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MS-related disability may be decreasing
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
STOCKHOLM – , according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”
At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.
The relative prevalence of mild disability has increased
About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”
The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.
The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.
Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.
Trend toward milder disability
The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.
In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.
International data show similar trends
Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.
More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.
In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.
In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.
Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.
The role of DMTs
The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.
Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.
Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.
Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.
Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.
SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.
EXPERT ANALYSIS FROM ECTRIMS 2019
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
Cannabis-using MS patients improve cognition with 28 days of abstinence
STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.
But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.
It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment.
The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.
All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.
By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.
The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).
She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.
SOURCE: Meza C. ECTRIMS 2019, Abstract P542.
STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.
But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.
It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment.
The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.
All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.
By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.
The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).
She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.
SOURCE: Meza C. ECTRIMS 2019, Abstract P542.
STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.
But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.
It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment.
The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.
All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.
By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.
The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).
She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.
SOURCE: Meza C. ECTRIMS 2019, Abstract P542.
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