostic criteria is probably the first step in becoming skilled at MS diagnosis. It’s important to know the criteria were not developed as a screening tool. The neurologist is essentially the screening tool. The diagnostic criteria can’t be used until a MS-typical syndrome with objective evidence of a CNS lesion is confirmed.
In what way was the previous criteria flawed?
I wouldn’t say any of the MS diagnostic criteria were flawed; they have evolved along with data in our field that has helped us make diagnosis of MS earlier in many patients. When using the criteria, it’s important to understand the types of patients in the cohorts used to validate our diagnostic criteria. They were primarily younger than 50, and usually Caucasian. They had only syndromes typical for MS with objective evidence of CNS damage corroborating these syndromes. Using the criteria more broadly in patients who do not fit this profile can reduce its specificity and lead to misdiagnosis.
For determination of MRI dissemination in time and dissemination space, there are also some misconceptions that frequently lead to misdiagnosis. Knowing which areas are required for dissemination in space in crucial. For example, the optic nerve currently is not an area that can be used to fulfill dissemination in space, which is a mistake people frequently make. Knowing that the terms “juxtacortical” and “periventricular” means touching the ventricle and touching the cortex is very important. This is a mistake that’s often made as well, and many disorders present with MRI lesions near but not touching the cortex or ventricle. Knowing each element of our diagnostic criteria and what those terms specifically mean is important. In the 2017 McDonald criteria there’s an excellent glossary that helps clinicians understand these terms and how to use them appropriately.5
What more needs to be done to prevent MS misdiagnosis?
First, we need to figure out how to better educate clinicians on how to use our diagnostic criteria appropriately.
We recently completed a study that suggests that residents in training, and even MS specialists, have trouble using the diagnostic criteria. This study was presented at the American Academy of Neurology Annual meeting but has not been published yet. Education on how to use the diagnostic criteria, and in which patients to use the criteria (and in which patients the criteria do not apply) is important, particularly when new revisions to the diagnostic criteria are published.
We published a paper recently that provided guidance on how to avoid misdiagnosis using the 2017 McDonald criteria, and how to approach patients where the diagnostic criteria didn’t apply.6 Sometimes additional clinical, laboratory, or MRI evaluation and monitoring is required in such patients to either confirm a diagnosis of MS, or determine that a patient does not have MS.
We also desperately need biomarkers that may help us diagnose MS more accurately in patients who have neurological symptoms and an abnormal MRI and are seeing a neurologist for the first time. There’s research going on now to find relevant biomarkers in the form of blood tests, as well as MRI assessments. In particular, ongoing research focused on the MRI finding we have termed the “central vein sign” suggests this approach may be helpful as a MRI-specific biomarker for MS.7,8 We need multicenter studies evaluating this and other biomarkers in patients who come to our clinics for a new evaluation for MS, to confirm that they are accurate. We need more researchers working on how to improve diagnosis of MS.
References:
1. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
2. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.
4. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.
5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173..
6. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.
7. Sati P, Oh J, Constable RT, et al; NAIMS Cooperative. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
8. Sinnecker T, Clarke MA, Meier D, et al. Evaluation of the central vein sign as a diagnostic imaging biomarker in multiple sclerosis [published online ahead of print August 19, 2019]. JAMA Neurology. 2019: doi: 10.1001/jamaneurol.2019.2478.
Andrew Solomon, MD, is a neurologist and Associate Professor in the Department of Neurological Sciences and Division Chief of Multiple Sclerosis at The University of Vermont. We sat down to talk with Dr. Solomon about his experience with multiple sclerosis (MS) misdiagnosis and what can be done to improve MS diagnosis going forward.
How prevalent is the misdiagnosis of MS and what are the effects that it has on patients?
The first thing to clarify is what we mean by MS misdiagnosis. In this case, we’re talking about patients who are incorrectly assigned a diagnosis of MS. MS is hard to diagnose. Sometimes we take too long to diagnose people who have MS, sometimes we incorrectly diagnose MS in people who don’t have it.
We don’t have very good data in terms of how frequent misdiagnosis is, but we have some. The earliest data we have is from the 1980s. In 1988 there was a study published involving approximately 500 patients who had been diagnosed with MS in life and subsequently died between the 1960s and the 1980s and had a postmortem exam. 6% of those people who had a diagnosis of MS during their lifetime didn’t actually have MS.1
In 2012, we did a survey of 122 MS specialists.2 We asked them if they had encountered patients incorrectly assigned a diagnosis of MS in the past year, and 95% of them had seen such a patient. This was not the most scientific study because it was just a survey and subject to recall bias. Still, many of these MS providers recalled having seen three to ten such patients in the last year where they strongly felt that a pre-existing MS diagnosis made by another provider was incorrect.
Another study was recently published by Dr. Kaisey.3 She looked at referrals to two academic MS centers on the West Coast, and specifically new patient referrals over 12 months to those two MS centers. She found that out of 241 patients referred to the two MS centers, almost one in five who was referred with a pre-existing diagnosis of MS who came to these MS centers was subsequently found not have MS. This included 17% of patients at Cedars Sinai and 19% at UCLA. That’s an alarmingly high number of patients. And that’s the best data we have right now.
We don’t know how representative that number is of other MS centers and clinical practice nationally, but the bottom line is that misdiagnosis of MS is, unfortunately, fairly common and there’s a lot of risks to patients associated with misdiagnosis, as well as costs to our health care system.
Can you elaborate on the risks to patients?
We published a study where we looked at records from 110 patients who had been incorrectly assigned a diagnosis of MS. Twenty-three MS specialists from 4 different MS centers participated in this study that was published in Neurology in 2016.4
70% of these patients had been receiving disease modifying therapy for MS, which certainly has risks and side effects associated with it. 24% received disease modifying therapy with a known risk of PML, which is a frequently fatal brain infection associated with these therapies. Approximately 30% of these patients who did not have MS were on disease modifying therapy for in 3 to 9 years and 30% were on disease modifying therapy for 10 years or more.
Dr. Kaisey’s study also supports our findings. She found approximately 110 patient-years of exposure to unnecessary disease modifying therapy in the misdiagnosed patients in her study.3 Patients suffer side effects in addition to unnecessary risk related to these therapies.
It’s also important to emphasize that many of these patients also received inadequate treatment for their correct diagnoses.
How did the 2017 revision to the McDonald criteria address the challenge of MS diagnosis?
The problem of MS misdiagnosis is prominently discussed in the 2017 McDonald criteria.5 Unfortunately, one of the likely causes of misdiagnosis is that many clinicians may not read the full manuscript of the McDonald criteria itself. They instead rely on summary cards or reproductions—condensed versions of how to diagnose MS—which often don’t really provide the full context that would allow physicians to think critically and avoid a misdiagnosis.
MS is still a clinical diagnosis, which means we’re reliant on physician decision-making to confirm a diagnosis of MS. There are multiple steps to it.
First, we must determine if somebody has a syndrome typical for MS and they have objective evidence of a CNS lesion. After that the McDonald criteria can be applied to determine if they meet dissemination in time, dissemination in space, and have no other explanation for this syndrome before making a diagnosis of MS. Each one of those steps is reliant on thoughtful clinical decision-making and may be prone to potential error.
Knowing the ins and outs and the details of each of those steps is important. Reading the diagnostic criteria is probably the first step in becoming skilled at MS diagnosis. It’s important to know the criteria were not developed as a screening tool. The neurologist is essentially the screening tool. The diagnostic criteria can’t be used until a MS-typical syndrome with objective evidence of a CNS lesion is confirmed.
In what way was the previous criteria flawed?
I wouldn’t say any of the MS diagnostic criteria were flawed; they have evolved along with data in our field that has helped us make diagnosis of MS earlier in many patients. When using the criteria, it’s important to understand the types of patients in the cohorts used to validate our diagnostic criteria. They were primarily younger than 50, and usually Caucasian. They had only syndromes typical for MS with objective evidence of CNS damage corroborating these syndromes. Using the criteria more broadly in patients who do not fit this profile can reduce its specificity and lead to misdiagnosis.
For determination of MRI dissemination in time and dissemination space, there are also some misconceptions that frequently lead to misdiagnosis. Knowing which areas are required for dissemination in space in crucial. For example, the optic nerve currently is not an area that can be used to fulfill dissemination in space, which is a mistake people frequently make. Knowing that the terms “juxtacortical” and “periventricular” means touching the ventricle and touching the cortex is very important. This is a mistake that’s often made as well, and many disorders present with MRI lesions near but not touching the cortex or ventricle. Knowing each element of our diagnostic criteria and what those terms specifically mean is important. In the 2017 McDonald criteria there’s an excellent glossary that helps clinicians understand these terms and how to use them appropriately.5
What more needs to be done to prevent MS misdiagnosis?
First, we need to figure out how to better educate clinicians on how to use our diagnostic criteria appropriately.
We recently completed a study that suggests that residents in training, and even MS specialists, have trouble using the diagnostic criteria. This study was presented at the American Academy of Neurology Annual meeting but has not been published yet. Education on how to use the diagnostic criteria, and in which patients to use the criteria (and in which patients the criteria do not apply) is important, particularly when new revisions to the diagnostic criteria are published.
We published a paper recently that provided guidance on how to avoid misdiagnosis using the 2017 McDonald criteria, and how to approach patients where the diagnostic criteria didn’t apply.6 Sometimes additional clinical, laboratory, or MRI evaluation and monitoring is required in such patients to either confirm a diagnosis of MS, or determine that a patient does not have MS.
We also desperately need biomarkers that may help us diagnose MS more accurately in patients who have neurological symptoms and an abnormal MRI and are seeing a neurologist for the first time. There’s research going on now to find relevant biomarkers in the form of blood tests, as well as MRI assessments. In particular, ongoing research focused on the MRI finding we have termed the “central vein sign” suggests this approach may be helpful as a MRI-specific biomarker for MS.7,8 We need multicenter studies evaluating this and other biomarkers in patients who come to our clinics for a new evaluation for MS, to confirm that they are accurate. We need more researchers working on how to improve diagnosis of MS.
References:
1. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.
2. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.
3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.
4. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.
5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173..
6. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.
7. Sati P, Oh J, Constable RT, et al; NAIMS Cooperative. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
8. Sinnecker T, Clarke MA, Meier D, et al. Evaluation of the central vein sign as a diagnostic imaging biomarker in multiple sclerosis [published online ahead of print August 19, 2019]. JAMA Neurology. 2019: doi: 10.1001/jamaneurol.2019.2478.
