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Particular lesions early after CIS predict long-term MS disability
BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.
Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.
There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.
There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.
Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.
The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.
“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.
“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”
Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.
“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.
EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.
“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).
Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.
“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”
During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”
Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.
“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”
The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.
SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.
BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.
Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.
There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.
There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.
Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.
The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.
“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.
“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”
Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.
“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.
EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.
“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).
Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.
“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”
During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”
Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.
“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”
The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.
SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.
BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.
Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.
There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.
There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.
Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.
The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.
“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.
“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”
Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.
“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.
EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.
“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).
Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.
“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”
During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”
Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.
“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”
The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.
SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.
REPORTING FROM ECTRIMS 2018
Key clinical point: Early magnetic resonance parameters can provide information that can help risk-stratify patients.
Major finding: Infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis were associated with high levels of disability 30 years later.
Study details: Data on 120 patients with clinically isolated syndrome recruited as part of the First London CIS Cohort between 1984 and 1987.
Disclosures: The MS Society of Great Britain funded the study. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.
Source: Chung K et al. Mult Scler. 2018;24(S2):58-9, Abstract 157.
FDA urged to bring rheumatologists into gadolinium safety discussion
CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.
The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.
The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.
Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.
“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.
He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”
Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”
Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.
Dr. Glaser and Dr. Kay reported having no financial conflicts.
CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.
The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.
The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.
Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.
“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.
He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”
Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”
Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.
Dr. Glaser and Dr. Kay reported having no financial conflicts.
CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.
The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.
The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.
Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.
“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.
He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”
Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”
Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.
Dr. Glaser and Dr. Kay reported having no financial conflicts.
EXPERT ANALYSIS FROM THE ACR ANNUAL MEETING
FDA warns stopping fingolimod linked to severe MS worsening
Patients with multiple sclerosis (MS) who stop taking the MS medication Gilenya (fingolimod) may experience severe disease worsening, according to a safety announcement from the Food and Drug Administration. The disease may become worse than it was before patients started the medication or while patients were taking the drug. Severe worsening is rare but can result in permanent disability, according to the FDA statement.
“The severe increase in disability in these patients was more severe than typical MS relapses, and in cases where baseline disability was known, appeared unrelated to the patients’ prior disease state,” according to the announcement. “Several patients who were able to walk without assistance prior to discontinuing Gilenya progressed to needing wheelchairs or becoming totally bed bound.” Seventeen of the patients partially recovered, eight had permanent disability, and six returned to the level of disability that they had before or during Gilenya treatment.
The patients most often discontinued treatment because they intended to or had become pregnant. Other reasons for halting therapy included lack of efficacy, lymphopenia, infections, or cancer.
The best approach to discontinuing treatment and the best way to treat a severe increase in disability if it occurs has not been determined, according to the FDA statement.
The drug’s safety labeling has been updated to include warnings about the potential for a severe increase in disability after stopping Gilenya. Health care professionals should tell patients about the risk of a severe increase in disability after stopping Gilenya and should monitor patients carefully if they do stop treatment. Patients should seek immediate medical attention after stopping the therapy if they have new or worsened MS symptoms, including trouble using their arms or legs, or changes in thinking, vision, or balance.
Patients with multiple sclerosis (MS) who stop taking the MS medication Gilenya (fingolimod) may experience severe disease worsening, according to a safety announcement from the Food and Drug Administration. The disease may become worse than it was before patients started the medication or while patients were taking the drug. Severe worsening is rare but can result in permanent disability, according to the FDA statement.
“The severe increase in disability in these patients was more severe than typical MS relapses, and in cases where baseline disability was known, appeared unrelated to the patients’ prior disease state,” according to the announcement. “Several patients who were able to walk without assistance prior to discontinuing Gilenya progressed to needing wheelchairs or becoming totally bed bound.” Seventeen of the patients partially recovered, eight had permanent disability, and six returned to the level of disability that they had before or during Gilenya treatment.
The patients most often discontinued treatment because they intended to or had become pregnant. Other reasons for halting therapy included lack of efficacy, lymphopenia, infections, or cancer.
The best approach to discontinuing treatment and the best way to treat a severe increase in disability if it occurs has not been determined, according to the FDA statement.
The drug’s safety labeling has been updated to include warnings about the potential for a severe increase in disability after stopping Gilenya. Health care professionals should tell patients about the risk of a severe increase in disability after stopping Gilenya and should monitor patients carefully if they do stop treatment. Patients should seek immediate medical attention after stopping the therapy if they have new or worsened MS symptoms, including trouble using their arms or legs, or changes in thinking, vision, or balance.
Patients with multiple sclerosis (MS) who stop taking the MS medication Gilenya (fingolimod) may experience severe disease worsening, according to a safety announcement from the Food and Drug Administration. The disease may become worse than it was before patients started the medication or while patients were taking the drug. Severe worsening is rare but can result in permanent disability, according to the FDA statement.
“The severe increase in disability in these patients was more severe than typical MS relapses, and in cases where baseline disability was known, appeared unrelated to the patients’ prior disease state,” according to the announcement. “Several patients who were able to walk without assistance prior to discontinuing Gilenya progressed to needing wheelchairs or becoming totally bed bound.” Seventeen of the patients partially recovered, eight had permanent disability, and six returned to the level of disability that they had before or during Gilenya treatment.
The patients most often discontinued treatment because they intended to or had become pregnant. Other reasons for halting therapy included lack of efficacy, lymphopenia, infections, or cancer.
The best approach to discontinuing treatment and the best way to treat a severe increase in disability if it occurs has not been determined, according to the FDA statement.
The drug’s safety labeling has been updated to include warnings about the potential for a severe increase in disability after stopping Gilenya. Health care professionals should tell patients about the risk of a severe increase in disability after stopping Gilenya and should monitor patients carefully if they do stop treatment. Patients should seek immediate medical attention after stopping the therapy if they have new or worsened MS symptoms, including trouble using their arms or legs, or changes in thinking, vision, or balance.
(Video) Relapsing-Remitting and Secondary-Progressive Multiple Sclerosis Video Discussion
Relapsing-remitting multiple sclerosis (RRMS) is a type of MS that is characterized by periods of disease flare-ups (relapses) and periods of recovery (remissions). RRMS often develops into secondary-progressive MS (SPMS), which is characterized by a patient’s disability steadily worsening. In this video, Daniel Kantor, MD, FAAN, FANA, and Benjamin Greenberg, MD, MHS, address important topics in both MS subtypes, including uncontrollable and modifiable risk factors, and how psychological health plays a role in the progression of MS in patients.
Disclosures
This video roundtable was produced by the Custom Programs division of Frontline Medical Communications.
The faculty received modest honoraria from the Custom Programs division of Frontline Medical Communications for their time participating in this roundtable. The faculty was solely responsible for the content presented.
Dr. Kantor reports relationships with Actelion, Avanir, Biogen, Celgene, Genentech, Mylan, Novartis, and Sanofi Genzyme.
Dr. Greenberg is a consultant for Novartis and EMD Serono, and has received grants from Genentech.
Relapsing-remitting multiple sclerosis (RRMS) is a type of MS that is characterized by periods of disease flare-ups (relapses) and periods of recovery (remissions). RRMS often develops into secondary-progressive MS (SPMS), which is characterized by a patient’s disability steadily worsening. In this video, Daniel Kantor, MD, FAAN, FANA, and Benjamin Greenberg, MD, MHS, address important topics in both MS subtypes, including uncontrollable and modifiable risk factors, and how psychological health plays a role in the progression of MS in patients.
Disclosures
This video roundtable was produced by the Custom Programs division of Frontline Medical Communications.
The faculty received modest honoraria from the Custom Programs division of Frontline Medical Communications for their time participating in this roundtable. The faculty was solely responsible for the content presented.
Dr. Kantor reports relationships with Actelion, Avanir, Biogen, Celgene, Genentech, Mylan, Novartis, and Sanofi Genzyme.
Dr. Greenberg is a consultant for Novartis and EMD Serono, and has received grants from Genentech.
Relapsing-remitting multiple sclerosis (RRMS) is a type of MS that is characterized by periods of disease flare-ups (relapses) and periods of recovery (remissions). RRMS often develops into secondary-progressive MS (SPMS), which is characterized by a patient’s disability steadily worsening. In this video, Daniel Kantor, MD, FAAN, FANA, and Benjamin Greenberg, MD, MHS, address important topics in both MS subtypes, including uncontrollable and modifiable risk factors, and how psychological health plays a role in the progression of MS in patients.
Disclosures
This video roundtable was produced by the Custom Programs division of Frontline Medical Communications.
The faculty received modest honoraria from the Custom Programs division of Frontline Medical Communications for their time participating in this roundtable. The faculty was solely responsible for the content presented.
Dr. Kantor reports relationships with Actelion, Avanir, Biogen, Celgene, Genentech, Mylan, Novartis, and Sanofi Genzyme.
Dr. Greenberg is a consultant for Novartis and EMD Serono, and has received grants from Genentech.
Panel Provides Recommendations for Managing Cognitive Changes in MS
Baseline screening and periodic reassessments aid in the monitoring of treatment response and disease progression.
The National Multiple Sclerosis (MS) Society has developed recommendations for the identification and management of cognitive impairment in MS. The recommendations, which were endorsed by the Consortium of MS Centers and the International MS Cognition Society, were published online ahead of print October 10 in Multiple Sclerosis Journal.
Cognitive change may affect between 34% and 65% of adults with MS. Decreases in information processing and memory are the most common changes, and cognitive impairment may arise before MRI abnormalities that indicate MS. These changes can affect patients’ ability to work, drive, manage money, and participate in activities.
Patients and Clinicians Need Information
Patients and caregivers should receive information about common cognitive changes in MS and how they affect everyday life, said Rosalind Kalb, PhD, Vice President of the Professional Resource Center at the National MS Society in New York, and coauthors. Patients and caregivers also should be told about the high prevalence of cognitive symptoms in MS and the need for ongoing assessments. Similarly, clinicians need information about how cognitive impairments affect medical decision-making and adherence, said the authors. Clinicians also need referral resources for cognitive assessment and treatment.
All adults and children age 8 or older diagnosed with MS should, as a minimum, undergo early baseline screening with the Symbol Digit Modalities Test (SDMT) or another validated screening tool, according to the recommendations. These patients should be reassessed with the same instrument annually or more often, as needed, to detect disease activity, assess for treatment effects or relapse recovery, monitor progression of cognitive impairment, and screen for new cognitive problems.
In addition to the SDMT, screening tools that have been validated in patients with MS include the Processing Speed Test, Computerized Speed Cognitive Test, MS Neuropsychological Screening Questionnaire, Brief International Cognitive Assessment for MS, Brief Repeatable Neuropsychological Battery, and Minimal Assessment of Cognitive Function in MS.
Interventions May Improve or Maintain Function
An adult who tests positive for cognitive impairment on initial screening should undergo a more comprehensive assessment, especially if the person has comorbidities that raise concerns or is applying for disability due to cognitive impairment. A child with an unexplained change in school performance should receive a neuropsychologic evaluation, said Dr. Kalb and colleagues.
Furthermore, adults and children should be offered remedial interventions or accommodations to improve function at home, work, or school. Appropriately trained professionals should deliver these interventions to address “objectively measured deficits in attention, processing speed, memory and learning, and performance of everyday functional tasks,” said the authors. Clinicians can consider contextualized treatment (eg, self-generated learning tasks) and noncontextualized treatment (eg, memory-retrieval practice and computer-based attention interventions) for remediation of everyday activities, according to the recommendations.
Emerging research supports the potential for exercise to benefit cognitive processing speed in patients with MS. Trials of symptomatic pharmacologic treatments for cognitive impairment related to MS have yielded inconclusive results, however. In addition, few pivotal trials of disease-modifying therapies have incorporated cognitive outcome measures.
—Erik Greb
Suggested Reading
Kalb R, Beier M, Benedict RH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018 Oct 10 [Epub ahead of print].
Baseline screening and periodic reassessments aid in the monitoring of treatment response and disease progression.
Baseline screening and periodic reassessments aid in the monitoring of treatment response and disease progression.
The National Multiple Sclerosis (MS) Society has developed recommendations for the identification and management of cognitive impairment in MS. The recommendations, which were endorsed by the Consortium of MS Centers and the International MS Cognition Society, were published online ahead of print October 10 in Multiple Sclerosis Journal.
Cognitive change may affect between 34% and 65% of adults with MS. Decreases in information processing and memory are the most common changes, and cognitive impairment may arise before MRI abnormalities that indicate MS. These changes can affect patients’ ability to work, drive, manage money, and participate in activities.
Patients and Clinicians Need Information
Patients and caregivers should receive information about common cognitive changes in MS and how they affect everyday life, said Rosalind Kalb, PhD, Vice President of the Professional Resource Center at the National MS Society in New York, and coauthors. Patients and caregivers also should be told about the high prevalence of cognitive symptoms in MS and the need for ongoing assessments. Similarly, clinicians need information about how cognitive impairments affect medical decision-making and adherence, said the authors. Clinicians also need referral resources for cognitive assessment and treatment.
All adults and children age 8 or older diagnosed with MS should, as a minimum, undergo early baseline screening with the Symbol Digit Modalities Test (SDMT) or another validated screening tool, according to the recommendations. These patients should be reassessed with the same instrument annually or more often, as needed, to detect disease activity, assess for treatment effects or relapse recovery, monitor progression of cognitive impairment, and screen for new cognitive problems.
In addition to the SDMT, screening tools that have been validated in patients with MS include the Processing Speed Test, Computerized Speed Cognitive Test, MS Neuropsychological Screening Questionnaire, Brief International Cognitive Assessment for MS, Brief Repeatable Neuropsychological Battery, and Minimal Assessment of Cognitive Function in MS.
Interventions May Improve or Maintain Function
An adult who tests positive for cognitive impairment on initial screening should undergo a more comprehensive assessment, especially if the person has comorbidities that raise concerns or is applying for disability due to cognitive impairment. A child with an unexplained change in school performance should receive a neuropsychologic evaluation, said Dr. Kalb and colleagues.
Furthermore, adults and children should be offered remedial interventions or accommodations to improve function at home, work, or school. Appropriately trained professionals should deliver these interventions to address “objectively measured deficits in attention, processing speed, memory and learning, and performance of everyday functional tasks,” said the authors. Clinicians can consider contextualized treatment (eg, self-generated learning tasks) and noncontextualized treatment (eg, memory-retrieval practice and computer-based attention interventions) for remediation of everyday activities, according to the recommendations.
Emerging research supports the potential for exercise to benefit cognitive processing speed in patients with MS. Trials of symptomatic pharmacologic treatments for cognitive impairment related to MS have yielded inconclusive results, however. In addition, few pivotal trials of disease-modifying therapies have incorporated cognitive outcome measures.
—Erik Greb
Suggested Reading
Kalb R, Beier M, Benedict RH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018 Oct 10 [Epub ahead of print].
The National Multiple Sclerosis (MS) Society has developed recommendations for the identification and management of cognitive impairment in MS. The recommendations, which were endorsed by the Consortium of MS Centers and the International MS Cognition Society, were published online ahead of print October 10 in Multiple Sclerosis Journal.
Cognitive change may affect between 34% and 65% of adults with MS. Decreases in information processing and memory are the most common changes, and cognitive impairment may arise before MRI abnormalities that indicate MS. These changes can affect patients’ ability to work, drive, manage money, and participate in activities.
Patients and Clinicians Need Information
Patients and caregivers should receive information about common cognitive changes in MS and how they affect everyday life, said Rosalind Kalb, PhD, Vice President of the Professional Resource Center at the National MS Society in New York, and coauthors. Patients and caregivers also should be told about the high prevalence of cognitive symptoms in MS and the need for ongoing assessments. Similarly, clinicians need information about how cognitive impairments affect medical decision-making and adherence, said the authors. Clinicians also need referral resources for cognitive assessment and treatment.
All adults and children age 8 or older diagnosed with MS should, as a minimum, undergo early baseline screening with the Symbol Digit Modalities Test (SDMT) or another validated screening tool, according to the recommendations. These patients should be reassessed with the same instrument annually or more often, as needed, to detect disease activity, assess for treatment effects or relapse recovery, monitor progression of cognitive impairment, and screen for new cognitive problems.
In addition to the SDMT, screening tools that have been validated in patients with MS include the Processing Speed Test, Computerized Speed Cognitive Test, MS Neuropsychological Screening Questionnaire, Brief International Cognitive Assessment for MS, Brief Repeatable Neuropsychological Battery, and Minimal Assessment of Cognitive Function in MS.
Interventions May Improve or Maintain Function
An adult who tests positive for cognitive impairment on initial screening should undergo a more comprehensive assessment, especially if the person has comorbidities that raise concerns or is applying for disability due to cognitive impairment. A child with an unexplained change in school performance should receive a neuropsychologic evaluation, said Dr. Kalb and colleagues.
Furthermore, adults and children should be offered remedial interventions or accommodations to improve function at home, work, or school. Appropriately trained professionals should deliver these interventions to address “objectively measured deficits in attention, processing speed, memory and learning, and performance of everyday functional tasks,” said the authors. Clinicians can consider contextualized treatment (eg, self-generated learning tasks) and noncontextualized treatment (eg, memory-retrieval practice and computer-based attention interventions) for remediation of everyday activities, according to the recommendations.
Emerging research supports the potential for exercise to benefit cognitive processing speed in patients with MS. Trials of symptomatic pharmacologic treatments for cognitive impairment related to MS have yielded inconclusive results, however. In addition, few pivotal trials of disease-modifying therapies have incorporated cognitive outcome measures.
—Erik Greb
Suggested Reading
Kalb R, Beier M, Benedict RH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018 Oct 10 [Epub ahead of print].
MS disease activity returns in one-third after fingolimod withdrawal
BERLIN – At least one-third of patients being treated with fingolimod (Gilenya) for multiple sclerosis (MS) will relapse after stopping the drug, according to data from two “real-world” studies reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, one of which was undertaken in pregnant women.
In a retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, around 35% experienced a recurrence of disease activity after fingolimod withdrawal. Study investigator Nuria Cerda, MD, of the Neurologic Clinic and Polyclinic at University Hospital Basel (Switzerland), reported that risk factors for increased disease activity were younger rather than older age at MS diagnosis (P = .01) and at discontinuation (P less than .0001), having had a shorter rather than longer disease duration (P = .01), and evidence of MRI-confirmed disease activity occurring while on treatment with fingolimod (P = .02).
“We aimed to describe the frequency of recurrence of disease activity after fingolimod discontinuation in a real-world cohort of MS patients,” Dr. Cerda said. She noted that there were conflicting data on reappearing disease activity after stopping the drug. Case reports and observational data suggest a frequency of 10%-53%, but post hoc analyses of phase 3 trials with fingolimod have not found any higher risk for recurrence versus placebo.
The study also compared “demographic and clinical characteristics in patients with and without recurrence of disease activity, in order to identify possible risk factors for reactivation of the disease.”
The patients included in the study had been treated with fingolimod for a median of 24 months (interquartile range, 10-43 months) and experienced 118 discontinuation events between them. The majority (n = 81) had relapsing-remitting MS, and the remainder (n = 19) were in transition from RRMS to secondary progressive MS.
The mean age at discontinuation was 40 years and, while 60% of patients switched to another disease-modifying therapy (DMT), 40% did not receive further DMT. The reasons for discontinuation were classified as being from disease activity in 44%, side effects in 21%, pregnancy or childbearing preferences in 16%, noncompliance in 2%, and other reasons in 17%.
Recurrence of disease activity was defined as clinical symptoms, gadolinium-enhancing (Gd+) lesions on MRI, or both, within 6 months of stopping fingolimod. This was seen in 38 patients with 41 events, giving a rate of recurrence of 35%. Of these: “almost 60% had clinical and MRI activity, almost 30% had clinical activity only without Gd+ lesions on MRI, and 12% had MRI activity only without ever having a relapse,” Dr. Cerda said. In those who relapsed, the recurrence took a median 8 weeks to happen after fingolimod discontinuation.
A further definition of severe recurrence of disease activity also was used, defined as either a worsening in the Expanded Disability Status Scale (EDSS) score of more than 2 points (signifying a severe relapse) with or without pronounced MRI activity with at least five cerebral Gd+ lesions within 6 months of fingolimod withdrawal. Thirteen severe events were seen in 11 patients, giving a frequency of approximately 11%. Dr. Cerda reported that patients with severe recurrence were significantly younger at MS diagnosis than were those who did not experience recurrence (P = .003). A trend toward a higher annualized relapse rate (ARR) was seen in patients with severely active versus inactive disease (0.84 vs. 0.54), but this was not statistically significant. In addition, “confirmed disability worsening of 1 EDSS point or more was observed in about 3%.”
Relapse rates coming off fingolimod before or during pregnancy
In another study, which used German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal, up to 56% of women who stopped fingolimod before pregnancy experienced a relapse during pregnancy versus 29% of those who stopped fingolimod upon a positive pregnancy test.
In a comparison of women who stopped fingolimod 1 year to 61 days before their last menstrual period against those who stopped less than 60 days prior to or after their last menstrual period, relapse rates were higher during the first (25.8% for early withdrawal vs. 12.5% with late withdrawal) and second trimesters (32.3% vs. 11.5%) than in the third (9.7% vs. 10.4%), Spalmai Hemat, MD, of the department of neurology at St. Josef Hospital, Ruhr University of Bochum (Germany) reported at the congress.
Relapse rates at 6 months postpartum proved to be similar at 36.7% for women who stopped fingolimod before their pregnancy and 38% in those who stopped later. Difference in the percentage of women experiencing disability progression during pregnancy did not prove to be statistically significant for stopping fingolimod before pregnancy (22.7%) vs. stopping later (11.1%; P = .283), while the 23.8% rate of disability progression after pregnancy among women who stopped the drug later versus 13.6% seen with stopping before was also not statistically significant (P = .31). Relapse during pregnancy was the only significant predictor for relapses postpartum.
“The large majority of women did not experience permanent disability,” Dr. Hemat said, but noted that as many as 10%-20% could experience substantial EDSS worsening (2 or more points) at 6 months postpartum.
Dr. Hemat concluded that more data were needed to see if reintroduction of fingolimod very soon after birth, such as within the first 2 weeks, could reduce the postpartum relapse risk.
Dr. Hemat and Dr. Cerda had no relevant disclosures.
SOURCES: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.
BERLIN – At least one-third of patients being treated with fingolimod (Gilenya) for multiple sclerosis (MS) will relapse after stopping the drug, according to data from two “real-world” studies reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, one of which was undertaken in pregnant women.
In a retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, around 35% experienced a recurrence of disease activity after fingolimod withdrawal. Study investigator Nuria Cerda, MD, of the Neurologic Clinic and Polyclinic at University Hospital Basel (Switzerland), reported that risk factors for increased disease activity were younger rather than older age at MS diagnosis (P = .01) and at discontinuation (P less than .0001), having had a shorter rather than longer disease duration (P = .01), and evidence of MRI-confirmed disease activity occurring while on treatment with fingolimod (P = .02).
“We aimed to describe the frequency of recurrence of disease activity after fingolimod discontinuation in a real-world cohort of MS patients,” Dr. Cerda said. She noted that there were conflicting data on reappearing disease activity after stopping the drug. Case reports and observational data suggest a frequency of 10%-53%, but post hoc analyses of phase 3 trials with fingolimod have not found any higher risk for recurrence versus placebo.
The study also compared “demographic and clinical characteristics in patients with and without recurrence of disease activity, in order to identify possible risk factors for reactivation of the disease.”
The patients included in the study had been treated with fingolimod for a median of 24 months (interquartile range, 10-43 months) and experienced 118 discontinuation events between them. The majority (n = 81) had relapsing-remitting MS, and the remainder (n = 19) were in transition from RRMS to secondary progressive MS.
The mean age at discontinuation was 40 years and, while 60% of patients switched to another disease-modifying therapy (DMT), 40% did not receive further DMT. The reasons for discontinuation were classified as being from disease activity in 44%, side effects in 21%, pregnancy or childbearing preferences in 16%, noncompliance in 2%, and other reasons in 17%.
Recurrence of disease activity was defined as clinical symptoms, gadolinium-enhancing (Gd+) lesions on MRI, or both, within 6 months of stopping fingolimod. This was seen in 38 patients with 41 events, giving a rate of recurrence of 35%. Of these: “almost 60% had clinical and MRI activity, almost 30% had clinical activity only without Gd+ lesions on MRI, and 12% had MRI activity only without ever having a relapse,” Dr. Cerda said. In those who relapsed, the recurrence took a median 8 weeks to happen after fingolimod discontinuation.
A further definition of severe recurrence of disease activity also was used, defined as either a worsening in the Expanded Disability Status Scale (EDSS) score of more than 2 points (signifying a severe relapse) with or without pronounced MRI activity with at least five cerebral Gd+ lesions within 6 months of fingolimod withdrawal. Thirteen severe events were seen in 11 patients, giving a frequency of approximately 11%. Dr. Cerda reported that patients with severe recurrence were significantly younger at MS diagnosis than were those who did not experience recurrence (P = .003). A trend toward a higher annualized relapse rate (ARR) was seen in patients with severely active versus inactive disease (0.84 vs. 0.54), but this was not statistically significant. In addition, “confirmed disability worsening of 1 EDSS point or more was observed in about 3%.”
Relapse rates coming off fingolimod before or during pregnancy
In another study, which used German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal, up to 56% of women who stopped fingolimod before pregnancy experienced a relapse during pregnancy versus 29% of those who stopped fingolimod upon a positive pregnancy test.
In a comparison of women who stopped fingolimod 1 year to 61 days before their last menstrual period against those who stopped less than 60 days prior to or after their last menstrual period, relapse rates were higher during the first (25.8% for early withdrawal vs. 12.5% with late withdrawal) and second trimesters (32.3% vs. 11.5%) than in the third (9.7% vs. 10.4%), Spalmai Hemat, MD, of the department of neurology at St. Josef Hospital, Ruhr University of Bochum (Germany) reported at the congress.
Relapse rates at 6 months postpartum proved to be similar at 36.7% for women who stopped fingolimod before their pregnancy and 38% in those who stopped later. Difference in the percentage of women experiencing disability progression during pregnancy did not prove to be statistically significant for stopping fingolimod before pregnancy (22.7%) vs. stopping later (11.1%; P = .283), while the 23.8% rate of disability progression after pregnancy among women who stopped the drug later versus 13.6% seen with stopping before was also not statistically significant (P = .31). Relapse during pregnancy was the only significant predictor for relapses postpartum.
“The large majority of women did not experience permanent disability,” Dr. Hemat said, but noted that as many as 10%-20% could experience substantial EDSS worsening (2 or more points) at 6 months postpartum.
Dr. Hemat concluded that more data were needed to see if reintroduction of fingolimod very soon after birth, such as within the first 2 weeks, could reduce the postpartum relapse risk.
Dr. Hemat and Dr. Cerda had no relevant disclosures.
SOURCES: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.
BERLIN – At least one-third of patients being treated with fingolimod (Gilenya) for multiple sclerosis (MS) will relapse after stopping the drug, according to data from two “real-world” studies reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, one of which was undertaken in pregnant women.
In a retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, around 35% experienced a recurrence of disease activity after fingolimod withdrawal. Study investigator Nuria Cerda, MD, of the Neurologic Clinic and Polyclinic at University Hospital Basel (Switzerland), reported that risk factors for increased disease activity were younger rather than older age at MS diagnosis (P = .01) and at discontinuation (P less than .0001), having had a shorter rather than longer disease duration (P = .01), and evidence of MRI-confirmed disease activity occurring while on treatment with fingolimod (P = .02).
“We aimed to describe the frequency of recurrence of disease activity after fingolimod discontinuation in a real-world cohort of MS patients,” Dr. Cerda said. She noted that there were conflicting data on reappearing disease activity after stopping the drug. Case reports and observational data suggest a frequency of 10%-53%, but post hoc analyses of phase 3 trials with fingolimod have not found any higher risk for recurrence versus placebo.
The study also compared “demographic and clinical characteristics in patients with and without recurrence of disease activity, in order to identify possible risk factors for reactivation of the disease.”
The patients included in the study had been treated with fingolimod for a median of 24 months (interquartile range, 10-43 months) and experienced 118 discontinuation events between them. The majority (n = 81) had relapsing-remitting MS, and the remainder (n = 19) were in transition from RRMS to secondary progressive MS.
The mean age at discontinuation was 40 years and, while 60% of patients switched to another disease-modifying therapy (DMT), 40% did not receive further DMT. The reasons for discontinuation were classified as being from disease activity in 44%, side effects in 21%, pregnancy or childbearing preferences in 16%, noncompliance in 2%, and other reasons in 17%.
Recurrence of disease activity was defined as clinical symptoms, gadolinium-enhancing (Gd+) lesions on MRI, or both, within 6 months of stopping fingolimod. This was seen in 38 patients with 41 events, giving a rate of recurrence of 35%. Of these: “almost 60% had clinical and MRI activity, almost 30% had clinical activity only without Gd+ lesions on MRI, and 12% had MRI activity only without ever having a relapse,” Dr. Cerda said. In those who relapsed, the recurrence took a median 8 weeks to happen after fingolimod discontinuation.
A further definition of severe recurrence of disease activity also was used, defined as either a worsening in the Expanded Disability Status Scale (EDSS) score of more than 2 points (signifying a severe relapse) with or without pronounced MRI activity with at least five cerebral Gd+ lesions within 6 months of fingolimod withdrawal. Thirteen severe events were seen in 11 patients, giving a frequency of approximately 11%. Dr. Cerda reported that patients with severe recurrence were significantly younger at MS diagnosis than were those who did not experience recurrence (P = .003). A trend toward a higher annualized relapse rate (ARR) was seen in patients with severely active versus inactive disease (0.84 vs. 0.54), but this was not statistically significant. In addition, “confirmed disability worsening of 1 EDSS point or more was observed in about 3%.”
Relapse rates coming off fingolimod before or during pregnancy
In another study, which used German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal, up to 56% of women who stopped fingolimod before pregnancy experienced a relapse during pregnancy versus 29% of those who stopped fingolimod upon a positive pregnancy test.
In a comparison of women who stopped fingolimod 1 year to 61 days before their last menstrual period against those who stopped less than 60 days prior to or after their last menstrual period, relapse rates were higher during the first (25.8% for early withdrawal vs. 12.5% with late withdrawal) and second trimesters (32.3% vs. 11.5%) than in the third (9.7% vs. 10.4%), Spalmai Hemat, MD, of the department of neurology at St. Josef Hospital, Ruhr University of Bochum (Germany) reported at the congress.
Relapse rates at 6 months postpartum proved to be similar at 36.7% for women who stopped fingolimod before their pregnancy and 38% in those who stopped later. Difference in the percentage of women experiencing disability progression during pregnancy did not prove to be statistically significant for stopping fingolimod before pregnancy (22.7%) vs. stopping later (11.1%; P = .283), while the 23.8% rate of disability progression after pregnancy among women who stopped the drug later versus 13.6% seen with stopping before was also not statistically significant (P = .31). Relapse during pregnancy was the only significant predictor for relapses postpartum.
“The large majority of women did not experience permanent disability,” Dr. Hemat said, but noted that as many as 10%-20% could experience substantial EDSS worsening (2 or more points) at 6 months postpartum.
Dr. Hemat concluded that more data were needed to see if reintroduction of fingolimod very soon after birth, such as within the first 2 weeks, could reduce the postpartum relapse risk.
Dr. Hemat and Dr. Cerda had no relevant disclosures.
SOURCES: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: A higher risk of recurrent disease activity was seen in younger MS patients with shorter disease duration and evidence of disease activity while on fingolimod treatment. Pregnant women who stopped more than 2 months before a planned pregnancy also had a higher risk versus those who stopped after a positive pregnancy test.
Study details: A retrospective analysis of 110 MS patients who discontinued fingolimod from a 433-patient cohort, and German registry data on 129 pregnancies that occurred around or after the time of fingolimod withdrawal.
Disclosures: Dr. Spalmai Hemat and Dr. Nuria Cerda had no relevant disclosures.
Sources: Cerda N et al. Mult Scler. 2018;24(S2):73-4, Abstract 206; Hemat S et al. Mult Scler. 2018;24(S2):74-5, Abstract 207.
Anti-MOG antibodies associated with non-MS, monophasic demyelinating disease in young children
BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.
“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”
The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.
The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.
The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.
Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.
Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).
The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”
Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.
Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).
Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.
Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.
Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.
Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.
SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.
“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”
The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.
The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.
The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.
Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.
Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).
The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”
Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.
Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).
Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.
Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.
Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.
Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.
SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.
“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”
The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.
The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.
The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.
Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.
Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).
The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”
Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.
Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).
Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.
Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.
Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.
Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.
SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Most children (81%) who were antibody positive at baseline experienced no relapses.
Study details: A cohort of 275 children from the prospective Canadian Pediatric Demyelinating Disease Study.
Disclosures: Dr. Fadda disclosed relationships with Atara Biotherapeutics and Sanofi-Genzyme.
Source: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
Demyelinating diseases, especially MS, disrupt normal brain development in children
BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.
While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.
Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.
“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”
But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”
A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”
The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.
The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).
In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.
“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”
MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.
The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.
“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”
Dr. Brown has been a consultant for NeuroRx Research and Biogen.
SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.
BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.
While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.
Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.
“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”
But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”
A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”
The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.
The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).
In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.
“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”
MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.
The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.
“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”
Dr. Brown has been a consultant for NeuroRx Research and Biogen.
SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.
BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.
While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.
Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.
“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”
But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”
A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”
The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.
The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).
In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.
“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”
MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.
The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.
“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”
Dr. Brown has been a consultant for NeuroRx Research and Biogen.
SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.
REPORTING FROM ECTRIMS 2018
Key clinical point: Demyelinating disorders disrupt brain growth in children.
Major finding: Children with MS had virtually no white matter growth, and those with ADM lagged significantly behind controls.
Study details: The prospective imaging study comprised 24 controls, 102 with an ADM, and 87 with MS.
Disclosures: Dr. Brown has been a consultant for NeuroRx Research and Biogen Idec.
Source: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63
Alemtuzumab switch linked to good MS outcomes
BERLIN – Switching to alemtuzumab from fingolimod is associated with improved disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to the results of a real-world study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Jessica Frau, MD, of the University of Cagliari (Italy) reported that a switch from fingolimod (Gilenya) to alemtuzumab (Lemtrada) in 77 patients treated at 11 Italian centers was able to “reduce dramatically disease activity in patients who did not respond to fingolimod.”
Dr. Frau reported: “When we compared in our cohort the last year of fingolimod with the first year after the first course of alemtuzumab, we found a significant decrease in the annualized relapse rate [ARR].” The ARRs were 0.60 for fingolimod and 0.20 after 1 year of alemtuzumab treatment.
“We found also a trend towards an improvement in the EDSS [Expanded Disability Status Scale] score (P = .23), and less evidence of disease activity on MRI, both in terms of new T2 lesions and gadolinium-enhancing (Gd+) lesions.”
The last MRI during fingolimod treatment showed new T2 and Gd+ enhancing lesions in 69.2% and 58.6% of patients, respectively. Corresponding figures for the first MRI during alemtuzumab treatment were 10.4% and 2.2% of patients.
The beneficial effects of switching to fingolimod in the Italian study “was not influenced by a shorter washout [period] or a low lymphocyte count when alemtuzumab was started,” Dr. Frau said. A shorter washout period has been hypothesized to account for recent accounts of disease flares seen when switching from fingolimod to alemtuzumab, she explained.
Indeed, Dr. Frau noted that there had been a few studies that reported MS disease reactivation soon after the switch to alemtuzumab was made, which could be because lymphocytes remain in the lymph nodes when alemtuzumab is administered, this means that potentially they could repopulate the central nervous system and reactivate the disease.
However, “when alemtuzumab is started after fingolimod it is not a risk factor for reactivation of the disease,” Dr. Frau said, based on the current study’s findings.
As expected, the frequency of relapses increased during the washout period after stopping fingolimod, going from 12.7% of patients with relapse in the first month, 18.2% at 2 months, and 22.2% at 3 months. The time to first relapse from the start of alemtuzumab treatment was 6 months for 2.9% of patients, 9 months for 10.5% of patients, and 1 year for 20.7% of patients.
Asked to comment on when the optimal time to switch from fingolimod to alemtuzumab might be, Dr. Frau said: “The optimal time could be 1 month when the lymphocyte count is not too low.” However, lymphocyte counts were not measured in the entire cohort, so “these data perhaps need to have more strength.”
The switch from natalizumab to alemtuzumab
Other data on switching to alemtuzumab, this time from natalizumab (Tysabri), in the ANSWERS MS study were presented by Paul Gallagher, MBChB, of Queen Elizabeth University Hospital, London, and the University of Glasgow (Scotland).
ANSWERS MS (Alemtuzumab after Natalizumab Switch in Evolving Rapidly Severe MS) is a retrospective, observational analysis of routinely collected data on the use of alemtuzumab by 13 centers the United Kingdom and Ireland. These centers have been collecting data since before alemtuzumab was licensed in 2014 for MS, Dr. Gallagher observed, with some centers having experience of making the switch for more than a decade.
ANSWERS MS addresses a common clinical question: “Is it safe and effective to switch to alemtuzumab if natalizumab fails in highly active MS?” Dr. Gallagher said. “The truth is we don’t really know the answer to this, although it’s becoming an increasingly used switch.”
Alemtuzumab was developed in Cambridge, England, in 1983, originally as an anticancer agent, and first started being used in MS patients in the 1990s. Natalizumab was first licensed in the United Kingdom in 2007.
The aim of the study was mainly to look at safety, but also examine efficacy, and to offer advice on how to best manage the switch. A total of 79 patients formed the safety cohort; 51 of these patients had more than 2 years of follow-up after their first infusion of alemtuzumab and formed the efficacy cohort.
Data were examined in five phases: before natalizumab, during natalizumab, during the switchover period, during alemtuzumab treatment, and after alemtuzumab treatment, with the latter starting 2 years after the first alemtuzumab infusion.
Dr. Gallagher noted that 43% started natalizumab as a first-line therapy, and almost half (49%) of patients stopped taking natalizumab because of breakthrough disease, making this a bit of an unusual cohort with highly active disease, although other cohort characteristics were pretty typical of an MS population.
“The headline is that there are no new safety concerns identified from this cohort,” Dr. Gallagher reported. “Most [61%] patients had infusion reactions with alemtuzumab as expected, but this gradually reduced with subsequent courses.”
Fewer than 20% of patients developed autoimmune thyroid disease, he added, and there were no cases of idiopathic thrombocytopenic purpura.
Infections were seen in nine patients, including three cases of shingles, two urinary tract infections – one of which was classed as a severe adverse event – and one case each of oral thrush, fungal skin infection, tonsillitis, and norovirus.
There was also one cytomegalovirus infection and one death from sepsis unrelated to alemtuzumab; both of these were classed as serious adverse events.
In terms of efficacy, mean ARRs were 2.3 before and 0.8 during natalizumab treatment, decreasing to 0.4 during alemtuzumab treatment and 0.5 post alemtuzumab. A “spike” in relapses was seen, however, during the switch period.
“There was a similar story with MRI imaging,” Dr. Gallagher said. “The profile suggests high disease activity during the switch phase in comparison to everything else.” The mean number of new or worsened MRI lesions was 4.32 per scan per year during the switch period. This fell, however, during alemtuzumab treatment to 0.006 per MRI scan per year and remained low after the end of alemtuzumab treatment at 0.017 per scan per year.
There was no real benefit to switching on the EDSS, with scores increasing from 3.4 in the pre-natalizumab period to 4.7 during the switch period, but then plateauing out to 4.4. and 4.3 after the initiation of alemtuzumab and in the post-alemtuzumab phase.
“These data were based on medical records, often incomplete, and so not all patients had an EDSS in every phase, for example,” Dr. Gallagher noted. He said an analysis was done to try to account for the missing information. This showed that there was an improvement in EDSS while on alemtuzumab, but the effect was not maintained.
It was evident in looking at the switch period that a shorter time between natalizumab and alemtuzumab was associated with the best outcomes, with the optimum time being around 2-4 months. Bridging therapy with fingolimod did not reduce disease activity during the switch, Dr. Gallagher said.
ANSWERS MS was funded by Sanofi-Genzyme. Paul Gallagher disclosed that he had received salary payment and travel funding for educational events from Sanofi-Genzyme and travel funding from Novartis and Biogen.
Dr. Frau disclosed that she serves on scientific advisory boards for Biogen, Merck, and Genzyme and that she has received honoraria for speaking from Merck Serono, Genzyme, Biogen, and Teva.
SOURCE: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.
BERLIN – Switching to alemtuzumab from fingolimod is associated with improved disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to the results of a real-world study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Jessica Frau, MD, of the University of Cagliari (Italy) reported that a switch from fingolimod (Gilenya) to alemtuzumab (Lemtrada) in 77 patients treated at 11 Italian centers was able to “reduce dramatically disease activity in patients who did not respond to fingolimod.”
Dr. Frau reported: “When we compared in our cohort the last year of fingolimod with the first year after the first course of alemtuzumab, we found a significant decrease in the annualized relapse rate [ARR].” The ARRs were 0.60 for fingolimod and 0.20 after 1 year of alemtuzumab treatment.
“We found also a trend towards an improvement in the EDSS [Expanded Disability Status Scale] score (P = .23), and less evidence of disease activity on MRI, both in terms of new T2 lesions and gadolinium-enhancing (Gd+) lesions.”
The last MRI during fingolimod treatment showed new T2 and Gd+ enhancing lesions in 69.2% and 58.6% of patients, respectively. Corresponding figures for the first MRI during alemtuzumab treatment were 10.4% and 2.2% of patients.
The beneficial effects of switching to fingolimod in the Italian study “was not influenced by a shorter washout [period] or a low lymphocyte count when alemtuzumab was started,” Dr. Frau said. A shorter washout period has been hypothesized to account for recent accounts of disease flares seen when switching from fingolimod to alemtuzumab, she explained.
Indeed, Dr. Frau noted that there had been a few studies that reported MS disease reactivation soon after the switch to alemtuzumab was made, which could be because lymphocytes remain in the lymph nodes when alemtuzumab is administered, this means that potentially they could repopulate the central nervous system and reactivate the disease.
However, “when alemtuzumab is started after fingolimod it is not a risk factor for reactivation of the disease,” Dr. Frau said, based on the current study’s findings.
As expected, the frequency of relapses increased during the washout period after stopping fingolimod, going from 12.7% of patients with relapse in the first month, 18.2% at 2 months, and 22.2% at 3 months. The time to first relapse from the start of alemtuzumab treatment was 6 months for 2.9% of patients, 9 months for 10.5% of patients, and 1 year for 20.7% of patients.
Asked to comment on when the optimal time to switch from fingolimod to alemtuzumab might be, Dr. Frau said: “The optimal time could be 1 month when the lymphocyte count is not too low.” However, lymphocyte counts were not measured in the entire cohort, so “these data perhaps need to have more strength.”
The switch from natalizumab to alemtuzumab
Other data on switching to alemtuzumab, this time from natalizumab (Tysabri), in the ANSWERS MS study were presented by Paul Gallagher, MBChB, of Queen Elizabeth University Hospital, London, and the University of Glasgow (Scotland).
ANSWERS MS (Alemtuzumab after Natalizumab Switch in Evolving Rapidly Severe MS) is a retrospective, observational analysis of routinely collected data on the use of alemtuzumab by 13 centers the United Kingdom and Ireland. These centers have been collecting data since before alemtuzumab was licensed in 2014 for MS, Dr. Gallagher observed, with some centers having experience of making the switch for more than a decade.
ANSWERS MS addresses a common clinical question: “Is it safe and effective to switch to alemtuzumab if natalizumab fails in highly active MS?” Dr. Gallagher said. “The truth is we don’t really know the answer to this, although it’s becoming an increasingly used switch.”
Alemtuzumab was developed in Cambridge, England, in 1983, originally as an anticancer agent, and first started being used in MS patients in the 1990s. Natalizumab was first licensed in the United Kingdom in 2007.
The aim of the study was mainly to look at safety, but also examine efficacy, and to offer advice on how to best manage the switch. A total of 79 patients formed the safety cohort; 51 of these patients had more than 2 years of follow-up after their first infusion of alemtuzumab and formed the efficacy cohort.
Data were examined in five phases: before natalizumab, during natalizumab, during the switchover period, during alemtuzumab treatment, and after alemtuzumab treatment, with the latter starting 2 years after the first alemtuzumab infusion.
Dr. Gallagher noted that 43% started natalizumab as a first-line therapy, and almost half (49%) of patients stopped taking natalizumab because of breakthrough disease, making this a bit of an unusual cohort with highly active disease, although other cohort characteristics were pretty typical of an MS population.
“The headline is that there are no new safety concerns identified from this cohort,” Dr. Gallagher reported. “Most [61%] patients had infusion reactions with alemtuzumab as expected, but this gradually reduced with subsequent courses.”
Fewer than 20% of patients developed autoimmune thyroid disease, he added, and there were no cases of idiopathic thrombocytopenic purpura.
Infections were seen in nine patients, including three cases of shingles, two urinary tract infections – one of which was classed as a severe adverse event – and one case each of oral thrush, fungal skin infection, tonsillitis, and norovirus.
There was also one cytomegalovirus infection and one death from sepsis unrelated to alemtuzumab; both of these were classed as serious adverse events.
In terms of efficacy, mean ARRs were 2.3 before and 0.8 during natalizumab treatment, decreasing to 0.4 during alemtuzumab treatment and 0.5 post alemtuzumab. A “spike” in relapses was seen, however, during the switch period.
“There was a similar story with MRI imaging,” Dr. Gallagher said. “The profile suggests high disease activity during the switch phase in comparison to everything else.” The mean number of new or worsened MRI lesions was 4.32 per scan per year during the switch period. This fell, however, during alemtuzumab treatment to 0.006 per MRI scan per year and remained low after the end of alemtuzumab treatment at 0.017 per scan per year.
There was no real benefit to switching on the EDSS, with scores increasing from 3.4 in the pre-natalizumab period to 4.7 during the switch period, but then plateauing out to 4.4. and 4.3 after the initiation of alemtuzumab and in the post-alemtuzumab phase.
“These data were based on medical records, often incomplete, and so not all patients had an EDSS in every phase, for example,” Dr. Gallagher noted. He said an analysis was done to try to account for the missing information. This showed that there was an improvement in EDSS while on alemtuzumab, but the effect was not maintained.
It was evident in looking at the switch period that a shorter time between natalizumab and alemtuzumab was associated with the best outcomes, with the optimum time being around 2-4 months. Bridging therapy with fingolimod did not reduce disease activity during the switch, Dr. Gallagher said.
ANSWERS MS was funded by Sanofi-Genzyme. Paul Gallagher disclosed that he had received salary payment and travel funding for educational events from Sanofi-Genzyme and travel funding from Novartis and Biogen.
Dr. Frau disclosed that she serves on scientific advisory boards for Biogen, Merck, and Genzyme and that she has received honoraria for speaking from Merck Serono, Genzyme, Biogen, and Teva.
SOURCE: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.
BERLIN – Switching to alemtuzumab from fingolimod is associated with improved disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), according to the results of a real-world study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Jessica Frau, MD, of the University of Cagliari (Italy) reported that a switch from fingolimod (Gilenya) to alemtuzumab (Lemtrada) in 77 patients treated at 11 Italian centers was able to “reduce dramatically disease activity in patients who did not respond to fingolimod.”
Dr. Frau reported: “When we compared in our cohort the last year of fingolimod with the first year after the first course of alemtuzumab, we found a significant decrease in the annualized relapse rate [ARR].” The ARRs were 0.60 for fingolimod and 0.20 after 1 year of alemtuzumab treatment.
“We found also a trend towards an improvement in the EDSS [Expanded Disability Status Scale] score (P = .23), and less evidence of disease activity on MRI, both in terms of new T2 lesions and gadolinium-enhancing (Gd+) lesions.”
The last MRI during fingolimod treatment showed new T2 and Gd+ enhancing lesions in 69.2% and 58.6% of patients, respectively. Corresponding figures for the first MRI during alemtuzumab treatment were 10.4% and 2.2% of patients.
The beneficial effects of switching to fingolimod in the Italian study “was not influenced by a shorter washout [period] or a low lymphocyte count when alemtuzumab was started,” Dr. Frau said. A shorter washout period has been hypothesized to account for recent accounts of disease flares seen when switching from fingolimod to alemtuzumab, she explained.
Indeed, Dr. Frau noted that there had been a few studies that reported MS disease reactivation soon after the switch to alemtuzumab was made, which could be because lymphocytes remain in the lymph nodes when alemtuzumab is administered, this means that potentially they could repopulate the central nervous system and reactivate the disease.
However, “when alemtuzumab is started after fingolimod it is not a risk factor for reactivation of the disease,” Dr. Frau said, based on the current study’s findings.
As expected, the frequency of relapses increased during the washout period after stopping fingolimod, going from 12.7% of patients with relapse in the first month, 18.2% at 2 months, and 22.2% at 3 months. The time to first relapse from the start of alemtuzumab treatment was 6 months for 2.9% of patients, 9 months for 10.5% of patients, and 1 year for 20.7% of patients.
Asked to comment on when the optimal time to switch from fingolimod to alemtuzumab might be, Dr. Frau said: “The optimal time could be 1 month when the lymphocyte count is not too low.” However, lymphocyte counts were not measured in the entire cohort, so “these data perhaps need to have more strength.”
The switch from natalizumab to alemtuzumab
Other data on switching to alemtuzumab, this time from natalizumab (Tysabri), in the ANSWERS MS study were presented by Paul Gallagher, MBChB, of Queen Elizabeth University Hospital, London, and the University of Glasgow (Scotland).
ANSWERS MS (Alemtuzumab after Natalizumab Switch in Evolving Rapidly Severe MS) is a retrospective, observational analysis of routinely collected data on the use of alemtuzumab by 13 centers the United Kingdom and Ireland. These centers have been collecting data since before alemtuzumab was licensed in 2014 for MS, Dr. Gallagher observed, with some centers having experience of making the switch for more than a decade.
ANSWERS MS addresses a common clinical question: “Is it safe and effective to switch to alemtuzumab if natalizumab fails in highly active MS?” Dr. Gallagher said. “The truth is we don’t really know the answer to this, although it’s becoming an increasingly used switch.”
Alemtuzumab was developed in Cambridge, England, in 1983, originally as an anticancer agent, and first started being used in MS patients in the 1990s. Natalizumab was first licensed in the United Kingdom in 2007.
The aim of the study was mainly to look at safety, but also examine efficacy, and to offer advice on how to best manage the switch. A total of 79 patients formed the safety cohort; 51 of these patients had more than 2 years of follow-up after their first infusion of alemtuzumab and formed the efficacy cohort.
Data were examined in five phases: before natalizumab, during natalizumab, during the switchover period, during alemtuzumab treatment, and after alemtuzumab treatment, with the latter starting 2 years after the first alemtuzumab infusion.
Dr. Gallagher noted that 43% started natalizumab as a first-line therapy, and almost half (49%) of patients stopped taking natalizumab because of breakthrough disease, making this a bit of an unusual cohort with highly active disease, although other cohort characteristics were pretty typical of an MS population.
“The headline is that there are no new safety concerns identified from this cohort,” Dr. Gallagher reported. “Most [61%] patients had infusion reactions with alemtuzumab as expected, but this gradually reduced with subsequent courses.”
Fewer than 20% of patients developed autoimmune thyroid disease, he added, and there were no cases of idiopathic thrombocytopenic purpura.
Infections were seen in nine patients, including three cases of shingles, two urinary tract infections – one of which was classed as a severe adverse event – and one case each of oral thrush, fungal skin infection, tonsillitis, and norovirus.
There was also one cytomegalovirus infection and one death from sepsis unrelated to alemtuzumab; both of these were classed as serious adverse events.
In terms of efficacy, mean ARRs were 2.3 before and 0.8 during natalizumab treatment, decreasing to 0.4 during alemtuzumab treatment and 0.5 post alemtuzumab. A “spike” in relapses was seen, however, during the switch period.
“There was a similar story with MRI imaging,” Dr. Gallagher said. “The profile suggests high disease activity during the switch phase in comparison to everything else.” The mean number of new or worsened MRI lesions was 4.32 per scan per year during the switch period. This fell, however, during alemtuzumab treatment to 0.006 per MRI scan per year and remained low after the end of alemtuzumab treatment at 0.017 per scan per year.
There was no real benefit to switching on the EDSS, with scores increasing from 3.4 in the pre-natalizumab period to 4.7 during the switch period, but then plateauing out to 4.4. and 4.3 after the initiation of alemtuzumab and in the post-alemtuzumab phase.
“These data were based on medical records, often incomplete, and so not all patients had an EDSS in every phase, for example,” Dr. Gallagher noted. He said an analysis was done to try to account for the missing information. This showed that there was an improvement in EDSS while on alemtuzumab, but the effect was not maintained.
It was evident in looking at the switch period that a shorter time between natalizumab and alemtuzumab was associated with the best outcomes, with the optimum time being around 2-4 months. Bridging therapy with fingolimod did not reduce disease activity during the switch, Dr. Gallagher said.
ANSWERS MS was funded by Sanofi-Genzyme. Paul Gallagher disclosed that he had received salary payment and travel funding for educational events from Sanofi-Genzyme and travel funding from Novartis and Biogen.
Dr. Frau disclosed that she serves on scientific advisory boards for Biogen, Merck, and Genzyme and that she has received honoraria for speaking from Merck Serono, Genzyme, Biogen, and Teva.
SOURCE: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.
REPORTING FROM ECTRIMS 2018
Key clinical point: Good results can be achieved by switching from fingolimod or natalizumab to alemtuzumab in relapsing-remitting multiple sclerosis (RRMS).
Major finding: Annualized relapse rates were 0.60 for fingolimod at the time of the switch and 0.20 after 1 year of alemtuzumab treatment in one real-world study. In another, alemtuzumab was effective in reducing inflammatory disease activity when natalizumab failed.
Study details: Two real-world, observational studies: one with 77 RRMS patients treated at 11 Italian centers and the other a retrospective analysis of routinely collected data on 79 patients.
Disclosures: Dr. Frau disclosed that she serves on scientific advisory board for Biogen, Merck, and Genzyme and that she has received honoraria for speaking from Merck Serono, Genzyme, Biogen, and Teva. ANSWERS MS was funded by Sanofi-Genzyme. Dr. Gallagher disclosed he had received salary payment and travel funding for educational events from Sanofi-Genzyme and travel funding from Novartis and Biogen.
Source: Frau J et al. Mult Scler. 2018;24(S2):100-1, Abstract 265; Gallagher P et al. Mult Scler. 2018;24(S2):99-100, Abstract 264.
Vitamin D Levels at Onset Predict Subsequent Cognition in MS
Smoking at baseline is associated with an increased risk of cognitive decline at Year 11.
BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.
“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”
The BENEFIT-11 Trial
According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.
Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.
Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.
The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.
“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.
A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.
“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.
Epstein-Barr antibodies were not associated with cognitive function at Year 11.
“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.
Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.
Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.
—Kari Oakes
Smoking at baseline is associated with an increased risk of cognitive decline at Year 11.
Smoking at baseline is associated with an increased risk of cognitive decline at Year 11.
BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.
“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”
The BENEFIT-11 Trial
According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.
Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.
Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.
The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.
“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.
A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.
“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.
Epstein-Barr antibodies were not associated with cognitive function at Year 11.
“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.
Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.
Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.
—Kari Oakes
BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.
“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”
The BENEFIT-11 Trial
According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.
Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.
Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.
The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.
“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.
A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.
“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.
Epstein-Barr antibodies were not associated with cognitive function at Year 11.
“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.
Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.
Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.
—Kari Oakes