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FDA approves diroximel fumarate for relapsing MS
The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.
The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.
Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.
Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.
Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.
The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.
The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.
Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.
Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.
Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.
The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.
The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.
Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.
Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.
Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.
Adolescent lung inflammation may trigger later MS
STOCKHOLM – Scott Montgomery, PhD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
This is speculative, he readily acknowledged, but it is a hypothesis supported by multiple lines of evidence provided by separate Swedish national health care registry studies he has led that showed associations between pneumonia or infectious mononucleosis occurring in early adolescence and increased risk of later MS.
These findings are consistent with the well-established observations that two other causes of lung irritation – cigarette smoking and exposure to organic solvents – are also linked to increased risk of MS (Neurology. 2018 Jul 31;91[5]:e455-62), noted Dr. Montgomery, head of the clinical epidemiology research group at Örebro (Sweden) University.
Moreover, he and his coinvestigators also found in yet another Swedish national registry cohort study that one concussion during adolescence was independently associated with a statistically significant 1.22-fold increased risk of later MS, while two or more were linked to a 2.33-fold increased risk. In contrast, concussions occurring before age 11 years were not associated with any increased risk of MS, which suggests an age-defined period of susceptibility (Ann Neurol. 2017 Oct;82[4]:554-61).
“There seems to be greater brain resilience in childhood as compared to adolescence,” Dr. Montgomery commented.
The new Swedish registry pneumonia study included 6,109 Swedish MS patients and 49,479 controls matched for age, gender, and locale. In an analysis adjusted for education level and history of infectious mononucleosis, history of having pneumonia at age 11-15 years was independently associated with a 2.8-fold increased risk of subsequent MS. Pneumonia occurring at age 16-20 years was associated with a more modest 1.38-fold increased risk, which did not achieve statistical significance, while pneumonia up to age 5 years or at age 6-10 years conferred no increased risk. The investigators restricted their analysis to cases of pneumonia occurring up to age 20 years because that is younger than the typical age of MS onset. The age restriction sidestepped the potential for confounding by reverse causation since it is known that pneumonia occurs with increased frequency in patients with MS.
Because MS patients also have an increased risk of urinary tract infections, Dr. Montgomery and coinvestigators also analyzed the same pediatric data set for UTI rates broken down by 5-year age groups. Rates were similar in individuals who later developed MS and in controls, which suggests that the observed increase in MS risk associated with pneumonia in early adolescence was not an expression of an MS prodromal illness, he explained.
The investigators focused on pneumonia in childhood and adolescence as a potential trigger for MS because pneumonia results in more profound and prolonged inflammation than do other common respiratory illnesses. For example, pneumonia has been shown to be linked to increased risks of cardiovascular disease and chronic kidney disease for up to 5 years after the infection.
Developmentally, age 11-15 years is a period defined by peripubertal reorganization and synaptogenesis, while synaptic pruning and axonal myelination are on the agenda at age 16-20 years, Dr. Montgomery observed.
The study of infectious mononucleosis as a potential risk factor for MS included 4,527 Swedish MS patients and 3.2 million controls, all born during 1970-2000 and followed until 2014. In this analysis, infectious mononucleosis occurring at age 11-15 years was associated with the greatest risk of subsequent MS, with an associated 3.47-fold greater risk of the neurologic disease versus that seen in patients who did not have infectious mononucleosis at age 11-15 years
“It does look like a causal association between Epstein-Barr virus infection and subsequent MS,” according to Dr. Montgomery.
He noted that a plausible mechanism by which lung inflammation could predispose future MS has been put forth by German investigators. Using an animal model, they demonstrated that autoreactive T cells are prepared in bronchus-associated lymphoid tissue and attain a migratory profile allowing them to cross the blood-brain barrier and induce CNS autoimmune disease (Nature. 2012 Aug 30;488[7413]:675-9).
All of this, as Dr. Montgomery emphasized, is speculative at this point in regard to MS pathogenesis. What is not speculative, he continued, is the solid evidence that infection-related mortality after diagnosis of MS has gone down substantially in the current era of newer disease-modifying treatments, as he and his coinvestigators have demonstrated (Neurology. 2017 Aug 8;89[6]:555-62).
“People with MS, compared to the general population, are still at increased risk, but not nearly as much as the infection-related mortality risk present back in the 1960s-80s. So things have improved somewhat,” Dr. Montgomery said.
Which MS patients are at increased risk for mortality caused by infection? His Swedish national registry research demonstrates that the risk is essentially confined to patients with secondary or primary progressive MS or an Expanded Disability Status Scale score of 6 or more.
Another new study he presented at the meeting focused on the types of infections that are more common in a contemporary MS population than in MS-free individuals. This Swedish national cohort study included 6,602 patients diagnosed with MS during 2008-2016 and 61,828 age-, sex-, and location-matched controls. Infections serious enough to have resulted in hospitalization occurred 2.59 times more frequently in the MS population. The risk of meningitis and encephalitis was increased 6.16-fold, opportunistic infections were 2.72-fold more frequent, the risk of urinary tract and kidney infections was increased 2.44-fold, herpes virus infections were increased 2.32-fold, and the combined rate of pneumonia and influenza was roughly double that seen in the matched general population.
Dr. Montgomery reported receiving research funding from F. Hoffmann–La Roche, Novartis, and AstraZeneca and serving on an advisory board for IQVIA.
SOURCE: Montgomery S. ECTRIMS 2019, Abstract 270.
STOCKHOLM – Scott Montgomery, PhD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
This is speculative, he readily acknowledged, but it is a hypothesis supported by multiple lines of evidence provided by separate Swedish national health care registry studies he has led that showed associations between pneumonia or infectious mononucleosis occurring in early adolescence and increased risk of later MS.
These findings are consistent with the well-established observations that two other causes of lung irritation – cigarette smoking and exposure to organic solvents – are also linked to increased risk of MS (Neurology. 2018 Jul 31;91[5]:e455-62), noted Dr. Montgomery, head of the clinical epidemiology research group at Örebro (Sweden) University.
Moreover, he and his coinvestigators also found in yet another Swedish national registry cohort study that one concussion during adolescence was independently associated with a statistically significant 1.22-fold increased risk of later MS, while two or more were linked to a 2.33-fold increased risk. In contrast, concussions occurring before age 11 years were not associated with any increased risk of MS, which suggests an age-defined period of susceptibility (Ann Neurol. 2017 Oct;82[4]:554-61).
“There seems to be greater brain resilience in childhood as compared to adolescence,” Dr. Montgomery commented.
The new Swedish registry pneumonia study included 6,109 Swedish MS patients and 49,479 controls matched for age, gender, and locale. In an analysis adjusted for education level and history of infectious mononucleosis, history of having pneumonia at age 11-15 years was independently associated with a 2.8-fold increased risk of subsequent MS. Pneumonia occurring at age 16-20 years was associated with a more modest 1.38-fold increased risk, which did not achieve statistical significance, while pneumonia up to age 5 years or at age 6-10 years conferred no increased risk. The investigators restricted their analysis to cases of pneumonia occurring up to age 20 years because that is younger than the typical age of MS onset. The age restriction sidestepped the potential for confounding by reverse causation since it is known that pneumonia occurs with increased frequency in patients with MS.
Because MS patients also have an increased risk of urinary tract infections, Dr. Montgomery and coinvestigators also analyzed the same pediatric data set for UTI rates broken down by 5-year age groups. Rates were similar in individuals who later developed MS and in controls, which suggests that the observed increase in MS risk associated with pneumonia in early adolescence was not an expression of an MS prodromal illness, he explained.
The investigators focused on pneumonia in childhood and adolescence as a potential trigger for MS because pneumonia results in more profound and prolonged inflammation than do other common respiratory illnesses. For example, pneumonia has been shown to be linked to increased risks of cardiovascular disease and chronic kidney disease for up to 5 years after the infection.
Developmentally, age 11-15 years is a period defined by peripubertal reorganization and synaptogenesis, while synaptic pruning and axonal myelination are on the agenda at age 16-20 years, Dr. Montgomery observed.
The study of infectious mononucleosis as a potential risk factor for MS included 4,527 Swedish MS patients and 3.2 million controls, all born during 1970-2000 and followed until 2014. In this analysis, infectious mononucleosis occurring at age 11-15 years was associated with the greatest risk of subsequent MS, with an associated 3.47-fold greater risk of the neurologic disease versus that seen in patients who did not have infectious mononucleosis at age 11-15 years
“It does look like a causal association between Epstein-Barr virus infection and subsequent MS,” according to Dr. Montgomery.
He noted that a plausible mechanism by which lung inflammation could predispose future MS has been put forth by German investigators. Using an animal model, they demonstrated that autoreactive T cells are prepared in bronchus-associated lymphoid tissue and attain a migratory profile allowing them to cross the blood-brain barrier and induce CNS autoimmune disease (Nature. 2012 Aug 30;488[7413]:675-9).
All of this, as Dr. Montgomery emphasized, is speculative at this point in regard to MS pathogenesis. What is not speculative, he continued, is the solid evidence that infection-related mortality after diagnosis of MS has gone down substantially in the current era of newer disease-modifying treatments, as he and his coinvestigators have demonstrated (Neurology. 2017 Aug 8;89[6]:555-62).
“People with MS, compared to the general population, are still at increased risk, but not nearly as much as the infection-related mortality risk present back in the 1960s-80s. So things have improved somewhat,” Dr. Montgomery said.
Which MS patients are at increased risk for mortality caused by infection? His Swedish national registry research demonstrates that the risk is essentially confined to patients with secondary or primary progressive MS or an Expanded Disability Status Scale score of 6 or more.
Another new study he presented at the meeting focused on the types of infections that are more common in a contemporary MS population than in MS-free individuals. This Swedish national cohort study included 6,602 patients diagnosed with MS during 2008-2016 and 61,828 age-, sex-, and location-matched controls. Infections serious enough to have resulted in hospitalization occurred 2.59 times more frequently in the MS population. The risk of meningitis and encephalitis was increased 6.16-fold, opportunistic infections were 2.72-fold more frequent, the risk of urinary tract and kidney infections was increased 2.44-fold, herpes virus infections were increased 2.32-fold, and the combined rate of pneumonia and influenza was roughly double that seen in the matched general population.
Dr. Montgomery reported receiving research funding from F. Hoffmann–La Roche, Novartis, and AstraZeneca and serving on an advisory board for IQVIA.
SOURCE: Montgomery S. ECTRIMS 2019, Abstract 270.
STOCKHOLM – Scott Montgomery, PhD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
This is speculative, he readily acknowledged, but it is a hypothesis supported by multiple lines of evidence provided by separate Swedish national health care registry studies he has led that showed associations between pneumonia or infectious mononucleosis occurring in early adolescence and increased risk of later MS.
These findings are consistent with the well-established observations that two other causes of lung irritation – cigarette smoking and exposure to organic solvents – are also linked to increased risk of MS (Neurology. 2018 Jul 31;91[5]:e455-62), noted Dr. Montgomery, head of the clinical epidemiology research group at Örebro (Sweden) University.
Moreover, he and his coinvestigators also found in yet another Swedish national registry cohort study that one concussion during adolescence was independently associated with a statistically significant 1.22-fold increased risk of later MS, while two or more were linked to a 2.33-fold increased risk. In contrast, concussions occurring before age 11 years were not associated with any increased risk of MS, which suggests an age-defined period of susceptibility (Ann Neurol. 2017 Oct;82[4]:554-61).
“There seems to be greater brain resilience in childhood as compared to adolescence,” Dr. Montgomery commented.
The new Swedish registry pneumonia study included 6,109 Swedish MS patients and 49,479 controls matched for age, gender, and locale. In an analysis adjusted for education level and history of infectious mononucleosis, history of having pneumonia at age 11-15 years was independently associated with a 2.8-fold increased risk of subsequent MS. Pneumonia occurring at age 16-20 years was associated with a more modest 1.38-fold increased risk, which did not achieve statistical significance, while pneumonia up to age 5 years or at age 6-10 years conferred no increased risk. The investigators restricted their analysis to cases of pneumonia occurring up to age 20 years because that is younger than the typical age of MS onset. The age restriction sidestepped the potential for confounding by reverse causation since it is known that pneumonia occurs with increased frequency in patients with MS.
Because MS patients also have an increased risk of urinary tract infections, Dr. Montgomery and coinvestigators also analyzed the same pediatric data set for UTI rates broken down by 5-year age groups. Rates were similar in individuals who later developed MS and in controls, which suggests that the observed increase in MS risk associated with pneumonia in early adolescence was not an expression of an MS prodromal illness, he explained.
The investigators focused on pneumonia in childhood and adolescence as a potential trigger for MS because pneumonia results in more profound and prolonged inflammation than do other common respiratory illnesses. For example, pneumonia has been shown to be linked to increased risks of cardiovascular disease and chronic kidney disease for up to 5 years after the infection.
Developmentally, age 11-15 years is a period defined by peripubertal reorganization and synaptogenesis, while synaptic pruning and axonal myelination are on the agenda at age 16-20 years, Dr. Montgomery observed.
The study of infectious mononucleosis as a potential risk factor for MS included 4,527 Swedish MS patients and 3.2 million controls, all born during 1970-2000 and followed until 2014. In this analysis, infectious mononucleosis occurring at age 11-15 years was associated with the greatest risk of subsequent MS, with an associated 3.47-fold greater risk of the neurologic disease versus that seen in patients who did not have infectious mononucleosis at age 11-15 years
“It does look like a causal association between Epstein-Barr virus infection and subsequent MS,” according to Dr. Montgomery.
He noted that a plausible mechanism by which lung inflammation could predispose future MS has been put forth by German investigators. Using an animal model, they demonstrated that autoreactive T cells are prepared in bronchus-associated lymphoid tissue and attain a migratory profile allowing them to cross the blood-brain barrier and induce CNS autoimmune disease (Nature. 2012 Aug 30;488[7413]:675-9).
All of this, as Dr. Montgomery emphasized, is speculative at this point in regard to MS pathogenesis. What is not speculative, he continued, is the solid evidence that infection-related mortality after diagnosis of MS has gone down substantially in the current era of newer disease-modifying treatments, as he and his coinvestigators have demonstrated (Neurology. 2017 Aug 8;89[6]:555-62).
“People with MS, compared to the general population, are still at increased risk, but not nearly as much as the infection-related mortality risk present back in the 1960s-80s. So things have improved somewhat,” Dr. Montgomery said.
Which MS patients are at increased risk for mortality caused by infection? His Swedish national registry research demonstrates that the risk is essentially confined to patients with secondary or primary progressive MS or an Expanded Disability Status Scale score of 6 or more.
Another new study he presented at the meeting focused on the types of infections that are more common in a contemporary MS population than in MS-free individuals. This Swedish national cohort study included 6,602 patients diagnosed with MS during 2008-2016 and 61,828 age-, sex-, and location-matched controls. Infections serious enough to have resulted in hospitalization occurred 2.59 times more frequently in the MS population. The risk of meningitis and encephalitis was increased 6.16-fold, opportunistic infections were 2.72-fold more frequent, the risk of urinary tract and kidney infections was increased 2.44-fold, herpes virus infections were increased 2.32-fold, and the combined rate of pneumonia and influenza was roughly double that seen in the matched general population.
Dr. Montgomery reported receiving research funding from F. Hoffmann–La Roche, Novartis, and AstraZeneca and serving on an advisory board for IQVIA.
SOURCE: Montgomery S. ECTRIMS 2019, Abstract 270.
REPORTING FROM ECTRIMS 2019
Smoking impairs cognition and shrinks brain volume in MS
STOCKHOLM – Ebtesam Alshehri, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found that smokers have reduced Processing Speed Test scores compared with nonsmokers. They also have more brain atrophy. And we found that former smokers had intermediate results between current smokers and never smokers, suggesting that there is a benefit of smoking cessation early in the course of the disease,” explained Dr. Alshehri, a clinical neuroimmunology fellow at the Cleveland Clinic.
Dr. Alshehri and colleagues presented a cross-sectional study of 997 patients with MS. At the Cleveland Clinic, patients with MS routinely undergo the Processing Speed Test (PST) – an electronic version of the Symbol Digit Modalities Test – at each clinical visit as a means of assessing cognitive function. All 997 patients also underwent quantitative brain MRI within 90 days of their cognitive function test. The study population consisted of 520 never smokers, 335 ex-smokers, and 142 current smokers. Seventy-seven percent of the patients had relapsing-remitting MS, and most of the rest had progressive disease.
The impetus for this hypothesis-generating study was a recognition that while smoking has previously been reported to be a risk factor for MS and has also been associated with accelerated progression of disability in patients who already have the disease, the impact of smoking on cognition and brain atrophy in the MS population has been a murky area, according to Dr. Alshehri.
In a multivariate analysis adjusted for age, disease duration, and disease course, smoking status was an independent predictor of PST score. Former smokers scored an average of 3.6 points lower than never smokers, and current smokers scored 5.9 points lower than the never smokers. Similarly, former smokers appeared better off than current smokers in terms of brain atrophy as measured by whole brain function on MRI: The ex-smokers had significantly greater brain atrophy than that of never smokers, an effect that was magnified in current smokers.
For Dr. Alshehri, these findings contain an important message for physicians: “I think as clinicians we should ask our patients with MS about tobacco use at each visit, remind patients about the risks of smoking and the negative impact not only on their general health, but also the impact on disease progression and disability worsening, encourage patients to stop smoking, and provide them with this encouraging data.”
She reported having no financial conflicts regarding this study, which was conducted free of commercial support.
STOCKHOLM – Ebtesam Alshehri, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found that smokers have reduced Processing Speed Test scores compared with nonsmokers. They also have more brain atrophy. And we found that former smokers had intermediate results between current smokers and never smokers, suggesting that there is a benefit of smoking cessation early in the course of the disease,” explained Dr. Alshehri, a clinical neuroimmunology fellow at the Cleveland Clinic.
Dr. Alshehri and colleagues presented a cross-sectional study of 997 patients with MS. At the Cleveland Clinic, patients with MS routinely undergo the Processing Speed Test (PST) – an electronic version of the Symbol Digit Modalities Test – at each clinical visit as a means of assessing cognitive function. All 997 patients also underwent quantitative brain MRI within 90 days of their cognitive function test. The study population consisted of 520 never smokers, 335 ex-smokers, and 142 current smokers. Seventy-seven percent of the patients had relapsing-remitting MS, and most of the rest had progressive disease.
The impetus for this hypothesis-generating study was a recognition that while smoking has previously been reported to be a risk factor for MS and has also been associated with accelerated progression of disability in patients who already have the disease, the impact of smoking on cognition and brain atrophy in the MS population has been a murky area, according to Dr. Alshehri.
In a multivariate analysis adjusted for age, disease duration, and disease course, smoking status was an independent predictor of PST score. Former smokers scored an average of 3.6 points lower than never smokers, and current smokers scored 5.9 points lower than the never smokers. Similarly, former smokers appeared better off than current smokers in terms of brain atrophy as measured by whole brain function on MRI: The ex-smokers had significantly greater brain atrophy than that of never smokers, an effect that was magnified in current smokers.
For Dr. Alshehri, these findings contain an important message for physicians: “I think as clinicians we should ask our patients with MS about tobacco use at each visit, remind patients about the risks of smoking and the negative impact not only on their general health, but also the impact on disease progression and disability worsening, encourage patients to stop smoking, and provide them with this encouraging data.”
She reported having no financial conflicts regarding this study, which was conducted free of commercial support.
STOCKHOLM – Ebtesam Alshehri, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found that smokers have reduced Processing Speed Test scores compared with nonsmokers. They also have more brain atrophy. And we found that former smokers had intermediate results between current smokers and never smokers, suggesting that there is a benefit of smoking cessation early in the course of the disease,” explained Dr. Alshehri, a clinical neuroimmunology fellow at the Cleveland Clinic.
Dr. Alshehri and colleagues presented a cross-sectional study of 997 patients with MS. At the Cleveland Clinic, patients with MS routinely undergo the Processing Speed Test (PST) – an electronic version of the Symbol Digit Modalities Test – at each clinical visit as a means of assessing cognitive function. All 997 patients also underwent quantitative brain MRI within 90 days of their cognitive function test. The study population consisted of 520 never smokers, 335 ex-smokers, and 142 current smokers. Seventy-seven percent of the patients had relapsing-remitting MS, and most of the rest had progressive disease.
The impetus for this hypothesis-generating study was a recognition that while smoking has previously been reported to be a risk factor for MS and has also been associated with accelerated progression of disability in patients who already have the disease, the impact of smoking on cognition and brain atrophy in the MS population has been a murky area, according to Dr. Alshehri.
In a multivariate analysis adjusted for age, disease duration, and disease course, smoking status was an independent predictor of PST score. Former smokers scored an average of 3.6 points lower than never smokers, and current smokers scored 5.9 points lower than the never smokers. Similarly, former smokers appeared better off than current smokers in terms of brain atrophy as measured by whole brain function on MRI: The ex-smokers had significantly greater brain atrophy than that of never smokers, an effect that was magnified in current smokers.
For Dr. Alshehri, these findings contain an important message for physicians: “I think as clinicians we should ask our patients with MS about tobacco use at each visit, remind patients about the risks of smoking and the negative impact not only on their general health, but also the impact on disease progression and disability worsening, encourage patients to stop smoking, and provide them with this encouraging data.”
She reported having no financial conflicts regarding this study, which was conducted free of commercial support.
REPORTING FROM ECTRIMS 2019
In patients with CIS, combined omics predicts conversion to clinically definite MS
STOCKHOLM –
Further, “combined omics improves diagnostic accuracy” over oligoclonal band (OCB) status alone in differentiating patients with multiple sclerosis (MS) from a group of normal control patients, said Fay Probert, PhD, speaking at a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Not everyone with clinically isolated syndrome (CIS) converts to clinically definite MS, and there is large variability in the time to progression, explained Dr. Probert, a postdoctoral fellow in the department of pharmacology at Oxford (England) University, and colleagues. Though the revised McDonald criteria now allow earlier diagnosis of MS, individuals who will be early converters cannot be identified by these criteria, they noted, citing earlier work showing that just over half (52%) of CIS patients who are OCB positive will have clinically definite MS at the 3-year mark.
To see whether combining analysis of multiple proteins and metabolites improved diagnostic accuracy, Dr. Probert and colleagues examined cerebrospinal fluid (CSF) samples from 41 patients with clinically definite MS, 71 patients with CIS, and 64 control participants without MS. In their analysis, the investigators used nuclear MR metabolomics and a commercially available proteomics assay that identifies and quantifies more than 5,000 proteins.
The multivariate analysis strategy achieved 10-fold external cross-validation of the samples, repeating training and testing of the analysis model while shuffling data. This, explained Dr. Probert and colleagues, “ensures that any discrimination observed cannot have occurred by chance.” Further analysis “identifies the optimal combination of proteomics and metabolomics features which results in the highest diagnostic accuracy.”
Both the nuclear MR metabolomics and the proteomic analyses were able to discriminate between those with clinically definite MS and the control participants, with accuracy of 71% and 75%, respectively.
The levels of seven metabolites present in CSF were predictive of clinically definite MS, compared with non-MS status, independent of OCB status. In fact, noted Dr. Probert and colleagues, “the CSF myoinositol concentration alone diagnosed [clinically definite] MS in this cohort with a specificity of 74% but did not outperform OCB status overall.”
Using the combined omics approach, though, “significantly improved the discrimination” between the non-MS control CSF samples and those of patients with clinically definite MS, wrote Dr. Probert and colleagues. Using a combination of up to five CSF proteins and metabolites yielded accuracy of 85 plus or minus 2%, sensitivity of 85 plus or minus 3%, and specificity of 85 plus or minus 3%. For comparison, using just OCB status provides accuracy of 74%, sensitivity of 88% and specificity of 63%.
Then, Dr. Probert and colleagues turned to the CSF samples from patients with CIS to look for predictors of “fast” (4 years or less) or “slow” (greater than 4 years) conversion to clinically definite MS. “While important for diagnosis, OCB status was not predictive of early conversion,” the investigators noted. However, baseline CSF proteomics analysis alone did differentiate the fast from the slow converters among the CIS subgroup, with an accuracy of 77%.
For patients with CIS who were OCB positive, their baseline metabolite and proteomic profiles were “indistinguishable” from those with clinically definite MS, wrote Dr. Probert and colleagues. The omics analysis was also able to distinguish between OCB-positive CIS patients and the non-MS control patients.
“These results indicate that combined metabolomics and proteomics analysis could not only be used as an adjunct in diagnosis of [clinically definite] MS but could be used as a prognostic test to identify CIS patients at high risk of a second clinical attack within 4 years of onset,” wrote Dr. Probert and coauthors. They noted that the method reported in the poster is the first to offer this prognostic accuracy, but that more work is needed before routine clinical use.
Dr. Probert reported that she had no financial conflicts of interest. One coauthor reported being a consultant to Novartis. Two coauthors reported financial relationships with multiple pharmaceutical companies, including Merck, which partially funded the study. Numares Health, the U.K. Medical Research Council, and the Multiple Sclerosis Society also provided funding support.
SOURCE: Probert F et al. ECTRIMS 2019, Abstract P586.
STOCKHOLM –
Further, “combined omics improves diagnostic accuracy” over oligoclonal band (OCB) status alone in differentiating patients with multiple sclerosis (MS) from a group of normal control patients, said Fay Probert, PhD, speaking at a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Not everyone with clinically isolated syndrome (CIS) converts to clinically definite MS, and there is large variability in the time to progression, explained Dr. Probert, a postdoctoral fellow in the department of pharmacology at Oxford (England) University, and colleagues. Though the revised McDonald criteria now allow earlier diagnosis of MS, individuals who will be early converters cannot be identified by these criteria, they noted, citing earlier work showing that just over half (52%) of CIS patients who are OCB positive will have clinically definite MS at the 3-year mark.
To see whether combining analysis of multiple proteins and metabolites improved diagnostic accuracy, Dr. Probert and colleagues examined cerebrospinal fluid (CSF) samples from 41 patients with clinically definite MS, 71 patients with CIS, and 64 control participants without MS. In their analysis, the investigators used nuclear MR metabolomics and a commercially available proteomics assay that identifies and quantifies more than 5,000 proteins.
The multivariate analysis strategy achieved 10-fold external cross-validation of the samples, repeating training and testing of the analysis model while shuffling data. This, explained Dr. Probert and colleagues, “ensures that any discrimination observed cannot have occurred by chance.” Further analysis “identifies the optimal combination of proteomics and metabolomics features which results in the highest diagnostic accuracy.”
Both the nuclear MR metabolomics and the proteomic analyses were able to discriminate between those with clinically definite MS and the control participants, with accuracy of 71% and 75%, respectively.
The levels of seven metabolites present in CSF were predictive of clinically definite MS, compared with non-MS status, independent of OCB status. In fact, noted Dr. Probert and colleagues, “the CSF myoinositol concentration alone diagnosed [clinically definite] MS in this cohort with a specificity of 74% but did not outperform OCB status overall.”
Using the combined omics approach, though, “significantly improved the discrimination” between the non-MS control CSF samples and those of patients with clinically definite MS, wrote Dr. Probert and colleagues. Using a combination of up to five CSF proteins and metabolites yielded accuracy of 85 plus or minus 2%, sensitivity of 85 plus or minus 3%, and specificity of 85 plus or minus 3%. For comparison, using just OCB status provides accuracy of 74%, sensitivity of 88% and specificity of 63%.
Then, Dr. Probert and colleagues turned to the CSF samples from patients with CIS to look for predictors of “fast” (4 years or less) or “slow” (greater than 4 years) conversion to clinically definite MS. “While important for diagnosis, OCB status was not predictive of early conversion,” the investigators noted. However, baseline CSF proteomics analysis alone did differentiate the fast from the slow converters among the CIS subgroup, with an accuracy of 77%.
For patients with CIS who were OCB positive, their baseline metabolite and proteomic profiles were “indistinguishable” from those with clinically definite MS, wrote Dr. Probert and colleagues. The omics analysis was also able to distinguish between OCB-positive CIS patients and the non-MS control patients.
“These results indicate that combined metabolomics and proteomics analysis could not only be used as an adjunct in diagnosis of [clinically definite] MS but could be used as a prognostic test to identify CIS patients at high risk of a second clinical attack within 4 years of onset,” wrote Dr. Probert and coauthors. They noted that the method reported in the poster is the first to offer this prognostic accuracy, but that more work is needed before routine clinical use.
Dr. Probert reported that she had no financial conflicts of interest. One coauthor reported being a consultant to Novartis. Two coauthors reported financial relationships with multiple pharmaceutical companies, including Merck, which partially funded the study. Numares Health, the U.K. Medical Research Council, and the Multiple Sclerosis Society also provided funding support.
SOURCE: Probert F et al. ECTRIMS 2019, Abstract P586.
STOCKHOLM –
Further, “combined omics improves diagnostic accuracy” over oligoclonal band (OCB) status alone in differentiating patients with multiple sclerosis (MS) from a group of normal control patients, said Fay Probert, PhD, speaking at a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Not everyone with clinically isolated syndrome (CIS) converts to clinically definite MS, and there is large variability in the time to progression, explained Dr. Probert, a postdoctoral fellow in the department of pharmacology at Oxford (England) University, and colleagues. Though the revised McDonald criteria now allow earlier diagnosis of MS, individuals who will be early converters cannot be identified by these criteria, they noted, citing earlier work showing that just over half (52%) of CIS patients who are OCB positive will have clinically definite MS at the 3-year mark.
To see whether combining analysis of multiple proteins and metabolites improved diagnostic accuracy, Dr. Probert and colleagues examined cerebrospinal fluid (CSF) samples from 41 patients with clinically definite MS, 71 patients with CIS, and 64 control participants without MS. In their analysis, the investigators used nuclear MR metabolomics and a commercially available proteomics assay that identifies and quantifies more than 5,000 proteins.
The multivariate analysis strategy achieved 10-fold external cross-validation of the samples, repeating training and testing of the analysis model while shuffling data. This, explained Dr. Probert and colleagues, “ensures that any discrimination observed cannot have occurred by chance.” Further analysis “identifies the optimal combination of proteomics and metabolomics features which results in the highest diagnostic accuracy.”
Both the nuclear MR metabolomics and the proteomic analyses were able to discriminate between those with clinically definite MS and the control participants, with accuracy of 71% and 75%, respectively.
The levels of seven metabolites present in CSF were predictive of clinically definite MS, compared with non-MS status, independent of OCB status. In fact, noted Dr. Probert and colleagues, “the CSF myoinositol concentration alone diagnosed [clinically definite] MS in this cohort with a specificity of 74% but did not outperform OCB status overall.”
Using the combined omics approach, though, “significantly improved the discrimination” between the non-MS control CSF samples and those of patients with clinically definite MS, wrote Dr. Probert and colleagues. Using a combination of up to five CSF proteins and metabolites yielded accuracy of 85 plus or minus 2%, sensitivity of 85 plus or minus 3%, and specificity of 85 plus or minus 3%. For comparison, using just OCB status provides accuracy of 74%, sensitivity of 88% and specificity of 63%.
Then, Dr. Probert and colleagues turned to the CSF samples from patients with CIS to look for predictors of “fast” (4 years or less) or “slow” (greater than 4 years) conversion to clinically definite MS. “While important for diagnosis, OCB status was not predictive of early conversion,” the investigators noted. However, baseline CSF proteomics analysis alone did differentiate the fast from the slow converters among the CIS subgroup, with an accuracy of 77%.
For patients with CIS who were OCB positive, their baseline metabolite and proteomic profiles were “indistinguishable” from those with clinically definite MS, wrote Dr. Probert and colleagues. The omics analysis was also able to distinguish between OCB-positive CIS patients and the non-MS control patients.
“These results indicate that combined metabolomics and proteomics analysis could not only be used as an adjunct in diagnosis of [clinically definite] MS but could be used as a prognostic test to identify CIS patients at high risk of a second clinical attack within 4 years of onset,” wrote Dr. Probert and coauthors. They noted that the method reported in the poster is the first to offer this prognostic accuracy, but that more work is needed before routine clinical use.
Dr. Probert reported that she had no financial conflicts of interest. One coauthor reported being a consultant to Novartis. Two coauthors reported financial relationships with multiple pharmaceutical companies, including Merck, which partially funded the study. Numares Health, the U.K. Medical Research Council, and the Multiple Sclerosis Society also provided funding support.
SOURCE: Probert F et al. ECTRIMS 2019, Abstract P586.
REPORTING FROM ECTRIMS 2019
Investigators use ARMSS score to predict future MS-related disability
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The resulting measurement is stable, not highly sensitive to age, and appropriate for research applications. “It could give a clinician an earlier indication of the potential disease course of a patient,” said Ryan Ramanujam, PhD, assistant professor of translational neuroepidemiology at Karolinska Institutet in Stockholm.
Researchers who study MS use various scores to measure disease severity, including the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). These scores cannot predict a patient’s future status, however, and they do not remain stable throughout the course of a patient’s disease. Fitting a linear model over a series of scores over time can provide a misleading impression of a patient’s disease progression. “What we need is a metric to give a holistic overview of disease course, regardless of when it’s measured in a patient’s disease progression,” said Dr. Ramanujam. Such a measurement could aid the search for genes that affect MS severity, he added.
Examining disability by patient age
Dr. Ramanujam and colleagues constructed their measure using the ARMSS score, which ranks EDSS score by age instead of by disease duration. The ARMSS score ranges from 0 to 10, and the median value is 5 for all patients at a given age. Investigators can calculate the score using a previously published global matrix of values for ARMSS and MSSS available in the R package ms.sev.
The investigators found that the ARMSS score is slightly superior to the MSSS in detecting small increases in EDSS. One benefit of the ARMSS score, compared with the MSSS, is that it allows investigators to study patients for whom time of disease onset is unknown. The ARMSS score also removes potential systematic bias that might result from a neurologist’s retrospective assignment of date of disease onset, said Dr. Ramanujam.
He and his colleagues used ARMSS to compare patients’ disease course with what is expected for that patient (i.e., an ARMSS that remains stable at 5). They extracted data for 15,831 patients participating in the Swedish MS registry, including age and EDSS score at each neurological visit. Eligible patients had serial EDSS scores for 10 years. Dr. Ramanujam and colleagues included 4,514 patients in their analysis.
Measures at 2 years correlated with those at 10 years
The researchers created what they called the ARMSS integral by calculating the ARMSS score’s change from 5 at each examination (e.g., −0.5 or 1). “The ARMSS integral can be thought of as the cumulative disability that a patient accrues over his or her disease course, relative to the average patient, who had the disease for the same ages,” said Dr. Ramanujam. At 2 years of follow-up and at 10 years of follow-up, the distribution of ARMSS integrals for the study population followed a normal pattern.
Next, the investigators sought to compare patients by standardizing their follow-up time. To do this, they calculated what they called the ARMSS-rate by dividing each patient’s ARMSS integral by the number of years of follow-up. The ARMSS-rate offers a “snapshot of disease severity and progression,” said Dr. Ramanujam. When the researchers compared ARMSS-rates at 2 years and 10 years for each patient, they found that the measure was “extremely stable over time and strongly correlated with future disability.” The correlation improved slightly when the researchers compared ARMSS-rates at 4 years and 10 years.
The investigators then categorized patients based on their ARMSS-rate at 2 years (e.g., 0 to 1, 1 to 2, 2 to 3). When they compared the values in these categories with the median ARMSS-rates for the same individuals over the subsequent 8 years, they found strong group-level correlations.
To analyze correlations on an individual level, Dr. Ramanujam and colleagues examined the ability of different metrics at the time closest to 2 years of follow-up to predict those measured at 10 years. They assigned the value 1 to the most severe quartile of outcomes and the value 0 to all other quartiles. For predictors and outcomes, the investigators examined ARMSS-rate and the integral of progression index, which they calculated using the integral of EDSS. They also included EDSS at 10 years as an outcome for progression index.
For predicting the subsequent 8 years of ARMSS-rates, ARMSS-rate at 2 years had an area under the curve (AUC) of 0.921. When the investigators performed the same analysis using a cohort of patients with MS from British Columbia, Canada, they obtained an AUC of 0.887. Progression index at 2 years had an AUC of 0.61 for predicting the most severe quartile of the next 8 years. Compared with this result, ARMSS integral up to 2 years was slightly better at predicting EDSS at 10 years, said Dr. Ramanujam. The progression index poorly predicted the most severe quartile of EDSS at 10 years.
The main limitation of the ARMSS integral and ARMSS-rate is that they are based on EDSS, he added. The EDSS gives great weight to mobility and largely does not measure cognitive disability. “Future metrics could therefore include additional data such as MRI, Symbol Digit Modalities Test, or neurofilament light levels,” said Dr. Ramanujam. “Also, self-assessment could be one area to improve in the future.”
Dr. Ramanujam had no conflicts of interest to disclose. He receives funding from the MultipleMS Project, which is part of the EU Horizon 2020 Framework.
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The resulting measurement is stable, not highly sensitive to age, and appropriate for research applications. “It could give a clinician an earlier indication of the potential disease course of a patient,” said Ryan Ramanujam, PhD, assistant professor of translational neuroepidemiology at Karolinska Institutet in Stockholm.
Researchers who study MS use various scores to measure disease severity, including the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). These scores cannot predict a patient’s future status, however, and they do not remain stable throughout the course of a patient’s disease. Fitting a linear model over a series of scores over time can provide a misleading impression of a patient’s disease progression. “What we need is a metric to give a holistic overview of disease course, regardless of when it’s measured in a patient’s disease progression,” said Dr. Ramanujam. Such a measurement could aid the search for genes that affect MS severity, he added.
Examining disability by patient age
Dr. Ramanujam and colleagues constructed their measure using the ARMSS score, which ranks EDSS score by age instead of by disease duration. The ARMSS score ranges from 0 to 10, and the median value is 5 for all patients at a given age. Investigators can calculate the score using a previously published global matrix of values for ARMSS and MSSS available in the R package ms.sev.
The investigators found that the ARMSS score is slightly superior to the MSSS in detecting small increases in EDSS. One benefit of the ARMSS score, compared with the MSSS, is that it allows investigators to study patients for whom time of disease onset is unknown. The ARMSS score also removes potential systematic bias that might result from a neurologist’s retrospective assignment of date of disease onset, said Dr. Ramanujam.
He and his colleagues used ARMSS to compare patients’ disease course with what is expected for that patient (i.e., an ARMSS that remains stable at 5). They extracted data for 15,831 patients participating in the Swedish MS registry, including age and EDSS score at each neurological visit. Eligible patients had serial EDSS scores for 10 years. Dr. Ramanujam and colleagues included 4,514 patients in their analysis.
Measures at 2 years correlated with those at 10 years
The researchers created what they called the ARMSS integral by calculating the ARMSS score’s change from 5 at each examination (e.g., −0.5 or 1). “The ARMSS integral can be thought of as the cumulative disability that a patient accrues over his or her disease course, relative to the average patient, who had the disease for the same ages,” said Dr. Ramanujam. At 2 years of follow-up and at 10 years of follow-up, the distribution of ARMSS integrals for the study population followed a normal pattern.
Next, the investigators sought to compare patients by standardizing their follow-up time. To do this, they calculated what they called the ARMSS-rate by dividing each patient’s ARMSS integral by the number of years of follow-up. The ARMSS-rate offers a “snapshot of disease severity and progression,” said Dr. Ramanujam. When the researchers compared ARMSS-rates at 2 years and 10 years for each patient, they found that the measure was “extremely stable over time and strongly correlated with future disability.” The correlation improved slightly when the researchers compared ARMSS-rates at 4 years and 10 years.
The investigators then categorized patients based on their ARMSS-rate at 2 years (e.g., 0 to 1, 1 to 2, 2 to 3). When they compared the values in these categories with the median ARMSS-rates for the same individuals over the subsequent 8 years, they found strong group-level correlations.
To analyze correlations on an individual level, Dr. Ramanujam and colleagues examined the ability of different metrics at the time closest to 2 years of follow-up to predict those measured at 10 years. They assigned the value 1 to the most severe quartile of outcomes and the value 0 to all other quartiles. For predictors and outcomes, the investigators examined ARMSS-rate and the integral of progression index, which they calculated using the integral of EDSS. They also included EDSS at 10 years as an outcome for progression index.
For predicting the subsequent 8 years of ARMSS-rates, ARMSS-rate at 2 years had an area under the curve (AUC) of 0.921. When the investigators performed the same analysis using a cohort of patients with MS from British Columbia, Canada, they obtained an AUC of 0.887. Progression index at 2 years had an AUC of 0.61 for predicting the most severe quartile of the next 8 years. Compared with this result, ARMSS integral up to 2 years was slightly better at predicting EDSS at 10 years, said Dr. Ramanujam. The progression index poorly predicted the most severe quartile of EDSS at 10 years.
The main limitation of the ARMSS integral and ARMSS-rate is that they are based on EDSS, he added. The EDSS gives great weight to mobility and largely does not measure cognitive disability. “Future metrics could therefore include additional data such as MRI, Symbol Digit Modalities Test, or neurofilament light levels,” said Dr. Ramanujam. “Also, self-assessment could be one area to improve in the future.”
Dr. Ramanujam had no conflicts of interest to disclose. He receives funding from the MultipleMS Project, which is part of the EU Horizon 2020 Framework.
STOCKHOLM – , according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The resulting measurement is stable, not highly sensitive to age, and appropriate for research applications. “It could give a clinician an earlier indication of the potential disease course of a patient,” said Ryan Ramanujam, PhD, assistant professor of translational neuroepidemiology at Karolinska Institutet in Stockholm.
Researchers who study MS use various scores to measure disease severity, including the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). These scores cannot predict a patient’s future status, however, and they do not remain stable throughout the course of a patient’s disease. Fitting a linear model over a series of scores over time can provide a misleading impression of a patient’s disease progression. “What we need is a metric to give a holistic overview of disease course, regardless of when it’s measured in a patient’s disease progression,” said Dr. Ramanujam. Such a measurement could aid the search for genes that affect MS severity, he added.
Examining disability by patient age
Dr. Ramanujam and colleagues constructed their measure using the ARMSS score, which ranks EDSS score by age instead of by disease duration. The ARMSS score ranges from 0 to 10, and the median value is 5 for all patients at a given age. Investigators can calculate the score using a previously published global matrix of values for ARMSS and MSSS available in the R package ms.sev.
The investigators found that the ARMSS score is slightly superior to the MSSS in detecting small increases in EDSS. One benefit of the ARMSS score, compared with the MSSS, is that it allows investigators to study patients for whom time of disease onset is unknown. The ARMSS score also removes potential systematic bias that might result from a neurologist’s retrospective assignment of date of disease onset, said Dr. Ramanujam.
He and his colleagues used ARMSS to compare patients’ disease course with what is expected for that patient (i.e., an ARMSS that remains stable at 5). They extracted data for 15,831 patients participating in the Swedish MS registry, including age and EDSS score at each neurological visit. Eligible patients had serial EDSS scores for 10 years. Dr. Ramanujam and colleagues included 4,514 patients in their analysis.
Measures at 2 years correlated with those at 10 years
The researchers created what they called the ARMSS integral by calculating the ARMSS score’s change from 5 at each examination (e.g., −0.5 or 1). “The ARMSS integral can be thought of as the cumulative disability that a patient accrues over his or her disease course, relative to the average patient, who had the disease for the same ages,” said Dr. Ramanujam. At 2 years of follow-up and at 10 years of follow-up, the distribution of ARMSS integrals for the study population followed a normal pattern.
Next, the investigators sought to compare patients by standardizing their follow-up time. To do this, they calculated what they called the ARMSS-rate by dividing each patient’s ARMSS integral by the number of years of follow-up. The ARMSS-rate offers a “snapshot of disease severity and progression,” said Dr. Ramanujam. When the researchers compared ARMSS-rates at 2 years and 10 years for each patient, they found that the measure was “extremely stable over time and strongly correlated with future disability.” The correlation improved slightly when the researchers compared ARMSS-rates at 4 years and 10 years.
The investigators then categorized patients based on their ARMSS-rate at 2 years (e.g., 0 to 1, 1 to 2, 2 to 3). When they compared the values in these categories with the median ARMSS-rates for the same individuals over the subsequent 8 years, they found strong group-level correlations.
To analyze correlations on an individual level, Dr. Ramanujam and colleagues examined the ability of different metrics at the time closest to 2 years of follow-up to predict those measured at 10 years. They assigned the value 1 to the most severe quartile of outcomes and the value 0 to all other quartiles. For predictors and outcomes, the investigators examined ARMSS-rate and the integral of progression index, which they calculated using the integral of EDSS. They also included EDSS at 10 years as an outcome for progression index.
For predicting the subsequent 8 years of ARMSS-rates, ARMSS-rate at 2 years had an area under the curve (AUC) of 0.921. When the investigators performed the same analysis using a cohort of patients with MS from British Columbia, Canada, they obtained an AUC of 0.887. Progression index at 2 years had an AUC of 0.61 for predicting the most severe quartile of the next 8 years. Compared with this result, ARMSS integral up to 2 years was slightly better at predicting EDSS at 10 years, said Dr. Ramanujam. The progression index poorly predicted the most severe quartile of EDSS at 10 years.
The main limitation of the ARMSS integral and ARMSS-rate is that they are based on EDSS, he added. The EDSS gives great weight to mobility and largely does not measure cognitive disability. “Future metrics could therefore include additional data such as MRI, Symbol Digit Modalities Test, or neurofilament light levels,” said Dr. Ramanujam. “Also, self-assessment could be one area to improve in the future.”
Dr. Ramanujam had no conflicts of interest to disclose. He receives funding from the MultipleMS Project, which is part of the EU Horizon 2020 Framework.
REPORTING FROM ECTRIMS 2019
Intensive cognitive training may be needed for memory gains in MS
STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.
in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.
To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.
Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.
After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.
To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.
Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.
Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.
Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.
“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.
Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.
Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.
STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.
in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.
To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.
Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.
After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.
To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.
Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.
Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.
Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.
“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.
Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.
Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.
STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.
in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.
To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.
Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.
After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.
To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.
Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.
Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.
Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.
“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.
Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.
Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.
REPORTING FROM ECTRIMS 2019
Baseline neurofilament light levels track with brain volume loss in MS
STOCKHOLM – according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).
Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.
Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.
Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.
NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.
To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.
Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.
Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.
Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).
Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.
Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.
“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.
Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.
STOCKHOLM – according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).
Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.
Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.
Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.
NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.
To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.
Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.
Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.
Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).
Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.
Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.
“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.
Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.
STOCKHOLM – according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).
Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.
Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.
Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.
NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.
To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.
Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.
Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.
Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).
Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.
Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.
“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.
Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.
REPORTING FROM ECTRIMS 2019
Tocilizumab beat azathioprine for NMOSD
STOCKHOLM – according to data reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorders (TANGO) trial, explained senior investigator Fu-Dong Shi, MD, PhD, tracked the time to first NMOSD relapse for patients randomized either to tocilizumab or azathioprine. After 60 weeks of participation in the head-to-head trial, 86% of patients receiving tocilizumab remained relapse-free, compared with 56.9% of those on azathioprine. By 90 weeks of therapy, the relapse-free rate held at 86% for those receiving tocilizumab, compared with 48.1% for those on azathioprine, for a 76.4% relative reduction in risk of relapse.
Patients with concomitant autoimmune disease saw particular benefit from tocilizumab compared with azathioprine. On tocilizumab, 78.8% of those with concomitant autoimmune disease remained relapse-free at 90 weeks, a rate that did not differ significantly from that seen in those without other autoimmune disease. However, 22.3% of those with concomitant autoimmune disease who received azathioprine remained relapse-free at 90 weeks, compared with 63.5% of those without autoimmune disease.
Dr. Shi, of the Tianjin (China) Medical University General Hospital, explained that there was limited evidence for the advantage of newer disease-modifying therapies (DMTs) over such older medications as azathioprine to treat NMOSD. Therefore, he said, he and other investigators in the Chinese Medical Network for Neuroinflammation (CMNN), including first author Chao Zhang, MD, initiated a randomized, multicenter, open-label trial that compared tocilizumab to azathioprine for highly relapsing NMOSD.
A total of 118 patients were enrolled. To participate, patients had to meet the 2015 international consensus criteria for NMOSD, and have had at least two relapses in the past year or three relapses within the preceding 2 years.
After a washout period, participants were randomized 1:1 to receive daily oral azathioprine dosed at 2-3 mg/kg or intravenous tocilizumab dosed at 8 mg/kg every 4 weeks. Participants continued on the assigned regimen for at least 60 weeks.
Secondary endpoints included 12-week confirmed disability progression. Here, 35.8% of those on azathioprine saw disability progression, compared with 9.9% on tocilizumab, for a 72.5% relative risk reduction. Serum aquaporin 4-IgG titers fell further for those taking tocilizumab.
In terms of safety, 83% of those on azathioprine and 61% of those receiving tocilizumab had a treatment-related adverse event, as determined by investigator assessment. About half of patients in each group experienced moderate adverse events, and about 90% had mild adverse events in each group. However, there were twice as many severe adverse events among those taking azathioprine. There was one NMOSD-related death in each group.
Subgroup analyses looked at baseline disability scores, number of previous relapses, disease duration, and age at randomization. None of these variables made a difference in the statistically better performance of tocilizumab compared with azathioprine, with hazard ratios ranging from 0.076 to 0.343 in favor of tocilizumab for all subgroups.
Patients were almost all female (92% overall) and about 47 years old at baseline, with a 6-year history of NMOSD.
Overall, 83% of the cohort had experienced optic neuritis over the preceding 2 years, and 94% had experienced acute myelitis. Other manifestations of NMOSD, such as acute brainstem syndrome and symptomatic cerebral syndrome, were much less frequent, occurring in 4%-30% of patients.
Most patients (71%) had been on oral corticosteroids before the washout period, and 34% had been taking mycophenolate mofetil. Azathioprine was taken by 44% of patients at baseline.
Additional data captured during the TANGO trial are being analyzed and will be reported at a later date, said Dr. Shi. These include optical coherence tomography and visual evoked potentials; magnetic resonance imaging of the brain, spinal cord, and optic nerve; and tracking serum B-cell subpopulations. He added that the investigators are continuing long-term, real-world follow-up of the TANGO patient cohort.
Dr. Shi acknowledged that TANGO was limited by the lack of an independent data monitoring committee and the open-label nature of the study.
The study was funded by Tianjin Medical University; Capital Medical University, Beijing; and the National Science Foundation of China. Dr. Shi and coauthors reported no conflicts of interest.
SOURCE: Zhang C et al. ECTRIMS 2019, Abstract 140.
STOCKHOLM – according to data reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorders (TANGO) trial, explained senior investigator Fu-Dong Shi, MD, PhD, tracked the time to first NMOSD relapse for patients randomized either to tocilizumab or azathioprine. After 60 weeks of participation in the head-to-head trial, 86% of patients receiving tocilizumab remained relapse-free, compared with 56.9% of those on azathioprine. By 90 weeks of therapy, the relapse-free rate held at 86% for those receiving tocilizumab, compared with 48.1% for those on azathioprine, for a 76.4% relative reduction in risk of relapse.
Patients with concomitant autoimmune disease saw particular benefit from tocilizumab compared with azathioprine. On tocilizumab, 78.8% of those with concomitant autoimmune disease remained relapse-free at 90 weeks, a rate that did not differ significantly from that seen in those without other autoimmune disease. However, 22.3% of those with concomitant autoimmune disease who received azathioprine remained relapse-free at 90 weeks, compared with 63.5% of those without autoimmune disease.
Dr. Shi, of the Tianjin (China) Medical University General Hospital, explained that there was limited evidence for the advantage of newer disease-modifying therapies (DMTs) over such older medications as azathioprine to treat NMOSD. Therefore, he said, he and other investigators in the Chinese Medical Network for Neuroinflammation (CMNN), including first author Chao Zhang, MD, initiated a randomized, multicenter, open-label trial that compared tocilizumab to azathioprine for highly relapsing NMOSD.
A total of 118 patients were enrolled. To participate, patients had to meet the 2015 international consensus criteria for NMOSD, and have had at least two relapses in the past year or three relapses within the preceding 2 years.
After a washout period, participants were randomized 1:1 to receive daily oral azathioprine dosed at 2-3 mg/kg or intravenous tocilizumab dosed at 8 mg/kg every 4 weeks. Participants continued on the assigned regimen for at least 60 weeks.
Secondary endpoints included 12-week confirmed disability progression. Here, 35.8% of those on azathioprine saw disability progression, compared with 9.9% on tocilizumab, for a 72.5% relative risk reduction. Serum aquaporin 4-IgG titers fell further for those taking tocilizumab.
In terms of safety, 83% of those on azathioprine and 61% of those receiving tocilizumab had a treatment-related adverse event, as determined by investigator assessment. About half of patients in each group experienced moderate adverse events, and about 90% had mild adverse events in each group. However, there were twice as many severe adverse events among those taking azathioprine. There was one NMOSD-related death in each group.
Subgroup analyses looked at baseline disability scores, number of previous relapses, disease duration, and age at randomization. None of these variables made a difference in the statistically better performance of tocilizumab compared with azathioprine, with hazard ratios ranging from 0.076 to 0.343 in favor of tocilizumab for all subgroups.
Patients were almost all female (92% overall) and about 47 years old at baseline, with a 6-year history of NMOSD.
Overall, 83% of the cohort had experienced optic neuritis over the preceding 2 years, and 94% had experienced acute myelitis. Other manifestations of NMOSD, such as acute brainstem syndrome and symptomatic cerebral syndrome, were much less frequent, occurring in 4%-30% of patients.
Most patients (71%) had been on oral corticosteroids before the washout period, and 34% had been taking mycophenolate mofetil. Azathioprine was taken by 44% of patients at baseline.
Additional data captured during the TANGO trial are being analyzed and will be reported at a later date, said Dr. Shi. These include optical coherence tomography and visual evoked potentials; magnetic resonance imaging of the brain, spinal cord, and optic nerve; and tracking serum B-cell subpopulations. He added that the investigators are continuing long-term, real-world follow-up of the TANGO patient cohort.
Dr. Shi acknowledged that TANGO was limited by the lack of an independent data monitoring committee and the open-label nature of the study.
The study was funded by Tianjin Medical University; Capital Medical University, Beijing; and the National Science Foundation of China. Dr. Shi and coauthors reported no conflicts of interest.
SOURCE: Zhang C et al. ECTRIMS 2019, Abstract 140.
STOCKHOLM – according to data reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorders (TANGO) trial, explained senior investigator Fu-Dong Shi, MD, PhD, tracked the time to first NMOSD relapse for patients randomized either to tocilizumab or azathioprine. After 60 weeks of participation in the head-to-head trial, 86% of patients receiving tocilizumab remained relapse-free, compared with 56.9% of those on azathioprine. By 90 weeks of therapy, the relapse-free rate held at 86% for those receiving tocilizumab, compared with 48.1% for those on azathioprine, for a 76.4% relative reduction in risk of relapse.
Patients with concomitant autoimmune disease saw particular benefit from tocilizumab compared with azathioprine. On tocilizumab, 78.8% of those with concomitant autoimmune disease remained relapse-free at 90 weeks, a rate that did not differ significantly from that seen in those without other autoimmune disease. However, 22.3% of those with concomitant autoimmune disease who received azathioprine remained relapse-free at 90 weeks, compared with 63.5% of those without autoimmune disease.
Dr. Shi, of the Tianjin (China) Medical University General Hospital, explained that there was limited evidence for the advantage of newer disease-modifying therapies (DMTs) over such older medications as azathioprine to treat NMOSD. Therefore, he said, he and other investigators in the Chinese Medical Network for Neuroinflammation (CMNN), including first author Chao Zhang, MD, initiated a randomized, multicenter, open-label trial that compared tocilizumab to azathioprine for highly relapsing NMOSD.
A total of 118 patients were enrolled. To participate, patients had to meet the 2015 international consensus criteria for NMOSD, and have had at least two relapses in the past year or three relapses within the preceding 2 years.
After a washout period, participants were randomized 1:1 to receive daily oral azathioprine dosed at 2-3 mg/kg or intravenous tocilizumab dosed at 8 mg/kg every 4 weeks. Participants continued on the assigned regimen for at least 60 weeks.
Secondary endpoints included 12-week confirmed disability progression. Here, 35.8% of those on azathioprine saw disability progression, compared with 9.9% on tocilizumab, for a 72.5% relative risk reduction. Serum aquaporin 4-IgG titers fell further for those taking tocilizumab.
In terms of safety, 83% of those on azathioprine and 61% of those receiving tocilizumab had a treatment-related adverse event, as determined by investigator assessment. About half of patients in each group experienced moderate adverse events, and about 90% had mild adverse events in each group. However, there were twice as many severe adverse events among those taking azathioprine. There was one NMOSD-related death in each group.
Subgroup analyses looked at baseline disability scores, number of previous relapses, disease duration, and age at randomization. None of these variables made a difference in the statistically better performance of tocilizumab compared with azathioprine, with hazard ratios ranging from 0.076 to 0.343 in favor of tocilizumab for all subgroups.
Patients were almost all female (92% overall) and about 47 years old at baseline, with a 6-year history of NMOSD.
Overall, 83% of the cohort had experienced optic neuritis over the preceding 2 years, and 94% had experienced acute myelitis. Other manifestations of NMOSD, such as acute brainstem syndrome and symptomatic cerebral syndrome, were much less frequent, occurring in 4%-30% of patients.
Most patients (71%) had been on oral corticosteroids before the washout period, and 34% had been taking mycophenolate mofetil. Azathioprine was taken by 44% of patients at baseline.
Additional data captured during the TANGO trial are being analyzed and will be reported at a later date, said Dr. Shi. These include optical coherence tomography and visual evoked potentials; magnetic resonance imaging of the brain, spinal cord, and optic nerve; and tracking serum B-cell subpopulations. He added that the investigators are continuing long-term, real-world follow-up of the TANGO patient cohort.
Dr. Shi acknowledged that TANGO was limited by the lack of an independent data monitoring committee and the open-label nature of the study.
The study was funded by Tianjin Medical University; Capital Medical University, Beijing; and the National Science Foundation of China. Dr. Shi and coauthors reported no conflicts of interest.
SOURCE: Zhang C et al. ECTRIMS 2019, Abstract 140.
REPORTING FROM ECTRIMS 2019
Continuation of natalizumab treatment reduces risk of MS relapses during pregnancy
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Continuation of treatment is not associated with major fetal risks.
Pregnancy influences the choice of treatment for patients with MS. Not all therapies are compatible with pregnancy; the newer, more effective treatments in particular may pose risks in this regard. “There is a need to accumulate new data on how to manage our highly active patients with MS – in particular, patients who are treated with natalizumab,” said Doriana Landi, MD, PhD, a research fellow at the University of Rome Tor Vergata.
Data suggest that suspension of natalizumab before pregnancy is associated with significant disease worsening. In 2018, Portaccio et al. found that suspending natalizumab treatment before conception is associated with a higher risk of relapses during pregnancy (Neurology. 2018 Mar 6;90[10]:e832-9). Suspending natalizumab treatment at conception, however, reduced the risk of relapse by a factor of three. Other data have suggested that continuing natalizumab treatment until the 30th week of gestation could protect mothers and guarantee fetal safety.
Comparing two cohorts of women with MS
To investigate this question further, Dr. Landi and colleagues investigated a cohort of 29 women with MS who were receiving natalizumab and became pregnant. They compared this cohort’s outcomes with those of the cohort that Portaccio et al. had studied. The investigators categorized participants in both cohorts into three groups according to the time of their last infusion of natalizumab in relation to their last menstrual period. Group 0 had their last infusion before their last menstrual period, group 1 had their last infusion during the first trimester of pregnancy, and group 2 continued treatment after the first trimester. All women restarted natalizumab post partum and had at least 12 months of follow-up after delivery.
Dr. Landi and colleagues calculated the annualized relapse rate during pregnancy and during 12 months post partum for all groups. They also compared the outcomes of newborns between groups.
Prematurity may have influenced rate of hematologic complications
In all, the researchers analyzed 90 completed pregnancies in 86 women with MS. There were no significant demographic differences between groups. The overall population’s mean age was approximately 31 years, and its median Expanded Disability Status Scale (EDSS) score was about 2. The women gave birth to 94 newborns. Mean gestational age was 38.42 weeks, mean birth weight was 2,878.08 mg, and mean length was 48.23 cm.
Group 0 included 31 patients, group 1 included 30 patients, and group 2 included 28 patients. The median interval between the last dose of natalizumab and last menstrual period was 70 days for group 0, 21 days for group 1, and 197 days for group 2. Group 2 received a median of five natalizumab infusions during pregnancy, with a median interval of 80 days between the last prepartum dose and delivery. The median interval between last prepartum dose and the first postpartum dose was 411 days in group 0, 288 in group 1, and 103 in group 2.
Most pregnancies in group 2 were exposed to natalizumab for at least 28 weeks of gestation. Women in group 2 restarted natalizumab treatment significantly earlier, compared with women in the other groups.
Group 0 had a significantly increased ARR during and after pregnancy, compared with the other groups, and group 2 had the lowest ARR during pregnancy. The mean ARR during pregnancy was 1.06 in group 0, 0.49 in group 1, and 0.09 in group 2. The ARR decreased to 0 in pregnancies exposed to natalizumab for more than 90 days. The mean ARR post partum was 0.39 in group 0, 0.23 in group 1, and 0.10 in group 2. Women in group 0 and group 1 had a higher EDSS during pregnancy than before conception.
Newborns’ mean gestational age, birth weight, and length did not differ significantly between groups. Five newborns in group 2, three of whom were premature, had anemia. This outcome is consistent with previous findings, and prematurity may be a confounding factor, said Dr. Landi. The frequency of birth defects was higher in group 2 than in the other groups, but most of them occurred in one twin, said Dr. Landi. The investigators observed malformations in one group 0 newborn (minor), four group 1 newborns (five minor and one major), and four (two minor and four major) group 2 newborns.
In pregnancy during which natalizumab treatment is prolonged until the third trimester, treatment should be restarted after delivery within 2 weeks of the last infusion to avoid potential doubled rebound, said Dr. Landi. Future studies should examine whether extended dosing is as effective as regular dosing. A larger sample size is needed to estimate risks correctly for newborns in exposed pregnancies and counsel patients appropriately.
Dr. Landi reported receiving travel funding from Biogen, Merck Serono, Sanofi-Genzyme, and Teva; honoraria for speaking from Sanofi-Genzyme and Teva; and consultation fees from Merck Serono and Teva. She is an investigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche, and Teva.
SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Continuation of treatment is not associated with major fetal risks.
Pregnancy influences the choice of treatment for patients with MS. Not all therapies are compatible with pregnancy; the newer, more effective treatments in particular may pose risks in this regard. “There is a need to accumulate new data on how to manage our highly active patients with MS – in particular, patients who are treated with natalizumab,” said Doriana Landi, MD, PhD, a research fellow at the University of Rome Tor Vergata.
Data suggest that suspension of natalizumab before pregnancy is associated with significant disease worsening. In 2018, Portaccio et al. found that suspending natalizumab treatment before conception is associated with a higher risk of relapses during pregnancy (Neurology. 2018 Mar 6;90[10]:e832-9). Suspending natalizumab treatment at conception, however, reduced the risk of relapse by a factor of three. Other data have suggested that continuing natalizumab treatment until the 30th week of gestation could protect mothers and guarantee fetal safety.
Comparing two cohorts of women with MS
To investigate this question further, Dr. Landi and colleagues investigated a cohort of 29 women with MS who were receiving natalizumab and became pregnant. They compared this cohort’s outcomes with those of the cohort that Portaccio et al. had studied. The investigators categorized participants in both cohorts into three groups according to the time of their last infusion of natalizumab in relation to their last menstrual period. Group 0 had their last infusion before their last menstrual period, group 1 had their last infusion during the first trimester of pregnancy, and group 2 continued treatment after the first trimester. All women restarted natalizumab post partum and had at least 12 months of follow-up after delivery.
Dr. Landi and colleagues calculated the annualized relapse rate during pregnancy and during 12 months post partum for all groups. They also compared the outcomes of newborns between groups.
Prematurity may have influenced rate of hematologic complications
In all, the researchers analyzed 90 completed pregnancies in 86 women with MS. There were no significant demographic differences between groups. The overall population’s mean age was approximately 31 years, and its median Expanded Disability Status Scale (EDSS) score was about 2. The women gave birth to 94 newborns. Mean gestational age was 38.42 weeks, mean birth weight was 2,878.08 mg, and mean length was 48.23 cm.
Group 0 included 31 patients, group 1 included 30 patients, and group 2 included 28 patients. The median interval between the last dose of natalizumab and last menstrual period was 70 days for group 0, 21 days for group 1, and 197 days for group 2. Group 2 received a median of five natalizumab infusions during pregnancy, with a median interval of 80 days between the last prepartum dose and delivery. The median interval between last prepartum dose and the first postpartum dose was 411 days in group 0, 288 in group 1, and 103 in group 2.
Most pregnancies in group 2 were exposed to natalizumab for at least 28 weeks of gestation. Women in group 2 restarted natalizumab treatment significantly earlier, compared with women in the other groups.
Group 0 had a significantly increased ARR during and after pregnancy, compared with the other groups, and group 2 had the lowest ARR during pregnancy. The mean ARR during pregnancy was 1.06 in group 0, 0.49 in group 1, and 0.09 in group 2. The ARR decreased to 0 in pregnancies exposed to natalizumab for more than 90 days. The mean ARR post partum was 0.39 in group 0, 0.23 in group 1, and 0.10 in group 2. Women in group 0 and group 1 had a higher EDSS during pregnancy than before conception.
Newborns’ mean gestational age, birth weight, and length did not differ significantly between groups. Five newborns in group 2, three of whom were premature, had anemia. This outcome is consistent with previous findings, and prematurity may be a confounding factor, said Dr. Landi. The frequency of birth defects was higher in group 2 than in the other groups, but most of them occurred in one twin, said Dr. Landi. The investigators observed malformations in one group 0 newborn (minor), four group 1 newborns (five minor and one major), and four (two minor and four major) group 2 newborns.
In pregnancy during which natalizumab treatment is prolonged until the third trimester, treatment should be restarted after delivery within 2 weeks of the last infusion to avoid potential doubled rebound, said Dr. Landi. Future studies should examine whether extended dosing is as effective as regular dosing. A larger sample size is needed to estimate risks correctly for newborns in exposed pregnancies and counsel patients appropriately.
Dr. Landi reported receiving travel funding from Biogen, Merck Serono, Sanofi-Genzyme, and Teva; honoraria for speaking from Sanofi-Genzyme and Teva; and consultation fees from Merck Serono and Teva. She is an investigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche, and Teva.
SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Continuation of treatment is not associated with major fetal risks.
Pregnancy influences the choice of treatment for patients with MS. Not all therapies are compatible with pregnancy; the newer, more effective treatments in particular may pose risks in this regard. “There is a need to accumulate new data on how to manage our highly active patients with MS – in particular, patients who are treated with natalizumab,” said Doriana Landi, MD, PhD, a research fellow at the University of Rome Tor Vergata.
Data suggest that suspension of natalizumab before pregnancy is associated with significant disease worsening. In 2018, Portaccio et al. found that suspending natalizumab treatment before conception is associated with a higher risk of relapses during pregnancy (Neurology. 2018 Mar 6;90[10]:e832-9). Suspending natalizumab treatment at conception, however, reduced the risk of relapse by a factor of three. Other data have suggested that continuing natalizumab treatment until the 30th week of gestation could protect mothers and guarantee fetal safety.
Comparing two cohorts of women with MS
To investigate this question further, Dr. Landi and colleagues investigated a cohort of 29 women with MS who were receiving natalizumab and became pregnant. They compared this cohort’s outcomes with those of the cohort that Portaccio et al. had studied. The investigators categorized participants in both cohorts into three groups according to the time of their last infusion of natalizumab in relation to their last menstrual period. Group 0 had their last infusion before their last menstrual period, group 1 had their last infusion during the first trimester of pregnancy, and group 2 continued treatment after the first trimester. All women restarted natalizumab post partum and had at least 12 months of follow-up after delivery.
Dr. Landi and colleagues calculated the annualized relapse rate during pregnancy and during 12 months post partum for all groups. They also compared the outcomes of newborns between groups.
Prematurity may have influenced rate of hematologic complications
In all, the researchers analyzed 90 completed pregnancies in 86 women with MS. There were no significant demographic differences between groups. The overall population’s mean age was approximately 31 years, and its median Expanded Disability Status Scale (EDSS) score was about 2. The women gave birth to 94 newborns. Mean gestational age was 38.42 weeks, mean birth weight was 2,878.08 mg, and mean length was 48.23 cm.
Group 0 included 31 patients, group 1 included 30 patients, and group 2 included 28 patients. The median interval between the last dose of natalizumab and last menstrual period was 70 days for group 0, 21 days for group 1, and 197 days for group 2. Group 2 received a median of five natalizumab infusions during pregnancy, with a median interval of 80 days between the last prepartum dose and delivery. The median interval between last prepartum dose and the first postpartum dose was 411 days in group 0, 288 in group 1, and 103 in group 2.
Most pregnancies in group 2 were exposed to natalizumab for at least 28 weeks of gestation. Women in group 2 restarted natalizumab treatment significantly earlier, compared with women in the other groups.
Group 0 had a significantly increased ARR during and after pregnancy, compared with the other groups, and group 2 had the lowest ARR during pregnancy. The mean ARR during pregnancy was 1.06 in group 0, 0.49 in group 1, and 0.09 in group 2. The ARR decreased to 0 in pregnancies exposed to natalizumab for more than 90 days. The mean ARR post partum was 0.39 in group 0, 0.23 in group 1, and 0.10 in group 2. Women in group 0 and group 1 had a higher EDSS during pregnancy than before conception.
Newborns’ mean gestational age, birth weight, and length did not differ significantly between groups. Five newborns in group 2, three of whom were premature, had anemia. This outcome is consistent with previous findings, and prematurity may be a confounding factor, said Dr. Landi. The frequency of birth defects was higher in group 2 than in the other groups, but most of them occurred in one twin, said Dr. Landi. The investigators observed malformations in one group 0 newborn (minor), four group 1 newborns (five minor and one major), and four (two minor and four major) group 2 newborns.
In pregnancy during which natalizumab treatment is prolonged until the third trimester, treatment should be restarted after delivery within 2 weeks of the last infusion to avoid potential doubled rebound, said Dr. Landi. Future studies should examine whether extended dosing is as effective as regular dosing. A larger sample size is needed to estimate risks correctly for newborns in exposed pregnancies and counsel patients appropriately.
Dr. Landi reported receiving travel funding from Biogen, Merck Serono, Sanofi-Genzyme, and Teva; honoraria for speaking from Sanofi-Genzyme and Teva; and consultation fees from Merck Serono and Teva. She is an investigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche, and Teva.
SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.
REPORTING FROM ECTRIMS 2019
Even with no disease activity, recurrence risk near 50% when stopping DMTs for MS
STOCKHOLM – according to data presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Of 49 patients who had been on DMT for at least 5 years and had shown no evidence of disease activity (NEDA) during that time, 26 continued to have NEDA through at least 5 years of follow-up, explained Tobias Monschein, MD, of the department of neurology at the Medical University of Vienna.
The cohort of patients had all been taking either interferon beta or glatiramer acetate after a first clinical episode leading to an initial diagnosis of MS. Patients all met Barkhof criteria for MS diagnosis on MRI, and all but six patients had oligoclonal bands found on examination of cerebrospinal fluid.
All patients in the cohort thus met criteria for clinically isolated syndrome (CIS) and MS under the 2017 revisions to the McDonald diagnostic criteria. “To our knowledge, this is the first study determining the risk of disease recurrence in a homogenous cohort of patients with CIS,” reported Dr. Monschein and collaborators.
Before stopping DMT, patients had to show at least 5 years of NEDA status; at that point, patients were offered the opportunity to discontinue medication. The decision to stop or continue taking a DMT was left to individual patient choice, Dr. Monschein said in an interview.
The cohort of patients who decided to discontinue DMT was seen yearly; they received a clinical examination that included expanded disability status scale (EDSS) rating. Patients also received an annual MRI.
Age at DMT discontinuation was predictive of remaining disease free, found Dr. Monschein and collaborators. The 26 patients who continued disease free after DMT discontinuation were a mean 29.7 years old, while patients who had disease recurrence were a mean 22.7 years old.
Looking at age as a dichotomous variable, the investigators found that the 16 patients who were 40 years or older when they stopped DMT had an 18.8% risk of MS recurrence, while the 33 patients younger than 40 years at the time of ceasing DMT had a 60.6% risk of recurrence.
Age, in fact, was the only patient, disease, or therapy characteristic that Dr. Monschein and colleagues found predictive of relapse: “Gender, type of DMT, treatment duration, and CIS symptom did not differ significantly between groups,” they reported.
The data “should not encourage patients to generally stop DMTs after a long NEDA period,” they noted.
In the context of shared patient decision-making, though, the data can inform discussion with patients who wish to discontinue DMTS after long disease-free periods, Dr. Monschein said.
“Physicians should encourage younger people to stay on DMTS despite long lasting NEDA status while in patients [older than] 40 years stopping DMTs together with regular clinical and radiological monitoring could be a reasonable option,” he and his colleagues advised.
Dr. Monschein reported no outside sources of funding and no conflicts of interest.
SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.
STOCKHOLM – according to data presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Of 49 patients who had been on DMT for at least 5 years and had shown no evidence of disease activity (NEDA) during that time, 26 continued to have NEDA through at least 5 years of follow-up, explained Tobias Monschein, MD, of the department of neurology at the Medical University of Vienna.
The cohort of patients had all been taking either interferon beta or glatiramer acetate after a first clinical episode leading to an initial diagnosis of MS. Patients all met Barkhof criteria for MS diagnosis on MRI, and all but six patients had oligoclonal bands found on examination of cerebrospinal fluid.
All patients in the cohort thus met criteria for clinically isolated syndrome (CIS) and MS under the 2017 revisions to the McDonald diagnostic criteria. “To our knowledge, this is the first study determining the risk of disease recurrence in a homogenous cohort of patients with CIS,” reported Dr. Monschein and collaborators.
Before stopping DMT, patients had to show at least 5 years of NEDA status; at that point, patients were offered the opportunity to discontinue medication. The decision to stop or continue taking a DMT was left to individual patient choice, Dr. Monschein said in an interview.
The cohort of patients who decided to discontinue DMT was seen yearly; they received a clinical examination that included expanded disability status scale (EDSS) rating. Patients also received an annual MRI.
Age at DMT discontinuation was predictive of remaining disease free, found Dr. Monschein and collaborators. The 26 patients who continued disease free after DMT discontinuation were a mean 29.7 years old, while patients who had disease recurrence were a mean 22.7 years old.
Looking at age as a dichotomous variable, the investigators found that the 16 patients who were 40 years or older when they stopped DMT had an 18.8% risk of MS recurrence, while the 33 patients younger than 40 years at the time of ceasing DMT had a 60.6% risk of recurrence.
Age, in fact, was the only patient, disease, or therapy characteristic that Dr. Monschein and colleagues found predictive of relapse: “Gender, type of DMT, treatment duration, and CIS symptom did not differ significantly between groups,” they reported.
The data “should not encourage patients to generally stop DMTs after a long NEDA period,” they noted.
In the context of shared patient decision-making, though, the data can inform discussion with patients who wish to discontinue DMTS after long disease-free periods, Dr. Monschein said.
“Physicians should encourage younger people to stay on DMTS despite long lasting NEDA status while in patients [older than] 40 years stopping DMTs together with regular clinical and radiological monitoring could be a reasonable option,” he and his colleagues advised.
Dr. Monschein reported no outside sources of funding and no conflicts of interest.
SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.
STOCKHOLM – according to data presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Of 49 patients who had been on DMT for at least 5 years and had shown no evidence of disease activity (NEDA) during that time, 26 continued to have NEDA through at least 5 years of follow-up, explained Tobias Monschein, MD, of the department of neurology at the Medical University of Vienna.
The cohort of patients had all been taking either interferon beta or glatiramer acetate after a first clinical episode leading to an initial diagnosis of MS. Patients all met Barkhof criteria for MS diagnosis on MRI, and all but six patients had oligoclonal bands found on examination of cerebrospinal fluid.
All patients in the cohort thus met criteria for clinically isolated syndrome (CIS) and MS under the 2017 revisions to the McDonald diagnostic criteria. “To our knowledge, this is the first study determining the risk of disease recurrence in a homogenous cohort of patients with CIS,” reported Dr. Monschein and collaborators.
Before stopping DMT, patients had to show at least 5 years of NEDA status; at that point, patients were offered the opportunity to discontinue medication. The decision to stop or continue taking a DMT was left to individual patient choice, Dr. Monschein said in an interview.
The cohort of patients who decided to discontinue DMT was seen yearly; they received a clinical examination that included expanded disability status scale (EDSS) rating. Patients also received an annual MRI.
Age at DMT discontinuation was predictive of remaining disease free, found Dr. Monschein and collaborators. The 26 patients who continued disease free after DMT discontinuation were a mean 29.7 years old, while patients who had disease recurrence were a mean 22.7 years old.
Looking at age as a dichotomous variable, the investigators found that the 16 patients who were 40 years or older when they stopped DMT had an 18.8% risk of MS recurrence, while the 33 patients younger than 40 years at the time of ceasing DMT had a 60.6% risk of recurrence.
Age, in fact, was the only patient, disease, or therapy characteristic that Dr. Monschein and colleagues found predictive of relapse: “Gender, type of DMT, treatment duration, and CIS symptom did not differ significantly between groups,” they reported.
The data “should not encourage patients to generally stop DMTs after a long NEDA period,” they noted.
In the context of shared patient decision-making, though, the data can inform discussion with patients who wish to discontinue DMTS after long disease-free periods, Dr. Monschein said.
“Physicians should encourage younger people to stay on DMTS despite long lasting NEDA status while in patients [older than] 40 years stopping DMTs together with regular clinical and radiological monitoring could be a reasonable option,” he and his colleagues advised.
Dr. Monschein reported no outside sources of funding and no conflicts of interest.
SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.
REPORTING FROM ECTRIMS 2019