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Rituximab more effective than other MS treatments?
, according to new research.
The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
COMBAT-MS study
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab reduced relapses
The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
‘The uncertainty continues’
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.
Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
A version of this article first appeared on Medscape.com.
, according to new research.
The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
COMBAT-MS study
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab reduced relapses
The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
‘The uncertainty continues’
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.
Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
A version of this article first appeared on Medscape.com.
, according to new research.
The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
COMBAT-MS study
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab reduced relapses
The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
‘The uncertainty continues’
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.
Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
A version of this article first appeared on Medscape.com.
From ECTRIMS 2021
ECTRIMS/EAN statement on COVID-19 vaccination in patients with MS
(MS).
The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.
This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.
Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”
“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
Risk for COVID-19 among patients with MS
On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.
The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.
As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.
However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
COVID-19 vaccine safety
Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.
All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.
In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.
Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.
“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
Are there different recommendations for different MS therapies?
On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.
Patients taking natalizumab will also likely be protected with COVID vaccination.
It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.
In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
Low antibody level with fingolimod
The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.
Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.
Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
Anti-CD20 antibody drugs
Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.
A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
Booster doses/antibody tests
The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.
Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.
Vaccination strategy after COVID
People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.
Pregnancy/children
Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.
Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.
A version of this article first appeared on Medscape.com.
(MS).
The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.
This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.
Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”
“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
Risk for COVID-19 among patients with MS
On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.
The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.
As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.
However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
COVID-19 vaccine safety
Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.
All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.
In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.
Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.
“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
Are there different recommendations for different MS therapies?
On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.
Patients taking natalizumab will also likely be protected with COVID vaccination.
It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.
In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
Low antibody level with fingolimod
The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.
Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.
Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
Anti-CD20 antibody drugs
Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.
A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
Booster doses/antibody tests
The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.
Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.
Vaccination strategy after COVID
People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.
Pregnancy/children
Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.
Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.
A version of this article first appeared on Medscape.com.
(MS).
The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.
This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.
Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”
“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
Risk for COVID-19 among patients with MS
On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.
The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.
As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.
However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
COVID-19 vaccine safety
Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.
All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.
In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.
Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.
“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
Are there different recommendations for different MS therapies?
On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.
Patients taking natalizumab will also likely be protected with COVID vaccination.
It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.
In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
Low antibody level with fingolimod
The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.
Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.
Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
Anti-CD20 antibody drugs
Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.
A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
Booster doses/antibody tests
The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.
Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.
Vaccination strategy after COVID
People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.
Pregnancy/children
Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.
Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
The Barcelona baseline risk score may predict long-term MS course
The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.
The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.
“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.
She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
Proof of concept
The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.
The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.
The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”
Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
Predicting time to EDSS 3.0
The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.
In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).
At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).
At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).
Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.
Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.
The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.
The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.
“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.
She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
Proof of concept
The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.
The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.
The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”
Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
Predicting time to EDSS 3.0
The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.
In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).
At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).
At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).
Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.
Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.
The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.
The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.
“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.
She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
Proof of concept
The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.
The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.
The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”
Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
Predicting time to EDSS 3.0
The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.
In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).
At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).
At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).
Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.
Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.
FROM ECTRIMS 2021
Ublituximab improves functional MS score: New ULTIMATE analysis
New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).
The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).
Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.
Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.
Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.
“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.
Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.
He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).
These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.
Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.
“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”
Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”
The ULTIMATE trials were funded by TG Therapeutics.
A version of this article first appeared on Medscape.com.
New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).
The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).
Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.
Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.
Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.
“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.
Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.
He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).
These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.
Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.
“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”
Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”
The ULTIMATE trials were funded by TG Therapeutics.
A version of this article first appeared on Medscape.com.
New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).
The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).
Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.
Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.
Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.
“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.
Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.
He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).
These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.
Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.
“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”
Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”
The ULTIMATE trials were funded by TG Therapeutics.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
In MS, baseline cortical lesions predict cognitive decline
, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.
“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.
That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.
The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.
Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.
The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.
A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).
In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).
Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.
Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).
In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).
Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.
During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.
, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.
“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.
That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.
The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.
Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.
The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.
A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).
In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).
Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.
Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).
In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).
Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.
During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.
, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.
“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.
That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.
The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.
Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.
The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.
A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).
In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).
Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.
Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).
In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).
Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.
During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.
FROM ECTRIMS 2021
Cortical lesions predict risk for secondary progressive MS
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
Melatonin improves sleep in MS
according to a new pilot study.
The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.
“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.
Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”
Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.
Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.
The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.
Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*
During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).
Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.
The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.
*This article was updated on Oct. 15.
according to a new pilot study.
The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.
“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.
Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”
Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.
Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.
The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.
Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*
During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).
Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.
The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.
*This article was updated on Oct. 15.
according to a new pilot study.
The study included only 30 patients, but the findings suggest that melatonin could potentially help patients with MS who have sleep issues, according to Wan-Yu Hsu, PhD, who presented the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
There is no optimal management of sleep issues for these patients, and objective studies of sleep in patients with MS are scarce, said Dr. Hsu, who is an associate specialist in the department of neurology at the University of California, San Francisco. She worked with Riley Bove, MD, who is an associate professor of neurology at UCSF Weill Institute for Neurosciences.
“Melatonin use was associated with improvement in sleep quality and sleep disturbance in MS patients, although there was no significant change in other outcomes, like daytime sleepiness, mood, and walking ability” Dr. Hsu said in an interview.
Melatonin is inexpensive and readily available over the counter, but it’s too soon to begin recommending it to MS patients experiencing sleep problems, according to Dr. Hsu. “It’s a good start that we’re seeing some effects here with this relatively small group of people. Larger studies are needed to unravel the complex relationship between MS and sleep disturbances, as well as develop successful interventions. But for now, since melatonin is an over-the-counter, low-cost supplement, many patients are trying it already.”
Melatonin regulates the sleep-wake cycle, and previous research has shown a decrease in melatonin serum levels as a result of corticosteroid administration. Other work has suggested that the decline of melatonin secretion in MS may reflect progressive failure of the pineal gland in the pathogenesis of MS. “The cause of sleep problems can be lesions and neural damage to brain structures involved in sleep, or symptoms that indirectly disrupt sleep,” she said.
Indeed, sleep issues in MS are common and wide-ranging, according to Mark Gudesblatt, MD, who was asked to comment on the study. His group previously reported that 65% of people with MS who reported fatigue had undiagnosed obstructive sleep apnea. He also pointed out that disruption of the neural network also disrupts sleep. “That is not only sleep-disordered breathing, that’s sleep onset, REM latency, and sleep efficiency,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y.
Dr. Gudesblatt cautioned that melatonin, as a dietary supplement, is unregulated. The potency listed on the package may not be accurate and also may not be the correct dose for the patient. “It’s fraught with problems, but ultimately it’s relatively safe,” said Dr. Gudesblatt.
The study was a double-blind, placebo-controlled, crossover study. Participants had a Pittsburgh Sleep Quality Index (PSQI) score of 5 or more, or an Insomnia Severity Index (ISI) score higher than 14 at baseline. Other baseline assessments included patient-reported outcomes for sleep disturbances, sleep quality, daytime sleepiness, fatigue, walking ability, and mood. Half of the participants received melatonin for the first 2 weeks and then switched to placebo. The other half started with placebo and moved over to melatonin at the beginning of week 3.
Participants in the trial started out at 0.5 mg melatonin and were stepped up to 3.0 mg after 3 days if they didn't feel it was working, both when taking melatonin and when taking placebo. Of the 30 patients, 24 stepped up to 3.0 mg when they were receiving melatonin.*
During the second and fourth weeks, participants wore an actigraph watch to measure their physical and sleep activities, and then repeated the patient-reported outcome measures at the end of weeks 2 and 4. Melatonin improved average sleep time (6.96 vs. 6.67 hours; P = .03) as measured by the actigraph watch. Sleep efficiency was also nominally improved (84.7% vs. 83.2%), though the result was not statistically significant (P = .07). Other trends toward statistical significance included improvements in ISI (–3.5 vs. –2.4; P = .07), change in PSQI component 1 (–0.03 vs. 0.0; P = .07), and change in the NeuroQoL-Fatigue score (–4.7 vs. –2.4; P = .06).
Dr. Hsu hopes to conduct larger studies to examine how the disease-modifying therapies might affect the results of the study.
The study was funded by the National Multiple Sclerosis Society. Dr. Hsu and Dr. Gudesblatt have no relevant financial disclosures.
*This article was updated on Oct. 15.
FROM ECTRIMS 2021
COVID-19 vaccination in MS: Lower response on certain medications
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
The results also show a reduced response to COVID vaccination in some patients on fingolimod.
The data come from a new series of vaccinated patients with MS from Madrid, which was presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, Madrid, concluded that “currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors [such as fingolimod] need further study.”
“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T-cell response to vaccination in these patients, and we are looking at that now.”
Assessing postvaccination antibody response
For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 patients with MS and 200 healthy controls.
Of the patients with MS, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.
Adverse events were similar in the two groups, and no increase in relapse activity was seen in the patients with MS.
Mean antibody titers were slightly lower in the patients with MS versus the healthy controls. At 3 weeks, mean titers were 7,910 AU/mL in the patients with MS and 9,397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the patients with MS and 18,120 in the healthy controls.
Patients with MS treated with interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.
Patients with MS receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.
However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All six patients treated with rituximab had no antibody response to the COVID vaccination.
Dr. Oreja-Guevara suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded five patients on ocrelizumab with COVID-19, four of whom were hospitalized,” she noted.
“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the washout period, the more antibodies are seen,” she said.
She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.
The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.
Dr. Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly.”
Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.
Dr. Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, 4 failed to develop a humoral response, 7 had a low antibody response, and 5 had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.
Cellular response also impaired with fingolimod
These data are consistent with those from another cohort from Israel reported previously.
In that study, which was published earlier in 2021, a team led by Anat Achiron, MD, Sheba Medical Center, Tel Aviv, analyzed humoral immunity in 125 patients with MS 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.
Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination, compared with 100% in untreated patients and 100% in patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.
For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective postvaccination humoral response,” the authors said.
They noted that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (<1,000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count above 1,000 cells/mm3, no humoral response was detected.
At the ECTRIMS meeting, Dr. Achiron presented further results from this study on memory B-cell and T-cell responses to the COVID vaccine in these patients.
The results showed that COVID-specific B- and T-cell responses were only present in about half of healthy subjects, untreated patients with MS, and those treated with cladribine.
While the B-cell response was almost completely impaired in the ocrelizumab-treated patients, the T-cell response was present to the same extent as in the control group. But fingolimod patients showed no B- or T-cell responses.
Dr. Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.
But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.
“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”
Dr. Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B-cell and T-cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B-cell response is “not 100%,” she added.
“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
MS plus depression can increase risk of death, vascular disease
, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.
The study was published in Neurology.
To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.
People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.
As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
Does treating depression decrease the likelihood of vascular disease?
“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?
“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?
“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
Evaluating the biological interaction between MS and depression
Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.
“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.
“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.
Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.
In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”
Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.
, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.
The study was published in Neurology.
To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.
People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.
As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
Does treating depression decrease the likelihood of vascular disease?
“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?
“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?
“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
Evaluating the biological interaction between MS and depression
Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.
“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.
“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.
Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.
In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”
Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.
, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.
The study was published in Neurology.
To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.
People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.
As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
Does treating depression decrease the likelihood of vascular disease?
“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?
“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?
“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
Evaluating the biological interaction between MS and depression
Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.
“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.
“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.
Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.
In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”
Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.
FROM NEUROLOGY
MRI is a poor disability predictor in secondary progressive MS
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Multiple Sclerosis Journal