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VIDEO: Could targeting gut dysbiosis in MS prevent disease?
SAN DIEGO – Compelling findings in a genetically engineered mouse model of multiple sclerosis identify mechanisms of how adolescence and gut dysbiosis contribute to the risk of MS. In addition, disparities in gut microbiome species could explain why some people are at higher risk for developing multiple sclerosis, while others seem to enjoy a protective effect against development of this and other autoimmune diseases.
The hope is that these findings could pave the way for clinicians to potentially prevent development of multiple sclerosis in people at higher risk, perhaps through altering the gut flora and probiotic therapy, Suhayl Dhib-Jalbut, MD, said in a video interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Dr. Dhib-Jalbut and his team discovered these findings using humanized transgenic mice – in other words, mice containing risk genes for triggering disease transferred from a patient with multiple sclerosis. The mice were more likely to develop MS-like disease at certain ages and in the presence of an altered gut microbiome or gut dysbiosis (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
Dr. Dhib-Jalbut is past president of ACTRIMS and is professor and chairman of the departments of neurology at Rutgers–Robert Wood Johnson Medical School, New Brunswick, N.J., and New Jersey Medical School, Newark. He has received research grants from Biogen and Teva, and is a consultant for Genzyme, Teva, Celgene, and, Mallinckrodt.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Compelling findings in a genetically engineered mouse model of multiple sclerosis identify mechanisms of how adolescence and gut dysbiosis contribute to the risk of MS. In addition, disparities in gut microbiome species could explain why some people are at higher risk for developing multiple sclerosis, while others seem to enjoy a protective effect against development of this and other autoimmune diseases.
The hope is that these findings could pave the way for clinicians to potentially prevent development of multiple sclerosis in people at higher risk, perhaps through altering the gut flora and probiotic therapy, Suhayl Dhib-Jalbut, MD, said in a video interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Dr. Dhib-Jalbut and his team discovered these findings using humanized transgenic mice – in other words, mice containing risk genes for triggering disease transferred from a patient with multiple sclerosis. The mice were more likely to develop MS-like disease at certain ages and in the presence of an altered gut microbiome or gut dysbiosis (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
Dr. Dhib-Jalbut is past president of ACTRIMS and is professor and chairman of the departments of neurology at Rutgers–Robert Wood Johnson Medical School, New Brunswick, N.J., and New Jersey Medical School, Newark. He has received research grants from Biogen and Teva, and is a consultant for Genzyme, Teva, Celgene, and, Mallinckrodt.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Compelling findings in a genetically engineered mouse model of multiple sclerosis identify mechanisms of how adolescence and gut dysbiosis contribute to the risk of MS. In addition, disparities in gut microbiome species could explain why some people are at higher risk for developing multiple sclerosis, while others seem to enjoy a protective effect against development of this and other autoimmune diseases.
The hope is that these findings could pave the way for clinicians to potentially prevent development of multiple sclerosis in people at higher risk, perhaps through altering the gut flora and probiotic therapy, Suhayl Dhib-Jalbut, MD, said in a video interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Dr. Dhib-Jalbut and his team discovered these findings using humanized transgenic mice – in other words, mice containing risk genes for triggering disease transferred from a patient with multiple sclerosis. The mice were more likely to develop MS-like disease at certain ages and in the presence of an altered gut microbiome or gut dysbiosis (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
Dr. Dhib-Jalbut is past president of ACTRIMS and is professor and chairman of the departments of neurology at Rutgers–Robert Wood Johnson Medical School, New Brunswick, N.J., and New Jersey Medical School, Newark. He has received research grants from Biogen and Teva, and is a consultant for Genzyme, Teva, Celgene, and, Mallinckrodt.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM ACTRIMS FORUM 2018
Rituximab fails to eliminate meningeal inflammation in progressive MS
Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.
The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.
Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.
The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.
“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”
The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.
But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.
This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.
The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.
The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.
The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.
SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.
The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.
Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.
The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.
“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”
The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.
But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.
This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.
The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.
The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.
The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.
SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.
The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.
Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.
The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.
“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”
The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.
But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.
This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.
The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.
The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.
The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.
SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
FROM ACTRIMS FORUM 2018
Key clinical point:
Major finding: No change in leptomeningeal inflammation was seen after two intrathecal doses of 25 mg of rituximab administered over 2 weeks.
Data source: Prospective study of eight patients with progressive MS and signs of meningeal inflammation.
Disclosures: The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Study presenter Pavan Bhargava, MD, reported no relevant disclosures.
Source: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
Fingolimod cuts pediatric MS relapse rate more than interferon beta-1a
Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.
A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.
The phase 3 PARADIGMS study is the first international controlled trial to evaluate the safety and efficacy of fingolimod in pediatric and adolescent patients. Dr. Chitnis and her colleagues randomized 215 participants aged 10-17 years to up to 0.5 mg/day of fingolimod based on body weight or to a once-a-week intramuscular injection of 30 mcg of interferon beta-1a. The trial lasted 2 years and was followed by an open-label extension for an additional 5 years.
The annualized relapse rate was the primary endpoint. The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
MRI findings and outcomes associated with relapse were secondary endpoints. The researchers found that, compared with the interferon beta-1a group, patients randomized to fingolimod had fewer lesions identified on MRI: There was a 53% annualized reduction in new or newly enlarged T2 lesions and 66% decrease in gadolinium-enhancing T1 lesions.
“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”
Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.
To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.
Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.
Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”
The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.
A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.
The phase 3 PARADIGMS study is the first international controlled trial to evaluate the safety and efficacy of fingolimod in pediatric and adolescent patients. Dr. Chitnis and her colleagues randomized 215 participants aged 10-17 years to up to 0.5 mg/day of fingolimod based on body weight or to a once-a-week intramuscular injection of 30 mcg of interferon beta-1a. The trial lasted 2 years and was followed by an open-label extension for an additional 5 years.
The annualized relapse rate was the primary endpoint. The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
MRI findings and outcomes associated with relapse were secondary endpoints. The researchers found that, compared with the interferon beta-1a group, patients randomized to fingolimod had fewer lesions identified on MRI: There was a 53% annualized reduction in new or newly enlarged T2 lesions and 66% decrease in gadolinium-enhancing T1 lesions.
“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”
Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.
To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.
Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.
Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”
The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.
A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.
The phase 3 PARADIGMS study is the first international controlled trial to evaluate the safety and efficacy of fingolimod in pediatric and adolescent patients. Dr. Chitnis and her colleagues randomized 215 participants aged 10-17 years to up to 0.5 mg/day of fingolimod based on body weight or to a once-a-week intramuscular injection of 30 mcg of interferon beta-1a. The trial lasted 2 years and was followed by an open-label extension for an additional 5 years.
The annualized relapse rate was the primary endpoint. The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
MRI findings and outcomes associated with relapse were secondary endpoints. The researchers found that, compared with the interferon beta-1a group, patients randomized to fingolimod had fewer lesions identified on MRI: There was a 53% annualized reduction in new or newly enlarged T2 lesions and 66% decrease in gadolinium-enhancing T1 lesions.
“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”
Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.
To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.
Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.
Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”
The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
FROM ACTRIMS FORUM 2018
Key clinical point:
Major finding: The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
Study details: International, randomized, double-blind, parallel-group study of 215 people aged 10-17 years.
Disclosures: The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
Source: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
Study finds rising use of newer DMTs in pediatric-onset MS
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
FROM ACTRIMS FORUM 2018
Key clinical point: Newer DMTs are often used in individuals with pediatric MS.
Major finding: Among pediatric MS patients, the first agent used was a newer DMT in 17% of cases.
Study details: A retrospective review of prospectively collected data on 1,023 pediatric patients with MS.
Disclosures: The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Source: Krysko K et al. ACTRIMS Forum 2018 Poster 68.
Barancik Prize winner to discuss MS biology advances
Two decades ago, multiple sclerosis researchers like the University of Cambridge’s, Robin Franklin, PhD, understood the crucial role of regeneration of the myelin coating on nerve fibers, and they knew the process went awry in MS patients. But, he recalled, “we knew very little about how remyelination came about and the processes that orchestrated it.”
Now, thanks in part to the work of Dr. Franklin’s team, research into remyelination is making tremendous advances. “We’ve begun to understand the mechanisms that are operating, and that is fundamental to devising new therapies,” he said in an interview. “You don’t develop effective new therapies unless you understand the underlying biology. Now, we’re on the brink of that biology leading to regenerative medicine in MS.”
Dr. Franklin is the winner of the international prize, which recognizes exceptional MS research and is administered by the National MS Society.
In recent years, Dr. Franklin and his colleagues have published multiple studies that reveal new details about the workings of myelin regeneration, especially the biology by which oligodendrocyte progenitor cells become new oligodendrocytes.
“There are simple steps in that process,” Dr. Franklin said. “What we’ve been able to do is decorate that simple model with a whole host of mechanisms that allow remyelination to take place.”
In 2011, Franklin and his colleagues published a study in rodents identifying the RXRg gene as a key promoter of remyelination, making it a potential target for therapy (Nat Neurosci. 2011;14:45-53).
“There’s still a lot more to be learned,” Dr. Franklin said, “but we’ve learned a sufficient amount that we can engage in a meaningful way with the pharmaceutical industry and MS clinicians to make regenerative medicines an effective component of the MS therapeutic armory.”
Dr. Franklin has no relevant disclosures.
Two decades ago, multiple sclerosis researchers like the University of Cambridge’s, Robin Franklin, PhD, understood the crucial role of regeneration of the myelin coating on nerve fibers, and they knew the process went awry in MS patients. But, he recalled, “we knew very little about how remyelination came about and the processes that orchestrated it.”
Now, thanks in part to the work of Dr. Franklin’s team, research into remyelination is making tremendous advances. “We’ve begun to understand the mechanisms that are operating, and that is fundamental to devising new therapies,” he said in an interview. “You don’t develop effective new therapies unless you understand the underlying biology. Now, we’re on the brink of that biology leading to regenerative medicine in MS.”
Dr. Franklin is the winner of the international prize, which recognizes exceptional MS research and is administered by the National MS Society.
In recent years, Dr. Franklin and his colleagues have published multiple studies that reveal new details about the workings of myelin regeneration, especially the biology by which oligodendrocyte progenitor cells become new oligodendrocytes.
“There are simple steps in that process,” Dr. Franklin said. “What we’ve been able to do is decorate that simple model with a whole host of mechanisms that allow remyelination to take place.”
In 2011, Franklin and his colleagues published a study in rodents identifying the RXRg gene as a key promoter of remyelination, making it a potential target for therapy (Nat Neurosci. 2011;14:45-53).
“There’s still a lot more to be learned,” Dr. Franklin said, “but we’ve learned a sufficient amount that we can engage in a meaningful way with the pharmaceutical industry and MS clinicians to make regenerative medicines an effective component of the MS therapeutic armory.”
Dr. Franklin has no relevant disclosures.
Two decades ago, multiple sclerosis researchers like the University of Cambridge’s, Robin Franklin, PhD, understood the crucial role of regeneration of the myelin coating on nerve fibers, and they knew the process went awry in MS patients. But, he recalled, “we knew very little about how remyelination came about and the processes that orchestrated it.”
Now, thanks in part to the work of Dr. Franklin’s team, research into remyelination is making tremendous advances. “We’ve begun to understand the mechanisms that are operating, and that is fundamental to devising new therapies,” he said in an interview. “You don’t develop effective new therapies unless you understand the underlying biology. Now, we’re on the brink of that biology leading to regenerative medicine in MS.”
Dr. Franklin is the winner of the international prize, which recognizes exceptional MS research and is administered by the National MS Society.
In recent years, Dr. Franklin and his colleagues have published multiple studies that reveal new details about the workings of myelin regeneration, especially the biology by which oligodendrocyte progenitor cells become new oligodendrocytes.
“There are simple steps in that process,” Dr. Franklin said. “What we’ve been able to do is decorate that simple model with a whole host of mechanisms that allow remyelination to take place.”
In 2011, Franklin and his colleagues published a study in rodents identifying the RXRg gene as a key promoter of remyelination, making it a potential target for therapy (Nat Neurosci. 2011;14:45-53).
“There’s still a lot more to be learned,” Dr. Franklin said, “but we’ve learned a sufficient amount that we can engage in a meaningful way with the pharmaceutical industry and MS clinicians to make regenerative medicines an effective component of the MS therapeutic armory.”
Dr. Franklin has no relevant disclosures.
FROM ACTRIMS FORUM 2018
Researcher’s talk will tackle aging and gut bacteria in MS
Germs, genes, and aging each play a role in the development of multiple sclerosis (MS), but researchers are still figuring out how they’re connected. Now, a speaker at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis will shed light on recent findings that offer new insight into a specific type of germ – gut bacteria.
Suhayl Dhib-Jalbut, MD, ACTRIMS’s former president, will highlight his team’s investigation into the links between aging and alterations in gut microbiota in MS during the Kenneth P. Johnson Memorial Lecture on Feb. 1 at the meeting in San Diego.
Dr. Dhib-Jalbut’s presentation will focus on findings of a study by his team that was published late last year in Proceedings of the National Academy of Sciences of the U.S.A. (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
As the study explains, Dr. Dhib-Jalbut and colleagues triggered spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice by disrupting gut bacteria during adolescence and early young adulthood. But the process of aging in the mice past early young adulthood suppressed EAE onset by boosting immunologic tolerance.
The findings in this animal model offer insight into why the incidence of MS peaks at ages 20-40 years in humans, he said. “The implication is that one can perhaps manipulate gut bacteria with antibiotics or other treatments to impact the course of MS.”
Germs, genes, and aging each play a role in the development of multiple sclerosis (MS), but researchers are still figuring out how they’re connected. Now, a speaker at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis will shed light on recent findings that offer new insight into a specific type of germ – gut bacteria.
Suhayl Dhib-Jalbut, MD, ACTRIMS’s former president, will highlight his team’s investigation into the links between aging and alterations in gut microbiota in MS during the Kenneth P. Johnson Memorial Lecture on Feb. 1 at the meeting in San Diego.
Dr. Dhib-Jalbut’s presentation will focus on findings of a study by his team that was published late last year in Proceedings of the National Academy of Sciences of the U.S.A. (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
As the study explains, Dr. Dhib-Jalbut and colleagues triggered spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice by disrupting gut bacteria during adolescence and early young adulthood. But the process of aging in the mice past early young adulthood suppressed EAE onset by boosting immunologic tolerance.
The findings in this animal model offer insight into why the incidence of MS peaks at ages 20-40 years in humans, he said. “The implication is that one can perhaps manipulate gut bacteria with antibiotics or other treatments to impact the course of MS.”
Germs, genes, and aging each play a role in the development of multiple sclerosis (MS), but researchers are still figuring out how they’re connected. Now, a speaker at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis will shed light on recent findings that offer new insight into a specific type of germ – gut bacteria.
Suhayl Dhib-Jalbut, MD, ACTRIMS’s former president, will highlight his team’s investigation into the links between aging and alterations in gut microbiota in MS during the Kenneth P. Johnson Memorial Lecture on Feb. 1 at the meeting in San Diego.
Dr. Dhib-Jalbut’s presentation will focus on findings of a study by his team that was published late last year in Proceedings of the National Academy of Sciences of the U.S.A. (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
As the study explains, Dr. Dhib-Jalbut and colleagues triggered spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice by disrupting gut bacteria during adolescence and early young adulthood. But the process of aging in the mice past early young adulthood suppressed EAE onset by boosting immunologic tolerance.
The findings in this animal model offer insight into why the incidence of MS peaks at ages 20-40 years in humans, he said. “The implication is that one can perhaps manipulate gut bacteria with antibiotics or other treatments to impact the course of MS.”
REPORTING FROM ACTRIMS FORUM 2018
ACTRIMS Forum 2018 highlights MS therapeutic targets
Current and future therapeutic targets will be the major focus of a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), according to the meeting’s scientific program committee chair.
As many as 1,000 attendees are expected at the ACTRIMS Forum in San Diego, Feb. 1-3, Dr. Segal said, and about 300 abstracts will be presented. “The idea is for the meeting to be academically rigorous and have a speaker roster composed of the thought leaders in the field to make it akin to more of a keystone symposium.”
The program begins on Feb. 1 with presentations from young investigators about Emerging Concepts in MS. The other sessions will feature discussions about the blood-brain barrier, lymphocytes, cutting-edge developments in MS research, microglia and macrophages, astrocytes, and oligodendrocytes and their precursors.
“The sessions will begin with an overview of the particular target and its role in MS,” Dr. Segal said. “For example, the blood-brain barrier session starts with an overview of the different cell types that maintain the barrier’s integrity and the different ways they could prevent inflammatory cells from entering the central nervous system and causing lesions.”
One presentation in that session, he said, will discuss lessons from research into the mechanism of action of natalizumab (Tysabri). Another presentation focuses on new adhesion molecules – a crucial component of the inflammatory system – that have been discovered in animal models and may lead to new blocking therapies, he said.
The discussion about lymphocytes – white blood cells – will include presentations about new and emerging therapies that deplete them in different ways, he said. “One talk is about alemtuzumab (Lemtrada), which blocks all lymphocytes and can make you susceptible to other autoimmune disorders. What does that mean about how MS is similar to or different than other autoimmune diseases?”
On the myelin front, he said, “there will be a number of talks about how we identify remyelinating agents for clinical trials and how can we enhance precursors of myelination and reconstitute the damaged myelin.”
Another session will look at astrocytes, the glial support cells that are attracting newfound attention. Researchers have known that they’re stimulated in MS, and now new research is suggesting they can cause damage, he said. “They might be a completely new target. There’s evidence that they can have a neuroprotective effect, but it depends on how they’re stimulated.”
Are we on the cusp of being able to reverse damage from MS? “The answers are highly speculative. Research is so unpredictable and clinical trials do take a while,” he said. Still, “we understand repair pathways better than we ever have, and there’s lots of exciting work being done in animal models. We’re closer than we ever have been, and I do believe those drugs will be tested in clinical trials, hopefully within the next 5-10 years.”
Dr. Segal disclosed receiving an investigator-initiated grant from Genentech and support from Mallinckrodt for a clinical trial.
Current and future therapeutic targets will be the major focus of a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), according to the meeting’s scientific program committee chair.
As many as 1,000 attendees are expected at the ACTRIMS Forum in San Diego, Feb. 1-3, Dr. Segal said, and about 300 abstracts will be presented. “The idea is for the meeting to be academically rigorous and have a speaker roster composed of the thought leaders in the field to make it akin to more of a keystone symposium.”
The program begins on Feb. 1 with presentations from young investigators about Emerging Concepts in MS. The other sessions will feature discussions about the blood-brain barrier, lymphocytes, cutting-edge developments in MS research, microglia and macrophages, astrocytes, and oligodendrocytes and their precursors.
“The sessions will begin with an overview of the particular target and its role in MS,” Dr. Segal said. “For example, the blood-brain barrier session starts with an overview of the different cell types that maintain the barrier’s integrity and the different ways they could prevent inflammatory cells from entering the central nervous system and causing lesions.”
One presentation in that session, he said, will discuss lessons from research into the mechanism of action of natalizumab (Tysabri). Another presentation focuses on new adhesion molecules – a crucial component of the inflammatory system – that have been discovered in animal models and may lead to new blocking therapies, he said.
The discussion about lymphocytes – white blood cells – will include presentations about new and emerging therapies that deplete them in different ways, he said. “One talk is about alemtuzumab (Lemtrada), which blocks all lymphocytes and can make you susceptible to other autoimmune disorders. What does that mean about how MS is similar to or different than other autoimmune diseases?”
On the myelin front, he said, “there will be a number of talks about how we identify remyelinating agents for clinical trials and how can we enhance precursors of myelination and reconstitute the damaged myelin.”
Another session will look at astrocytes, the glial support cells that are attracting newfound attention. Researchers have known that they’re stimulated in MS, and now new research is suggesting they can cause damage, he said. “They might be a completely new target. There’s evidence that they can have a neuroprotective effect, but it depends on how they’re stimulated.”
Are we on the cusp of being able to reverse damage from MS? “The answers are highly speculative. Research is so unpredictable and clinical trials do take a while,” he said. Still, “we understand repair pathways better than we ever have, and there’s lots of exciting work being done in animal models. We’re closer than we ever have been, and I do believe those drugs will be tested in clinical trials, hopefully within the next 5-10 years.”
Dr. Segal disclosed receiving an investigator-initiated grant from Genentech and support from Mallinckrodt for a clinical trial.
Current and future therapeutic targets will be the major focus of a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), according to the meeting’s scientific program committee chair.
As many as 1,000 attendees are expected at the ACTRIMS Forum in San Diego, Feb. 1-3, Dr. Segal said, and about 300 abstracts will be presented. “The idea is for the meeting to be academically rigorous and have a speaker roster composed of the thought leaders in the field to make it akin to more of a keystone symposium.”
The program begins on Feb. 1 with presentations from young investigators about Emerging Concepts in MS. The other sessions will feature discussions about the blood-brain barrier, lymphocytes, cutting-edge developments in MS research, microglia and macrophages, astrocytes, and oligodendrocytes and their precursors.
“The sessions will begin with an overview of the particular target and its role in MS,” Dr. Segal said. “For example, the blood-brain barrier session starts with an overview of the different cell types that maintain the barrier’s integrity and the different ways they could prevent inflammatory cells from entering the central nervous system and causing lesions.”
One presentation in that session, he said, will discuss lessons from research into the mechanism of action of natalizumab (Tysabri). Another presentation focuses on new adhesion molecules – a crucial component of the inflammatory system – that have been discovered in animal models and may lead to new blocking therapies, he said.
The discussion about lymphocytes – white blood cells – will include presentations about new and emerging therapies that deplete them in different ways, he said. “One talk is about alemtuzumab (Lemtrada), which blocks all lymphocytes and can make you susceptible to other autoimmune disorders. What does that mean about how MS is similar to or different than other autoimmune diseases?”
On the myelin front, he said, “there will be a number of talks about how we identify remyelinating agents for clinical trials and how can we enhance precursors of myelination and reconstitute the damaged myelin.”
Another session will look at astrocytes, the glial support cells that are attracting newfound attention. Researchers have known that they’re stimulated in MS, and now new research is suggesting they can cause damage, he said. “They might be a completely new target. There’s evidence that they can have a neuroprotective effect, but it depends on how they’re stimulated.”
Are we on the cusp of being able to reverse damage from MS? “The answers are highly speculative. Research is so unpredictable and clinical trials do take a while,” he said. Still, “we understand repair pathways better than we ever have, and there’s lots of exciting work being done in animal models. We’re closer than we ever have been, and I do believe those drugs will be tested in clinical trials, hopefully within the next 5-10 years.”
Dr. Segal disclosed receiving an investigator-initiated grant from Genentech and support from Mallinckrodt for a clinical trial.
FROM ACTRIMS FORUM 2018
Generic Glatiramer Acetate Remains Safe and Effective for Two Years
Generic glatiramer acetate remains effective and safe over two years of treatment for patients with relapsing-remitting multiple sclerosis (MS), according to data published in the December 2017 issue of Multiple Sclerosis Journal. The data also indicate that switching from branded glatiramer acetate to a generic formulation is safe and well tolerated.
The European Medicines Agency required clinical trial data to support the authorization of generic glatiramer acetate. Krzysztof Selmaj, MD, a neurologist at the Neurology Center Lodz in Poland, and colleagues conducted a nine-month study to assess the equivalence of generic glatiramer acetate with that of Copaxone, a branded formulation of the drug. The double-blind, phase III GATE trial suggested that the drugs had equivalent efficacy, safety, and tolerability.
An Open-Label Extension
Patients who completed the nine-month trial were eligible to continue into a 15-month open-label extension on generic glatiramer acetate. The goals of the extension were to evaluate the effects of long-term exposure to the drug and to assess whether switching from branded to generic glatiramer acetate influenced drug safety and efficacy.
The researchers enrolled 796 patients from 17 countries into the double-blind study. Eligible patients were between ages 18 and 55, had relapsing-remitting MS, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Patients were randomized to receive 20 mg/mL/day of generic glatiramer acetate, 20 mg/mL/day of branded glatiramer acetate, or matching placebo.
The investigators performed safety evaluations at months 12, 15, 18, 21, and 24. They conducted EDSS scoring and brain MRI scans at months 12, 18, and 24. To assess glatiramer acetate antidrug antibodies, the researchers collected serum samples at baseline and months 1, 3, 6, 9, 12, 18, and 24.
Branded and Generic Formulations Produced Similar Outcomes
In all, 735 participants completed the double-blind study. In addition, 728 patients entered the open-label extension, and 670 completed it.
The proportion of patients completing the trial was 93.8% among patients who received generic treatment throughout, 92.9% among patients who switched from branded to generic, and 81.5% among patients who switched from placebo to generic glatiramer acetate.
The mean number of gadolinium-enhancing lesions was similar at months 12, 18, and 24 for patients who had started the blinded study on generic glatiramer acetate and those who had started on branded glatiramer acetate. The changes in the other MRI outcomes were similar for these two groups.
The estimated annualized relapse rates in the extension study were 0.21 for patients who took generic glatiramer acetate throughout, 0.24 for patients who switched from branded to generic glatiramer acetate, and 0.23 for patients who switched from placebo to generic glatiramer acetate.
The rate of adverse events was similar for patients who took generic glatiramer acetate throughout (33.3%) and those who switched from branded to generic treatment (36.5%). The rate of adverse events was 43.2% among patients who switched from placebo to generic glatiramer acetate. Severe and serious adverse events were uncommon and occurred at similar rates among patients who started on generic treatment and those who started on branded treatment.
During the blinded phase, antidrug antibodies formed with comparable frequency among patients who received generic and branded glatiramer treatment. During the open-label extension, the antidrug antibody titers in the group switching from branded to generic glatiramer treatment remained similar to that of the group continuing on generic treatment.
“These data should help patients and prescribers to positively consider generic glatiramer acetate as an alternative to branded glatiramer acetate,” said Dr. Selmaj.
—Erik Greb
Suggested Reading
Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23(14):1909-1917.
Generic glatiramer acetate remains effective and safe over two years of treatment for patients with relapsing-remitting multiple sclerosis (MS), according to data published in the December 2017 issue of Multiple Sclerosis Journal. The data also indicate that switching from branded glatiramer acetate to a generic formulation is safe and well tolerated.
The European Medicines Agency required clinical trial data to support the authorization of generic glatiramer acetate. Krzysztof Selmaj, MD, a neurologist at the Neurology Center Lodz in Poland, and colleagues conducted a nine-month study to assess the equivalence of generic glatiramer acetate with that of Copaxone, a branded formulation of the drug. The double-blind, phase III GATE trial suggested that the drugs had equivalent efficacy, safety, and tolerability.
An Open-Label Extension
Patients who completed the nine-month trial were eligible to continue into a 15-month open-label extension on generic glatiramer acetate. The goals of the extension were to evaluate the effects of long-term exposure to the drug and to assess whether switching from branded to generic glatiramer acetate influenced drug safety and efficacy.
The researchers enrolled 796 patients from 17 countries into the double-blind study. Eligible patients were between ages 18 and 55, had relapsing-remitting MS, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Patients were randomized to receive 20 mg/mL/day of generic glatiramer acetate, 20 mg/mL/day of branded glatiramer acetate, or matching placebo.
The investigators performed safety evaluations at months 12, 15, 18, 21, and 24. They conducted EDSS scoring and brain MRI scans at months 12, 18, and 24. To assess glatiramer acetate antidrug antibodies, the researchers collected serum samples at baseline and months 1, 3, 6, 9, 12, 18, and 24.
Branded and Generic Formulations Produced Similar Outcomes
In all, 735 participants completed the double-blind study. In addition, 728 patients entered the open-label extension, and 670 completed it.
The proportion of patients completing the trial was 93.8% among patients who received generic treatment throughout, 92.9% among patients who switched from branded to generic, and 81.5% among patients who switched from placebo to generic glatiramer acetate.
The mean number of gadolinium-enhancing lesions was similar at months 12, 18, and 24 for patients who had started the blinded study on generic glatiramer acetate and those who had started on branded glatiramer acetate. The changes in the other MRI outcomes were similar for these two groups.
The estimated annualized relapse rates in the extension study were 0.21 for patients who took generic glatiramer acetate throughout, 0.24 for patients who switched from branded to generic glatiramer acetate, and 0.23 for patients who switched from placebo to generic glatiramer acetate.
The rate of adverse events was similar for patients who took generic glatiramer acetate throughout (33.3%) and those who switched from branded to generic treatment (36.5%). The rate of adverse events was 43.2% among patients who switched from placebo to generic glatiramer acetate. Severe and serious adverse events were uncommon and occurred at similar rates among patients who started on generic treatment and those who started on branded treatment.
During the blinded phase, antidrug antibodies formed with comparable frequency among patients who received generic and branded glatiramer treatment. During the open-label extension, the antidrug antibody titers in the group switching from branded to generic glatiramer treatment remained similar to that of the group continuing on generic treatment.
“These data should help patients and prescribers to positively consider generic glatiramer acetate as an alternative to branded glatiramer acetate,” said Dr. Selmaj.
—Erik Greb
Suggested Reading
Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23(14):1909-1917.
Generic glatiramer acetate remains effective and safe over two years of treatment for patients with relapsing-remitting multiple sclerosis (MS), according to data published in the December 2017 issue of Multiple Sclerosis Journal. The data also indicate that switching from branded glatiramer acetate to a generic formulation is safe and well tolerated.
The European Medicines Agency required clinical trial data to support the authorization of generic glatiramer acetate. Krzysztof Selmaj, MD, a neurologist at the Neurology Center Lodz in Poland, and colleagues conducted a nine-month study to assess the equivalence of generic glatiramer acetate with that of Copaxone, a branded formulation of the drug. The double-blind, phase III GATE trial suggested that the drugs had equivalent efficacy, safety, and tolerability.
An Open-Label Extension
Patients who completed the nine-month trial were eligible to continue into a 15-month open-label extension on generic glatiramer acetate. The goals of the extension were to evaluate the effects of long-term exposure to the drug and to assess whether switching from branded to generic glatiramer acetate influenced drug safety and efficacy.
The researchers enrolled 796 patients from 17 countries into the double-blind study. Eligible patients were between ages 18 and 55, had relapsing-remitting MS, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Patients were randomized to receive 20 mg/mL/day of generic glatiramer acetate, 20 mg/mL/day of branded glatiramer acetate, or matching placebo.
The investigators performed safety evaluations at months 12, 15, 18, 21, and 24. They conducted EDSS scoring and brain MRI scans at months 12, 18, and 24. To assess glatiramer acetate antidrug antibodies, the researchers collected serum samples at baseline and months 1, 3, 6, 9, 12, 18, and 24.
Branded and Generic Formulations Produced Similar Outcomes
In all, 735 participants completed the double-blind study. In addition, 728 patients entered the open-label extension, and 670 completed it.
The proportion of patients completing the trial was 93.8% among patients who received generic treatment throughout, 92.9% among patients who switched from branded to generic, and 81.5% among patients who switched from placebo to generic glatiramer acetate.
The mean number of gadolinium-enhancing lesions was similar at months 12, 18, and 24 for patients who had started the blinded study on generic glatiramer acetate and those who had started on branded glatiramer acetate. The changes in the other MRI outcomes were similar for these two groups.
The estimated annualized relapse rates in the extension study were 0.21 for patients who took generic glatiramer acetate throughout, 0.24 for patients who switched from branded to generic glatiramer acetate, and 0.23 for patients who switched from placebo to generic glatiramer acetate.
The rate of adverse events was similar for patients who took generic glatiramer acetate throughout (33.3%) and those who switched from branded to generic treatment (36.5%). The rate of adverse events was 43.2% among patients who switched from placebo to generic glatiramer acetate. Severe and serious adverse events were uncommon and occurred at similar rates among patients who started on generic treatment and those who started on branded treatment.
During the blinded phase, antidrug antibodies formed with comparable frequency among patients who received generic and branded glatiramer treatment. During the open-label extension, the antidrug antibody titers in the group switching from branded to generic glatiramer treatment remained similar to that of the group continuing on generic treatment.
“These data should help patients and prescribers to positively consider generic glatiramer acetate as an alternative to branded glatiramer acetate,” said Dr. Selmaj.
—Erik Greb
Suggested Reading
Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23(14):1909-1917.
2017 update to McDonald criteria loosens MS diagnosis somewhat
Updates to the McDonald criteria for diagnosing multiple sclerosis (MS), first introduced in 2010, should allow initiation of therapy earlier in the time point of disease. The changes expand some of the criteria that can be used for diagnosis of disease.
The McDonald criteria should be applied primarily to patients with a typical clinically isolated syndrome – that is, in whom the probability of MS is high. They are best applied to patients 11 years or older, according to first author Alan J. Thompson, MD, and his colleagues on the International Panel on Diagnosis of Multiple Sclerosis. Their update to the 2010 criteria was published online Dec. 21, 2017, in The Lancet Neurology.
The changes include:
• Cerebrospinal fluid-specific oligoclonal bands can now be used to diagnose MS in patients with a typical clinically isolated syndrome in whom MRI or clinical signs point to dissemination in space (DIS), and if there is no other, better explanation for clinical signs.
• Symptomatic or asymptomatic MRI lesions can be used in the determination of DIS or dissemination in time (DIT). An exception is MRI lesions in the optic nerve in patients with optic neuritis, due to insufficient evidence. Specifically, the panel notes that DIS “can be demonstrated by one or more T2-hyperintense lesions [symptomatic or asymptomatic] that are characteristic of multiple sclerosis in two or more of four areas of the CNS: periventricular, cortical or juxtacortical, and infratentorial brain regions, and the spinal cord.” DIT is defined by “the simultaneous presence of gadolinium-enhancing and non-enhancing lesions [symptomatic or asymptomatic] at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI.”
• In patients experiencing brainstem or spinal cord clinically isolated syndrome, symptomatic lesions are sufficient to determine DIS or DIT.
• Cortical or juxtacortical lesions can be used in determining DIS.
• When MS is diagnosed, physicians should determine disease course (relapsing-remitting, primary progressive, or secondary progressive), whether the disease is active or not, and whether it is progressive, using the clinical history over the previous year.
The update was driven by a range of factors, including ongoing developments in imaging, the performance of the 2010 guidelines in diverse populations, and potential confusion between MS and other conditions with similar imaging characteristics, such as neuromyelitis optica spectrum disorders, which should always be considered because symptoms can overlap with MS. These conditions demand different treatment protocols. In addition, in 2016, the European Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network suggested changes to the MRI criteria for diagnosing multiple sclerosis.
Updates to the guidelines are hardly finished. The panel called for future examination of optic nerve involvement, diverse populations, advanced imaging techniques, and biomarkers.
Some of the panel members reported financial ties to the pharmaceutical industry.
SOURCE: Thompson A et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30470-2
Earlier diagnosis and treatment initiation is increasingly important to prevent long-term disability. In recent years, MRI has become a more powerful diagnostic tool. These guidelines present useful improvements, but challenges remain. Due to a lack of data, it is not clear how well the McDonald criteria perform in nonwhite and non-Western populations, as well as in patients with atypical presentation of a clinically isolated syndrome. The guidelines also offer little help in the treatment of asymptomatic patients with radiologically isolated syndromes who eventually develop dissemination in time or space as determined by MRI findings.
Careful application of the new criteria should reduce misdiagnosis between MS and migraine, fibromyalgia, psychiatric disorders, and neuromyelitis optica spectrum disorders, but vigilance is required and clinicians should keep an open mind regarding alternative diagnoses.
Stephen Hauser, MD, and Riley Bove, MD, are with the University of California, San Francisco. Dr. Hauser serves on the board of trustees for Neurona Therapeutics, and scientific advisory boards for Symbiotix, Annexon, Bionure, and Molecular Stethoscope, and he has received travel reimbursement and writing support from F. Hoffmann La Roche. Dr. Bove has received fees from Genzyme-Sanofi, Roche-Genentech, and Novartis. Their comments are derived from an editorial accompanying the 2017 McDonald criteria (Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422[17]30461-1)
Earlier diagnosis and treatment initiation is increasingly important to prevent long-term disability. In recent years, MRI has become a more powerful diagnostic tool. These guidelines present useful improvements, but challenges remain. Due to a lack of data, it is not clear how well the McDonald criteria perform in nonwhite and non-Western populations, as well as in patients with atypical presentation of a clinically isolated syndrome. The guidelines also offer little help in the treatment of asymptomatic patients with radiologically isolated syndromes who eventually develop dissemination in time or space as determined by MRI findings.
Careful application of the new criteria should reduce misdiagnosis between MS and migraine, fibromyalgia, psychiatric disorders, and neuromyelitis optica spectrum disorders, but vigilance is required and clinicians should keep an open mind regarding alternative diagnoses.
Stephen Hauser, MD, and Riley Bove, MD, are with the University of California, San Francisco. Dr. Hauser serves on the board of trustees for Neurona Therapeutics, and scientific advisory boards for Symbiotix, Annexon, Bionure, and Molecular Stethoscope, and he has received travel reimbursement and writing support from F. Hoffmann La Roche. Dr. Bove has received fees from Genzyme-Sanofi, Roche-Genentech, and Novartis. Their comments are derived from an editorial accompanying the 2017 McDonald criteria (Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422[17]30461-1)
Earlier diagnosis and treatment initiation is increasingly important to prevent long-term disability. In recent years, MRI has become a more powerful diagnostic tool. These guidelines present useful improvements, but challenges remain. Due to a lack of data, it is not clear how well the McDonald criteria perform in nonwhite and non-Western populations, as well as in patients with atypical presentation of a clinically isolated syndrome. The guidelines also offer little help in the treatment of asymptomatic patients with radiologically isolated syndromes who eventually develop dissemination in time or space as determined by MRI findings.
Careful application of the new criteria should reduce misdiagnosis between MS and migraine, fibromyalgia, psychiatric disorders, and neuromyelitis optica spectrum disorders, but vigilance is required and clinicians should keep an open mind regarding alternative diagnoses.
Stephen Hauser, MD, and Riley Bove, MD, are with the University of California, San Francisco. Dr. Hauser serves on the board of trustees for Neurona Therapeutics, and scientific advisory boards for Symbiotix, Annexon, Bionure, and Molecular Stethoscope, and he has received travel reimbursement and writing support from F. Hoffmann La Roche. Dr. Bove has received fees from Genzyme-Sanofi, Roche-Genentech, and Novartis. Their comments are derived from an editorial accompanying the 2017 McDonald criteria (Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422[17]30461-1)
Updates to the McDonald criteria for diagnosing multiple sclerosis (MS), first introduced in 2010, should allow initiation of therapy earlier in the time point of disease. The changes expand some of the criteria that can be used for diagnosis of disease.
The McDonald criteria should be applied primarily to patients with a typical clinically isolated syndrome – that is, in whom the probability of MS is high. They are best applied to patients 11 years or older, according to first author Alan J. Thompson, MD, and his colleagues on the International Panel on Diagnosis of Multiple Sclerosis. Their update to the 2010 criteria was published online Dec. 21, 2017, in The Lancet Neurology.
The changes include:
• Cerebrospinal fluid-specific oligoclonal bands can now be used to diagnose MS in patients with a typical clinically isolated syndrome in whom MRI or clinical signs point to dissemination in space (DIS), and if there is no other, better explanation for clinical signs.
• Symptomatic or asymptomatic MRI lesions can be used in the determination of DIS or dissemination in time (DIT). An exception is MRI lesions in the optic nerve in patients with optic neuritis, due to insufficient evidence. Specifically, the panel notes that DIS “can be demonstrated by one or more T2-hyperintense lesions [symptomatic or asymptomatic] that are characteristic of multiple sclerosis in two or more of four areas of the CNS: periventricular, cortical or juxtacortical, and infratentorial brain regions, and the spinal cord.” DIT is defined by “the simultaneous presence of gadolinium-enhancing and non-enhancing lesions [symptomatic or asymptomatic] at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI.”
• In patients experiencing brainstem or spinal cord clinically isolated syndrome, symptomatic lesions are sufficient to determine DIS or DIT.
• Cortical or juxtacortical lesions can be used in determining DIS.
• When MS is diagnosed, physicians should determine disease course (relapsing-remitting, primary progressive, or secondary progressive), whether the disease is active or not, and whether it is progressive, using the clinical history over the previous year.
The update was driven by a range of factors, including ongoing developments in imaging, the performance of the 2010 guidelines in diverse populations, and potential confusion between MS and other conditions with similar imaging characteristics, such as neuromyelitis optica spectrum disorders, which should always be considered because symptoms can overlap with MS. These conditions demand different treatment protocols. In addition, in 2016, the European Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network suggested changes to the MRI criteria for diagnosing multiple sclerosis.
Updates to the guidelines are hardly finished. The panel called for future examination of optic nerve involvement, diverse populations, advanced imaging techniques, and biomarkers.
Some of the panel members reported financial ties to the pharmaceutical industry.
SOURCE: Thompson A et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30470-2
Updates to the McDonald criteria for diagnosing multiple sclerosis (MS), first introduced in 2010, should allow initiation of therapy earlier in the time point of disease. The changes expand some of the criteria that can be used for diagnosis of disease.
The McDonald criteria should be applied primarily to patients with a typical clinically isolated syndrome – that is, in whom the probability of MS is high. They are best applied to patients 11 years or older, according to first author Alan J. Thompson, MD, and his colleagues on the International Panel on Diagnosis of Multiple Sclerosis. Their update to the 2010 criteria was published online Dec. 21, 2017, in The Lancet Neurology.
The changes include:
• Cerebrospinal fluid-specific oligoclonal bands can now be used to diagnose MS in patients with a typical clinically isolated syndrome in whom MRI or clinical signs point to dissemination in space (DIS), and if there is no other, better explanation for clinical signs.
• Symptomatic or asymptomatic MRI lesions can be used in the determination of DIS or dissemination in time (DIT). An exception is MRI lesions in the optic nerve in patients with optic neuritis, due to insufficient evidence. Specifically, the panel notes that DIS “can be demonstrated by one or more T2-hyperintense lesions [symptomatic or asymptomatic] that are characteristic of multiple sclerosis in two or more of four areas of the CNS: periventricular, cortical or juxtacortical, and infratentorial brain regions, and the spinal cord.” DIT is defined by “the simultaneous presence of gadolinium-enhancing and non-enhancing lesions [symptomatic or asymptomatic] at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI.”
• In patients experiencing brainstem or spinal cord clinically isolated syndrome, symptomatic lesions are sufficient to determine DIS or DIT.
• Cortical or juxtacortical lesions can be used in determining DIS.
• When MS is diagnosed, physicians should determine disease course (relapsing-remitting, primary progressive, or secondary progressive), whether the disease is active or not, and whether it is progressive, using the clinical history over the previous year.
The update was driven by a range of factors, including ongoing developments in imaging, the performance of the 2010 guidelines in diverse populations, and potential confusion between MS and other conditions with similar imaging characteristics, such as neuromyelitis optica spectrum disorders, which should always be considered because symptoms can overlap with MS. These conditions demand different treatment protocols. In addition, in 2016, the European Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network suggested changes to the MRI criteria for diagnosing multiple sclerosis.
Updates to the guidelines are hardly finished. The panel called for future examination of optic nerve involvement, diverse populations, advanced imaging techniques, and biomarkers.
Some of the panel members reported financial ties to the pharmaceutical industry.
SOURCE: Thompson A et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30470-2
FROM THE LANCET NEUROLOGY
Two MS diagnostic criteria found to have similar accuracy
The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria showed accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis, a retrospective study found.
“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration is given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” wrote researchers led by Massimo Filippi, MD. The report was published Dec. 21, 2017, in The Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment and more studies should be done to evaluate the effect of including optic nerve assessment as an additional DIS [dissemination in space] criterion.”
Dr. Filippi, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University, Milan, and his coauthors at eight centers reported that of the 368 patients, 189 (51%) developed clinically definite MS at the last evaluation, which occurred at a median of 50 months. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs. 93%, respectively), similar specificity (33% vs. 32%), and similar area under the curve values (AUC, 0.62 vs. 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (it stood at 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity fell to 26% and AUC dropped to 0.59.
The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.
“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (e.g., using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite multiple sclerosis.
The study was funded by the U.K. MS Society, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, and the Dutch MS Research Foundation. The authors reported having numerous financial disclosures with the pharmaceutical industry.
SOURCE: Filippi M et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30469-6.
As multiple sclerosis diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, which in turn has helped clinicians establish earlier diagnosis. In an editorial published online Dec. 21, 2017, in The Lancet Neurology (doi: 10.1016/S1474-4422(17)30459-3), Anne H. Cross, MD, and Robert N. Naismith, MD, point out that while the study by Dr. Filippi et al. showed that for both sets of MRI criteria sensitivity was greater than specificity for predicting clinically definite multiple sclerosis, the modest specificity is cause for concern. They cited one study (Neurology 2016;87:1393-9) that emphasized the importance of not misdiagnosing other CNS diseases as multiple sclerosis. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” wrote Dr. Cross and Dr. Naismith, both with the department of neurology at Washington University, St. Louis. “[Seventy percent] of the 110 individuals had received disease-modifying therapy and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with non-specific neurological symptoms.”
The authors noted that vascular and other diseases can cause MRI abnormalities that could meet the 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) recommendations or the 2010 and 2017 McDonald MRI criteria. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for dissemination in time, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, they advise clinicians to weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses.
Dr. Cross has received consulting fees from AbbVie, Bayer, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckodt, Novartis, and Teva. Dr. Naismith has consulted for Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Teva.
As multiple sclerosis diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, which in turn has helped clinicians establish earlier diagnosis. In an editorial published online Dec. 21, 2017, in The Lancet Neurology (doi: 10.1016/S1474-4422(17)30459-3), Anne H. Cross, MD, and Robert N. Naismith, MD, point out that while the study by Dr. Filippi et al. showed that for both sets of MRI criteria sensitivity was greater than specificity for predicting clinically definite multiple sclerosis, the modest specificity is cause for concern. They cited one study (Neurology 2016;87:1393-9) that emphasized the importance of not misdiagnosing other CNS diseases as multiple sclerosis. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” wrote Dr. Cross and Dr. Naismith, both with the department of neurology at Washington University, St. Louis. “[Seventy percent] of the 110 individuals had received disease-modifying therapy and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with non-specific neurological symptoms.”
The authors noted that vascular and other diseases can cause MRI abnormalities that could meet the 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) recommendations or the 2010 and 2017 McDonald MRI criteria. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for dissemination in time, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, they advise clinicians to weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses.
Dr. Cross has received consulting fees from AbbVie, Bayer, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckodt, Novartis, and Teva. Dr. Naismith has consulted for Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Teva.
As multiple sclerosis diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, which in turn has helped clinicians establish earlier diagnosis. In an editorial published online Dec. 21, 2017, in The Lancet Neurology (doi: 10.1016/S1474-4422(17)30459-3), Anne H. Cross, MD, and Robert N. Naismith, MD, point out that while the study by Dr. Filippi et al. showed that for both sets of MRI criteria sensitivity was greater than specificity for predicting clinically definite multiple sclerosis, the modest specificity is cause for concern. They cited one study (Neurology 2016;87:1393-9) that emphasized the importance of not misdiagnosing other CNS diseases as multiple sclerosis. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” wrote Dr. Cross and Dr. Naismith, both with the department of neurology at Washington University, St. Louis. “[Seventy percent] of the 110 individuals had received disease-modifying therapy and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with non-specific neurological symptoms.”
The authors noted that vascular and other diseases can cause MRI abnormalities that could meet the 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) recommendations or the 2010 and 2017 McDonald MRI criteria. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for dissemination in time, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, they advise clinicians to weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses.
Dr. Cross has received consulting fees from AbbVie, Bayer, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckodt, Novartis, and Teva. Dr. Naismith has consulted for Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Teva.
The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria showed accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis, a retrospective study found.
“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration is given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” wrote researchers led by Massimo Filippi, MD. The report was published Dec. 21, 2017, in The Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment and more studies should be done to evaluate the effect of including optic nerve assessment as an additional DIS [dissemination in space] criterion.”
Dr. Filippi, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University, Milan, and his coauthors at eight centers reported that of the 368 patients, 189 (51%) developed clinically definite MS at the last evaluation, which occurred at a median of 50 months. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs. 93%, respectively), similar specificity (33% vs. 32%), and similar area under the curve values (AUC, 0.62 vs. 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (it stood at 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity fell to 26% and AUC dropped to 0.59.
The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.
“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (e.g., using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite multiple sclerosis.
The study was funded by the U.K. MS Society, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, and the Dutch MS Research Foundation. The authors reported having numerous financial disclosures with the pharmaceutical industry.
SOURCE: Filippi M et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30469-6.
The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria showed accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis, a retrospective study found.
“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration is given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” wrote researchers led by Massimo Filippi, MD. The report was published Dec. 21, 2017, in The Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment and more studies should be done to evaluate the effect of including optic nerve assessment as an additional DIS [dissemination in space] criterion.”
Dr. Filippi, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University, Milan, and his coauthors at eight centers reported that of the 368 patients, 189 (51%) developed clinically definite MS at the last evaluation, which occurred at a median of 50 months. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs. 93%, respectively), similar specificity (33% vs. 32%), and similar area under the curve values (AUC, 0.62 vs. 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (it stood at 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity fell to 26% and AUC dropped to 0.59.
The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.
“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (e.g., using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite multiple sclerosis.
The study was funded by the U.K. MS Society, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, and the Dutch MS Research Foundation. The authors reported having numerous financial disclosures with the pharmaceutical industry.
SOURCE: Filippi M et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30469-6.
FROM THE LANCET NEUROLOGY
Key clinical point:
Major finding: The 2016 MAGNIMS criteria and 2010 McDonald criteria performed similarly for predicting clinically definite multiple sclerosis (a sensitivity of 91% and 93%, respectively, and a specificity of 33% and 32%).
Study details: A retrospective study of 368 patients with clinically isolated syndrome.
Disclosures: The study was funded by the U.K. MS Society, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, and the Dutch MS Research Foundation. The study authors reported having numerous financial disclosures.
Source: Filippi M et al., Lancet Neurol. 2017 Dec 21. doi: 10.1016/S1474-4422(17)30469-6.