User login
Multiple Sclerosis Hub
In MS, baseline cortical lesions predict cognitive decline
, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.
“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.
That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.
The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.
Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.
The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.
A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).
In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).
Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.
Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).
In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).
Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.
During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.
, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.
“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.
That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.
The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.
Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.
The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.
A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).
In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).
Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.
Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).
In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).
Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.
During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.
, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.
“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.
That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.
The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.
Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.
The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.
A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).
In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).
Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.
Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).
In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).
Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.
During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.
FROM ECTRIMS 2021
Cortical lesions predict risk for secondary progressive MS
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
Melatonin improves sleep in MS
according to a new pilot study.
The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.
“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.
Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”
Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.
Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.
The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.
Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*
During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).
Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.
The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.
*This article was updated on Oct. 15.
according to a new pilot study.
The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.
“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.
Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”
Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.
Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.
The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.
Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*
During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).
Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.
The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.
*This article was updated on Oct. 15.
according to a new pilot study.
The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.
“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.
Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”
Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.
Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.
The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.
Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*
During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).
Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.
The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.
*This article was updated on Oct. 15.
FROM ECTRIMS 2021
COVID-19 vaccination in MS: Lower response on certain medications
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
MS plus depression can increase risk of death, vascular disease
, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.
The study was published in Neurology.
To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.
People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.
As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
Does treating depression decrease the likelihood of vascular disease?
“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?
“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?
“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
Evaluating the biological interaction between MS and depression
Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.
“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.
“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.
Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.
In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”
Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.
, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.
The study was published in Neurology.
To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.
People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.
As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
Does treating depression decrease the likelihood of vascular disease?
“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?
“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?
“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
Evaluating the biological interaction between MS and depression
Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.
“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.
“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.
Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.
In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”
Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.
, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.
The study was published in Neurology.
To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.
People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.
As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
Does treating depression decrease the likelihood of vascular disease?
“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?
“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?
“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
Evaluating the biological interaction between MS and depression
Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.
“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.
“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.
Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.
In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”
Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.
FROM NEUROLOGY
MRI is a poor disability predictor in secondary progressive MS
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Multiple Sclerosis Journal
Progressive disability in MS explained?
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Neurology
Guidance on additional COVID-19 vaccine dose for MS patients
Patients aged 12 years and older with multiple sclerosis (MS) who are fully immunized against COVID-19 with either the Pfizer-BioNTech or Moderna mRNA vaccine may be eligible to receive an additional dose now, the National Multiple Sclerosis Society has announced.
New guidance, which is “based on available data from studies and expert consensus opinion” by a panel of MS neurologists and experts, was published Aug. 19 on the organization’s website.
The Food and Drug Administration has authorized an additional dose of the coronavirus vaccine for patients who are expected to not have a normal or adequate immune response to the first two doses. Patients with MS who use certain treatments have a reduced or absent antibody response to the vaccine, according to recent data.
“We want people living with MS to be aware of this additional dose and discuss when they need an additional dose or booster dose with their health care provider,” Julie Fiol, RN, MSW, associate vice president of health care access, National MS Society, said in an interview.
Those who may benefit from an additional dose include patients with MS who use sphingosine 1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, or alemtuzumab (Lemtrada), the National MS Society noted. These particular disease modifying therapies (DMTs) have a stronger effect on the immune system than do other treatments.
Protecting ‘the most vulnerable’
Sphingosine 1-phosphate receptor modulators include fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), and ponesimod (Ponvory).
Anti-CD20 monoclonal antibodies include ocrelizumab (Ocrevus), ofatumumab (Kesimpta), rituximab (Rituxan), and corresponding biosimilars.
Current data do not support an additional dose for immunocompromised patients who received the Johnson & Johnson vaccine. The FDA and the Centers for Disease Control and Prevention are developing recommendations for these patients, and the National MS Society will update its guidance as needed, the organization noted in its statement.
“Like other medical decisions, the decision to get an additional dose is best made in partnership with your health care provider,” said Ms. Fiol. “Talk to your MS health care provider to determine what is best for you.”
MS itself does not compromise the immune system, but some MS therapies alter the immune system and reduce the body’s response to vaccination. Patients with MS who use B cell-depleting therapies have a better antibody response when they receive the vaccine 3 months or more after the last dose of MS therapy, according to the National MS Society.
Data suggest that patients with MS are not more susceptible to COVID-19 infection, severe illness, or death than are patients without MS. However, certain groups of patients with MS, such as those who receive B cell-depleting treatments, are more susceptible to having a severe case of COVID-19.
That said, “everyone will need a booster at some point. Those who take DMTs that have greater impact on the immune system are the most urgent need now,” the organization noted.
“Vaccination against COVID-19 is critical for public safety and, especially, the safety of the most vulnerable among us,” said Ms. Fiol. “We encourage everyone with MS get vaccinated.”
A version of this article first appeared on Medscape.com.
Patients aged 12 years and older with multiple sclerosis (MS) who are fully immunized against COVID-19 with either the Pfizer-BioNTech or Moderna mRNA vaccine may be eligible to receive an additional dose now, the National Multiple Sclerosis Society has announced.
New guidance, which is “based on available data from studies and expert consensus opinion” by a panel of MS neurologists and experts, was published Aug. 19 on the organization’s website.
The Food and Drug Administration has authorized an additional dose of the coronavirus vaccine for patients who are expected to not have a normal or adequate immune response to the first two doses. Patients with MS who use certain treatments have a reduced or absent antibody response to the vaccine, according to recent data.
“We want people living with MS to be aware of this additional dose and discuss when they need an additional dose or booster dose with their health care provider,” Julie Fiol, RN, MSW, associate vice president of health care access, National MS Society, said in an interview.
Those who may benefit from an additional dose include patients with MS who use sphingosine 1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, or alemtuzumab (Lemtrada), the National MS Society noted. These particular disease modifying therapies (DMTs) have a stronger effect on the immune system than do other treatments.
Protecting ‘the most vulnerable’
Sphingosine 1-phosphate receptor modulators include fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), and ponesimod (Ponvory).
Anti-CD20 monoclonal antibodies include ocrelizumab (Ocrevus), ofatumumab (Kesimpta), rituximab (Rituxan), and corresponding biosimilars.
Current data do not support an additional dose for immunocompromised patients who received the Johnson & Johnson vaccine. The FDA and the Centers for Disease Control and Prevention are developing recommendations for these patients, and the National MS Society will update its guidance as needed, the organization noted in its statement.
“Like other medical decisions, the decision to get an additional dose is best made in partnership with your health care provider,” said Ms. Fiol. “Talk to your MS health care provider to determine what is best for you.”
MS itself does not compromise the immune system, but some MS therapies alter the immune system and reduce the body’s response to vaccination. Patients with MS who use B cell-depleting therapies have a better antibody response when they receive the vaccine 3 months or more after the last dose of MS therapy, according to the National MS Society.
Data suggest that patients with MS are not more susceptible to COVID-19 infection, severe illness, or death than are patients without MS. However, certain groups of patients with MS, such as those who receive B cell-depleting treatments, are more susceptible to having a severe case of COVID-19.
That said, “everyone will need a booster at some point. Those who take DMTs that have greater impact on the immune system are the most urgent need now,” the organization noted.
“Vaccination against COVID-19 is critical for public safety and, especially, the safety of the most vulnerable among us,” said Ms. Fiol. “We encourage everyone with MS get vaccinated.”
A version of this article first appeared on Medscape.com.
Patients aged 12 years and older with multiple sclerosis (MS) who are fully immunized against COVID-19 with either the Pfizer-BioNTech or Moderna mRNA vaccine may be eligible to receive an additional dose now, the National Multiple Sclerosis Society has announced.
New guidance, which is “based on available data from studies and expert consensus opinion” by a panel of MS neurologists and experts, was published Aug. 19 on the organization’s website.
The Food and Drug Administration has authorized an additional dose of the coronavirus vaccine for patients who are expected to not have a normal or adequate immune response to the first two doses. Patients with MS who use certain treatments have a reduced or absent antibody response to the vaccine, according to recent data.
“We want people living with MS to be aware of this additional dose and discuss when they need an additional dose or booster dose with their health care provider,” Julie Fiol, RN, MSW, associate vice president of health care access, National MS Society, said in an interview.
Those who may benefit from an additional dose include patients with MS who use sphingosine 1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, or alemtuzumab (Lemtrada), the National MS Society noted. These particular disease modifying therapies (DMTs) have a stronger effect on the immune system than do other treatments.
Protecting ‘the most vulnerable’
Sphingosine 1-phosphate receptor modulators include fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), and ponesimod (Ponvory).
Anti-CD20 monoclonal antibodies include ocrelizumab (Ocrevus), ofatumumab (Kesimpta), rituximab (Rituxan), and corresponding biosimilars.
Current data do not support an additional dose for immunocompromised patients who received the Johnson & Johnson vaccine. The FDA and the Centers for Disease Control and Prevention are developing recommendations for these patients, and the National MS Society will update its guidance as needed, the organization noted in its statement.
“Like other medical decisions, the decision to get an additional dose is best made in partnership with your health care provider,” said Ms. Fiol. “Talk to your MS health care provider to determine what is best for you.”
MS itself does not compromise the immune system, but some MS therapies alter the immune system and reduce the body’s response to vaccination. Patients with MS who use B cell-depleting therapies have a better antibody response when they receive the vaccine 3 months or more after the last dose of MS therapy, according to the National MS Society.
Data suggest that patients with MS are not more susceptible to COVID-19 infection, severe illness, or death than are patients without MS. However, certain groups of patients with MS, such as those who receive B cell-depleting treatments, are more susceptible to having a severe case of COVID-19.
That said, “everyone will need a booster at some point. Those who take DMTs that have greater impact on the immune system are the most urgent need now,” the organization noted.
“Vaccination against COVID-19 is critical for public safety and, especially, the safety of the most vulnerable among us,” said Ms. Fiol. “We encourage everyone with MS get vaccinated.”
A version of this article first appeared on Medscape.com.
A less expensive, more convenient treatment option for MS?
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
From EAN 2021
Investigational drug reduces brain lesions in highly active MS
new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.
Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.
The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.
The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.
Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.
The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.
The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.
Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.
The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.
The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAN 2021