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VIDEO: New MS ambulatory measure could fill clinical gap
REPORTING FROM ACTRIMS FORUM 2018
SAN DIEGO – Although clinical tools to assess ambulatory function among people with multiple sclerosis exist, some measure it as part of a comprehensive assessment while others require the patient to answer many questions and then clinicians to calculate a score.
To devise a more targeted, simpler instrument, Emily Evans, MD, and her colleagues developed the PDAS or Patient Derived Ambulation Scale. They evaluated the correlation of this single-item scale to assess ambulation – an important measure of patient function – and evaluated how the results correlated with existing tools such as the Patient Determined Disease Steps and 12-item MS Walking Scale. Dr. Evans presented preliminary findings at the ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“We feel this is a quick test that can be readily implemented into clinical practice,” Dr. Evans, a neurologist at the John L. Trotter MS Center at Washington University in St. Louis, said in a video interview.
REPORTING FROM ACTRIMS FORUM 2018
SAN DIEGO – Although clinical tools to assess ambulatory function among people with multiple sclerosis exist, some measure it as part of a comprehensive assessment while others require the patient to answer many questions and then clinicians to calculate a score.
To devise a more targeted, simpler instrument, Emily Evans, MD, and her colleagues developed the PDAS or Patient Derived Ambulation Scale. They evaluated the correlation of this single-item scale to assess ambulation – an important measure of patient function – and evaluated how the results correlated with existing tools such as the Patient Determined Disease Steps and 12-item MS Walking Scale. Dr. Evans presented preliminary findings at the ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“We feel this is a quick test that can be readily implemented into clinical practice,” Dr. Evans, a neurologist at the John L. Trotter MS Center at Washington University in St. Louis, said in a video interview.
REPORTING FROM ACTRIMS FORUM 2018
SAN DIEGO – Although clinical tools to assess ambulatory function among people with multiple sclerosis exist, some measure it as part of a comprehensive assessment while others require the patient to answer many questions and then clinicians to calculate a score.
To devise a more targeted, simpler instrument, Emily Evans, MD, and her colleagues developed the PDAS or Patient Derived Ambulation Scale. They evaluated the correlation of this single-item scale to assess ambulation – an important measure of patient function – and evaluated how the results correlated with existing tools such as the Patient Determined Disease Steps and 12-item MS Walking Scale. Dr. Evans presented preliminary findings at the ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“We feel this is a quick test that can be readily implemented into clinical practice,” Dr. Evans, a neurologist at the John L. Trotter MS Center at Washington University in St. Louis, said in a video interview.
VIDEO: Alemtuzumab associated with long-term MS control in TOPAZ study
SAN DIEGO – A majority of patients with active relapsing-remitting multiple sclerosis and inadequate response to previous therapy achieved a durable response after treatment with alemtuzumab in the TOPAZ trial, a 5-year extension to the CARE-MS II study.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Almost half of the 317 participants in TOPAZ received no further therapy beyond their initial two courses of alemtuzumab infusion therapy that they received as part of the CARE-MS II study.
“If you follow patients over time ... you’re seeing a significant group of patients who have improvement. It’s very unexpected, especially when you look at the patients who entered the clinical trial who had a fair amount of active disease,” said Barry A. Singer, MD, director of The MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.
At the 7-year evaluation of patients in TOPAZ, the annualized relapse rate was 0.14. In addition, 87% of patients remained relapse-free in year 7. Dr. Singer and his colleagues also reported that 73% of TOPAZ participants were stable or improved based on their Expanded Disability Status Scale (EDSS) scores.
“As we follow the data out and follow these patients out, we’re seeing how the clinical course for these patients is dramatically improving for the majority of patients,” Dr. Singer said in a video interview at ACTRIMS Forum 2018, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The TOPAZ study also revealed that 69% of patients were free of clinical disease worsening and 44% experienced clinical disease improvement in the 6 months before year 7. The majority also had no evidence of disease activity, Dr. Singer reported.
“One of the attributes that makes alemtuzumab so attractive as a clinician and for patients is you can go through a couple of series of medication [treatments] ... and really alter your disease course – that is the exciting thing,” he said.
The Food and Drug Administration approved alemtuzumab (Lemtrada) in November 2014 for the treatment of patients with relapsing forms of multiple sclerosis. Use of alemtuzumab is generally reserved for patients who have had an inadequate response to two or more previous drugs indicated for the treatment of multiple sclerosis.
In CARE-MS II, participants received two annual courses of alemtuzumab: intravenous infusion of 12 mg/day for 5 days at baseline and again for 3 days at 12 months. Additional treatment in TOPAZ for relapse or MRI evidence of disease was at the discretion of the investigator and could include alemtuzumab retreatment 12 mg/day on 3 consecutive days 12 months or more after a previous course, or another disease-modifying therapy at any time. Annual follow-up exams included an MRI scan.
A durable treatment effect was achieved by a majority of patients, even though 47% received no further treatment with alemtuzumab or another disease-modifying therapy after the initial two alemtuzumab courses.
The incidence of most adverse events, including infusion-associated reactions and infections, decreased over the course of the TOPAZ study and were lower than the incidence reported in the 2-year CARE-MS II trial. Of note, the incidence of thyroid-related adverse events peaked in the third year of the follow-up and continued to decline out to 7 years, Dr. Singer said. “We’re not seeing any new safety issues.”
Dr. Singer and his coinvestigators plan to continue the research, monitoring and scoring patients over time.
The TOPAZ trial was funded by Sanofi Genzyme, which markets alemtuzumab. Dr. Singer disclosed that he receives clinical research support and is a speaker for Sanofi Genzyme.
SOURCE: Singer B et al. ACTRIMS Forum 2018, abstract P026.
SAN DIEGO – A majority of patients with active relapsing-remitting multiple sclerosis and inadequate response to previous therapy achieved a durable response after treatment with alemtuzumab in the TOPAZ trial, a 5-year extension to the CARE-MS II study.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Almost half of the 317 participants in TOPAZ received no further therapy beyond their initial two courses of alemtuzumab infusion therapy that they received as part of the CARE-MS II study.
“If you follow patients over time ... you’re seeing a significant group of patients who have improvement. It’s very unexpected, especially when you look at the patients who entered the clinical trial who had a fair amount of active disease,” said Barry A. Singer, MD, director of The MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.
At the 7-year evaluation of patients in TOPAZ, the annualized relapse rate was 0.14. In addition, 87% of patients remained relapse-free in year 7. Dr. Singer and his colleagues also reported that 73% of TOPAZ participants were stable or improved based on their Expanded Disability Status Scale (EDSS) scores.
“As we follow the data out and follow these patients out, we’re seeing how the clinical course for these patients is dramatically improving for the majority of patients,” Dr. Singer said in a video interview at ACTRIMS Forum 2018, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The TOPAZ study also revealed that 69% of patients were free of clinical disease worsening and 44% experienced clinical disease improvement in the 6 months before year 7. The majority also had no evidence of disease activity, Dr. Singer reported.
“One of the attributes that makes alemtuzumab so attractive as a clinician and for patients is you can go through a couple of series of medication [treatments] ... and really alter your disease course – that is the exciting thing,” he said.
The Food and Drug Administration approved alemtuzumab (Lemtrada) in November 2014 for the treatment of patients with relapsing forms of multiple sclerosis. Use of alemtuzumab is generally reserved for patients who have had an inadequate response to two or more previous drugs indicated for the treatment of multiple sclerosis.
In CARE-MS II, participants received two annual courses of alemtuzumab: intravenous infusion of 12 mg/day for 5 days at baseline and again for 3 days at 12 months. Additional treatment in TOPAZ for relapse or MRI evidence of disease was at the discretion of the investigator and could include alemtuzumab retreatment 12 mg/day on 3 consecutive days 12 months or more after a previous course, or another disease-modifying therapy at any time. Annual follow-up exams included an MRI scan.
A durable treatment effect was achieved by a majority of patients, even though 47% received no further treatment with alemtuzumab or another disease-modifying therapy after the initial two alemtuzumab courses.
The incidence of most adverse events, including infusion-associated reactions and infections, decreased over the course of the TOPAZ study and were lower than the incidence reported in the 2-year CARE-MS II trial. Of note, the incidence of thyroid-related adverse events peaked in the third year of the follow-up and continued to decline out to 7 years, Dr. Singer said. “We’re not seeing any new safety issues.”
Dr. Singer and his coinvestigators plan to continue the research, monitoring and scoring patients over time.
The TOPAZ trial was funded by Sanofi Genzyme, which markets alemtuzumab. Dr. Singer disclosed that he receives clinical research support and is a speaker for Sanofi Genzyme.
SOURCE: Singer B et al. ACTRIMS Forum 2018, abstract P026.
SAN DIEGO – A majority of patients with active relapsing-remitting multiple sclerosis and inadequate response to previous therapy achieved a durable response after treatment with alemtuzumab in the TOPAZ trial, a 5-year extension to the CARE-MS II study.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Almost half of the 317 participants in TOPAZ received no further therapy beyond their initial two courses of alemtuzumab infusion therapy that they received as part of the CARE-MS II study.
“If you follow patients over time ... you’re seeing a significant group of patients who have improvement. It’s very unexpected, especially when you look at the patients who entered the clinical trial who had a fair amount of active disease,” said Barry A. Singer, MD, director of The MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.
At the 7-year evaluation of patients in TOPAZ, the annualized relapse rate was 0.14. In addition, 87% of patients remained relapse-free in year 7. Dr. Singer and his colleagues also reported that 73% of TOPAZ participants were stable or improved based on their Expanded Disability Status Scale (EDSS) scores.
“As we follow the data out and follow these patients out, we’re seeing how the clinical course for these patients is dramatically improving for the majority of patients,” Dr. Singer said in a video interview at ACTRIMS Forum 2018, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The TOPAZ study also revealed that 69% of patients were free of clinical disease worsening and 44% experienced clinical disease improvement in the 6 months before year 7. The majority also had no evidence of disease activity, Dr. Singer reported.
“One of the attributes that makes alemtuzumab so attractive as a clinician and for patients is you can go through a couple of series of medication [treatments] ... and really alter your disease course – that is the exciting thing,” he said.
The Food and Drug Administration approved alemtuzumab (Lemtrada) in November 2014 for the treatment of patients with relapsing forms of multiple sclerosis. Use of alemtuzumab is generally reserved for patients who have had an inadequate response to two or more previous drugs indicated for the treatment of multiple sclerosis.
In CARE-MS II, participants received two annual courses of alemtuzumab: intravenous infusion of 12 mg/day for 5 days at baseline and again for 3 days at 12 months. Additional treatment in TOPAZ for relapse or MRI evidence of disease was at the discretion of the investigator and could include alemtuzumab retreatment 12 mg/day on 3 consecutive days 12 months or more after a previous course, or another disease-modifying therapy at any time. Annual follow-up exams included an MRI scan.
A durable treatment effect was achieved by a majority of patients, even though 47% received no further treatment with alemtuzumab or another disease-modifying therapy after the initial two alemtuzumab courses.
The incidence of most adverse events, including infusion-associated reactions and infections, decreased over the course of the TOPAZ study and were lower than the incidence reported in the 2-year CARE-MS II trial. Of note, the incidence of thyroid-related adverse events peaked in the third year of the follow-up and continued to decline out to 7 years, Dr. Singer said. “We’re not seeing any new safety issues.”
Dr. Singer and his coinvestigators plan to continue the research, monitoring and scoring patients over time.
The TOPAZ trial was funded by Sanofi Genzyme, which markets alemtuzumab. Dr. Singer disclosed that he receives clinical research support and is a speaker for Sanofi Genzyme.
SOURCE: Singer B et al. ACTRIMS Forum 2018, abstract P026.
REPORTING FROM ACTRIMS FORUM 2018
Key clinical point:
Major finding: The annualized relapse rate was 0.14 at year 7 among the 87% of participants who remained in the TOPAZ study.
Study details: A 5-year extension study of 317 participants from the initial CARE-MS II trial.
Disclosures: The TOPAZ trial was funded by Sanofi Genzyme, which markets alemtuzumab. Dr. Singer disclosed that he receives clinical research support and is a speaker for Sanofi Genzyme.
Source: Singer B et al. ACTRIMS Forum 2018, abstract P026.
Ibudilast shows promise in progressive MS
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
REPORTING FROM ACTRIMS FORUM 2018
Key clinical point: Ibudilast’s positive phase 2 trial results in progressive multiple sclerosis patients bode well for future development.
Major finding: Ibudilast treatment was associated with a 48% slowing in the rate of decline in brain atrophy as measured by brain parenchymal fraction.
Study details: A randomized trial of 255 subjects with progressive MS enrolled at 28 U.S. sites.
Disclosures: The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
Source: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
MS may be a transmissible protein misfolding disorder, study suggests
SAN DIEGO – MS may even be caused by prions, potentially putting it into the same category as Creutzfeldt-Jakob disease.
Researchers don’t think MS is contagious between humans. But their findings in mice do suggest that the disease is transmissible from “a seed of protein misfolding,” Shigeki Tsutsui, DVM, PhD, of the University of Calgary (Alta.), said in an interview in advance of his presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“The next question is: ‘What is actually causing primary damage?’ ” he said. “Our hypothesis is that it’s protein misfolding. If protein misfolding targets the central neuron cells, then those damaged cells release a kind of a trigger to start an immune response.”
This isn’t an unusual concept. Protein misfolding is believed to cause several chronic neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, Dr. Tsutsui said.
The researchers focused on the potential transmissibility of human prion protein “since we thought that the prion protein might be the candidate causing the MS,” he said.
Prion diseases are extremely rare and often deadly. They appear when normal cellular prion proteins are induced to misfold when they come in contact with infectious agents known as prions.
In humans, prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru (a condition spread among cannibals who eat the brains of other humans). Most famously, a variant of Creutzfeldt-Jakob disease has been linked – but not conclusively – to the eating of meat from cows infected with mad cow disease.
Depending on the condition, prion diseases can appear spontaneously, via inheritance or through infection.
In the new study, researchers intracerebrally injected brain homogenate from 10 patients with primary or secondary-progressive MS into 36 transgenic mice. All the mice over-expressed human prion protein. A control group of 23 mice were injected with homogenate from six donor brains.
At 6-12 months, the control mice did not develop pathology. However, the mice injected with brain matter from MS patients developed various levels of significant pathology. The researchers also managed to transmit illness from affected mice into another group of transgenic mice that over-expressed human prion protein via injection of brain homogenate.
While the mice in the study represent “a very extreme case” since their levels of prion protein expression were very high, it’s clear that “MS is actually transmissible,” Dr. Tsutsui said.
The study authors speculate that pathogenic prion protein triggers an autoimmune response by degenerating myelin and causing the release of cellular debris.
Could MS also be contagious? It may not be, even if it’s a prion disease, Dr. Tsutsui said. Some prion disease variants are neither contagious nor infectious.
The researchers plan to study the animal model they’ve created and explore the potential for its use in research, Dr. Tsutsui said.
The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
SOURCE: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
SAN DIEGO – MS may even be caused by prions, potentially putting it into the same category as Creutzfeldt-Jakob disease.
Researchers don’t think MS is contagious between humans. But their findings in mice do suggest that the disease is transmissible from “a seed of protein misfolding,” Shigeki Tsutsui, DVM, PhD, of the University of Calgary (Alta.), said in an interview in advance of his presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“The next question is: ‘What is actually causing primary damage?’ ” he said. “Our hypothesis is that it’s protein misfolding. If protein misfolding targets the central neuron cells, then those damaged cells release a kind of a trigger to start an immune response.”
This isn’t an unusual concept. Protein misfolding is believed to cause several chronic neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, Dr. Tsutsui said.
The researchers focused on the potential transmissibility of human prion protein “since we thought that the prion protein might be the candidate causing the MS,” he said.
Prion diseases are extremely rare and often deadly. They appear when normal cellular prion proteins are induced to misfold when they come in contact with infectious agents known as prions.
In humans, prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru (a condition spread among cannibals who eat the brains of other humans). Most famously, a variant of Creutzfeldt-Jakob disease has been linked – but not conclusively – to the eating of meat from cows infected with mad cow disease.
Depending on the condition, prion diseases can appear spontaneously, via inheritance or through infection.
In the new study, researchers intracerebrally injected brain homogenate from 10 patients with primary or secondary-progressive MS into 36 transgenic mice. All the mice over-expressed human prion protein. A control group of 23 mice were injected with homogenate from six donor brains.
At 6-12 months, the control mice did not develop pathology. However, the mice injected with brain matter from MS patients developed various levels of significant pathology. The researchers also managed to transmit illness from affected mice into another group of transgenic mice that over-expressed human prion protein via injection of brain homogenate.
While the mice in the study represent “a very extreme case” since their levels of prion protein expression were very high, it’s clear that “MS is actually transmissible,” Dr. Tsutsui said.
The study authors speculate that pathogenic prion protein triggers an autoimmune response by degenerating myelin and causing the release of cellular debris.
Could MS also be contagious? It may not be, even if it’s a prion disease, Dr. Tsutsui said. Some prion disease variants are neither contagious nor infectious.
The researchers plan to study the animal model they’ve created and explore the potential for its use in research, Dr. Tsutsui said.
The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
SOURCE: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
SAN DIEGO – MS may even be caused by prions, potentially putting it into the same category as Creutzfeldt-Jakob disease.
Researchers don’t think MS is contagious between humans. But their findings in mice do suggest that the disease is transmissible from “a seed of protein misfolding,” Shigeki Tsutsui, DVM, PhD, of the University of Calgary (Alta.), said in an interview in advance of his presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“The next question is: ‘What is actually causing primary damage?’ ” he said. “Our hypothesis is that it’s protein misfolding. If protein misfolding targets the central neuron cells, then those damaged cells release a kind of a trigger to start an immune response.”
This isn’t an unusual concept. Protein misfolding is believed to cause several chronic neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, Dr. Tsutsui said.
The researchers focused on the potential transmissibility of human prion protein “since we thought that the prion protein might be the candidate causing the MS,” he said.
Prion diseases are extremely rare and often deadly. They appear when normal cellular prion proteins are induced to misfold when they come in contact with infectious agents known as prions.
In humans, prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru (a condition spread among cannibals who eat the brains of other humans). Most famously, a variant of Creutzfeldt-Jakob disease has been linked – but not conclusively – to the eating of meat from cows infected with mad cow disease.
Depending on the condition, prion diseases can appear spontaneously, via inheritance or through infection.
In the new study, researchers intracerebrally injected brain homogenate from 10 patients with primary or secondary-progressive MS into 36 transgenic mice. All the mice over-expressed human prion protein. A control group of 23 mice were injected with homogenate from six donor brains.
At 6-12 months, the control mice did not develop pathology. However, the mice injected with brain matter from MS patients developed various levels of significant pathology. The researchers also managed to transmit illness from affected mice into another group of transgenic mice that over-expressed human prion protein via injection of brain homogenate.
While the mice in the study represent “a very extreme case” since their levels of prion protein expression were very high, it’s clear that “MS is actually transmissible,” Dr. Tsutsui said.
The study authors speculate that pathogenic prion protein triggers an autoimmune response by degenerating myelin and causing the release of cellular debris.
Could MS also be contagious? It may not be, even if it’s a prion disease, Dr. Tsutsui said. Some prion disease variants are neither contagious nor infectious.
The researchers plan to study the animal model they’ve created and explore the potential for its use in research, Dr. Tsutsui said.
The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
SOURCE: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
REPORTING FROM ACTRIMS FORUM 2018
Key clinical point: Translational research suggests the primary damage in MS may be caused by transmissible protein misfolding.
Major finding: Transgenic mice over-expressing human prion protein that were injected with brain matter from MS patients developed various levels of significant pathology, and brain homogenate from these mice could transmit illness to naive transgenic mice.
Study details: Transgenic mice over-expressing human prion protein received intracerebral injection of brain homogenate from patients with primary or secondary-progressive MS
Disclosures: The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
Source: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
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
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.
Rituximab may outperform some other first-line multiple sclerosis treatments
Rituximab was associated with a lower drug discontinuation rate versus all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (RRMS) in a retrospective study of patient data from a Swedish multiple sclerosis registry.
In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to results of the study, which appeared online Jan. 8 in JAMA Neurology.
Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for RRMS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. RRMS is not an approved indication for rituximab in the United States, whereas across Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”
The addition of new DMTs for RRMS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (that is, interferon beta and glatiramer acetate) within 2 years, suggesting a need for better treatment options.
To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that 494 included who received a diagnosis of RRMS between January 1, 2012, and October 31, 2015.
The largest subset of patients (n = 215) received injectable DMTs, while the rest received rituximab (n = 120), dimethyl fumarate (n = 86), natalizumab (Tysabri; n = 50), fingolimod (Gilenya; n = 17), or another treatment (n = 6), according to data in the report.
The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs, study authors found. Compared with rituximab, the hazard ratios for drug discontinuation after adjusting for covariates and propensity score were 11.4 (95% confidence interval, 4.7-27.4) for injectable DMTs, 15.1 (95% CI, 3.9-58.0) for dimethyl fumarate, 5.9 (95% CI, 1.5-23.4) for fingolimod, and 11.3 (95% CI 3.2-39.4) for natalizumab.
Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with injectable DMTs or dimethyl fumarate, according to the investigators.
In comparison with fingolimod and natalizumab, relapse rates and gadolinium-enhancing lesions with rituximab were less frequent, but the authors said those differences did not reach statistical significance in all analyses.
The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
SOURCE: Granqvist M et al. JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4011
Rituximab was associated with a lower drug discontinuation rate versus all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (RRMS) in a retrospective study of patient data from a Swedish multiple sclerosis registry.
In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to results of the study, which appeared online Jan. 8 in JAMA Neurology.
Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for RRMS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. RRMS is not an approved indication for rituximab in the United States, whereas across Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”
The addition of new DMTs for RRMS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (that is, interferon beta and glatiramer acetate) within 2 years, suggesting a need for better treatment options.
To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that 494 included who received a diagnosis of RRMS between January 1, 2012, and October 31, 2015.
The largest subset of patients (n = 215) received injectable DMTs, while the rest received rituximab (n = 120), dimethyl fumarate (n = 86), natalizumab (Tysabri; n = 50), fingolimod (Gilenya; n = 17), or another treatment (n = 6), according to data in the report.
The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs, study authors found. Compared with rituximab, the hazard ratios for drug discontinuation after adjusting for covariates and propensity score were 11.4 (95% confidence interval, 4.7-27.4) for injectable DMTs, 15.1 (95% CI, 3.9-58.0) for dimethyl fumarate, 5.9 (95% CI, 1.5-23.4) for fingolimod, and 11.3 (95% CI 3.2-39.4) for natalizumab.
Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with injectable DMTs or dimethyl fumarate, according to the investigators.
In comparison with fingolimod and natalizumab, relapse rates and gadolinium-enhancing lesions with rituximab were less frequent, but the authors said those differences did not reach statistical significance in all analyses.
The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
SOURCE: Granqvist M et al. JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4011
Rituximab was associated with a lower drug discontinuation rate versus all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (RRMS) in a retrospective study of patient data from a Swedish multiple sclerosis registry.
In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to results of the study, which appeared online Jan. 8 in JAMA Neurology.
Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for RRMS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. RRMS is not an approved indication for rituximab in the United States, whereas across Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”
The addition of new DMTs for RRMS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (that is, interferon beta and glatiramer acetate) within 2 years, suggesting a need for better treatment options.
To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that 494 included who received a diagnosis of RRMS between January 1, 2012, and October 31, 2015.
The largest subset of patients (n = 215) received injectable DMTs, while the rest received rituximab (n = 120), dimethyl fumarate (n = 86), natalizumab (Tysabri; n = 50), fingolimod (Gilenya; n = 17), or another treatment (n = 6), according to data in the report.
The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs, study authors found. Compared with rituximab, the hazard ratios for drug discontinuation after adjusting for covariates and propensity score were 11.4 (95% confidence interval, 4.7-27.4) for injectable DMTs, 15.1 (95% CI, 3.9-58.0) for dimethyl fumarate, 5.9 (95% CI, 1.5-23.4) for fingolimod, and 11.3 (95% CI 3.2-39.4) for natalizumab.
Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with injectable DMTs or dimethyl fumarate, according to the investigators.
In comparison with fingolimod and natalizumab, relapse rates and gadolinium-enhancing lesions with rituximab were less frequent, but the authors said those differences did not reach statistical significance in all analyses.
The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
SOURCE: Granqvist M et al. JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4011
FROM JAMA NEUROLOGY
Key clinical point:
Major finding: Rituximab-treated patients had significantly lower rates of discontinuation, compared with injectable DMTs, fingolimod, natalizumab, and dimethyl fumarate. Relapse rates with rituximab were lower than they were with injectable DMTs and dimethyl fumarate.
Data source: Retrospective cohort study of data from a Swedish multiple sclerosis registry that included 494 patients with a diagnosis of RRMS.
Disclosures: The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
Source: Granqvist M et al. JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4011
Ibudilast May Slow Brain Atrophy in Progressive MS
PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.
Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.
Examining Ibudilast in a Phase II Trial
Robert Fox, MD, a neurologist at the Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate. 
Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.
The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.
Researchers Observed Gastrointestinal Side Effects
The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.
In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.
Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.
There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.
Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.
—Erik Greb
Suggested Reading
Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.
Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.
PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.
Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.
Examining Ibudilast in a Phase II Trial
Robert Fox, MD, a neurologist at the Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate.
Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.
The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.
Researchers Observed Gastrointestinal Side Effects
The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.
In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.
Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.
There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.
Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.
—Erik Greb
Suggested Reading
Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.
Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.
PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.
Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.
Examining Ibudilast in a Phase II Trial
Robert Fox, MD, a neurologist at the Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate.
Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.
The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.
Researchers Observed Gastrointestinal Side Effects
The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.
In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.
Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.
There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.
Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.
—Erik Greb
Suggested Reading
Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.
Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.