ICYMI Multiple Sclerosis

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

WEST PALM BEACH, FLA. – Women with multiple sclerosis (MS) undergoing assisted reproductive technologies (ART) have an increased relapse risk if they are not treated with disease-modifying therapy (DMT), new research suggests. In a cohort study of women undergoing ART, those who did not receive DMTs had a significantly higher relapse risk than their peers who were treated with the drugs.

In addition, the likelihood of achieving pregnancy through ART while having MS appeared favorable, researchers noted.

“In this modern case series and the largest cohort to date, we identified a lower risk of relapses after ART than previously reported,” Edith L. Graham, MD, of the department of neurology, Northwestern University, Chicago, and colleagues  wrote. “Importantly, continuing DMT during ART may reduce risk of relapse during this period of marked hormonal fluctuations and stressors,” they added.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Study details

Previous research shows a wide range of relapse risk in patients with MS undergoing ART.

To investigate the potential role of DMTs in mitigating relapse risk, the researchers evaluated data on 37 women with either relapsing-remitting MS (n = 31) or clinically isolated syndrome (CIS; n = 6) who underwent ART. The women all had low disability, with a median Expanded Disability Status Scale (EDSS) score of 1.0. All participants had undergone one to five cycles of reproductive therapy between 2010 and 2021.

Most (78%) were receiving ART because of infertility or a need for preimplantation genetic testing, whereas 22% were undergoing the treatment for the preservation of fertility. Average age of the participants was 35 years and average disease duration was 7.4 years.

Among 19 of the 37 patients who were taking DMTs prior to ART, 10 remained on the medication throughout ovarian hyperstimulation.

In those who received DMTs in the 12 months prior to ART, treatment included glatiramer acetate (n = 9), interferons (n = 3), and dimethyl fumarate (n = 1). Three participants received B-cell–depleting agents.

In addition, three women received medication in response to a rebound after discontinuation. Of these, two received fingolimod and one natalizumab.

Five patients (13.5%) experienced MS relapses in the 12 months following ART therapy. Among those experiencing relapse, none were treated with DMTs during the preceding 12 months.

Of the relapses, three occurred within 3 months of the ART treatment, one within 6 months, and one within 12 months.
 

High rate of successful pregnancy

Overall, 24 of 29 women (83%) underwent in vitro fertilization (IVF) with embryo transfer as part of ART achieved pregnancy. The remaining five patients were undergoing egg cryopreservation.

Although 14 of the 24 who achieved pregnancy were on DMTs and 2 of 5 who did not achieve pregnancy were on the therapies, Dr. Graham noted, “these numbers seem too small to draw conclusions.”

In particular, patients may benefit from treatment with rituximab or ocrelizumab 3-6 months prior to ART, “which gives better protection during ART cycle with low risk of fetal exposure,” she said.

“Treatment does not need to be discontinued if undergoing embryo banking only,” Dr. Graham added. “The risk to the fetus occurs only after embryo transfer.”

Although there is a lack of research examining whether MS relapse lowers the chance of pregnancy, Dr. Graham noted, “in theory, relapsing MS may compromise ART success because [patients] may have a narrower window to undergo ART treatments if they are trying to mitigate DMT exposure to the fetus.” 

However, the study’s results generally suggest favorable outcomes with ART among women with MS, she added. “We found that overall ART is actually very successful among people with MS. I was actually very surprised by this high rate of successful pregnancy,” Dr. Graham said.

She noted that as women with MS increasingly undergo IVF as well as egg cryopreservation, research on these issues is gaining importance for clinicians. “This is going to be something that MS specialists need to know more about, particularly the safety of ART in their patients,” said Dr. Graham.

“What’s important is there are no [formal] recommendations along these lines, so this represents an opportunity to get the word out to clinicians that you want to make sure patients with MS are protected throughout the ART cycle and that you’re not discontinuing their DMT too early,” she added.
 

Protective against relapse?

Commenting on the study, Jiwon Oh, MD, PhD, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, noted that, while there are many guidelines/recommendations regarding use of older DMTs peripregnancy, data on many newer therapies is more limited.

“Often, when people do not have definitive evidence, they tend to take a conservative approach, which is why there is likely reluctance to keep patients on DMTs during ART as well as in early pregnancy,” said Dr. Oh, who was not involved in the research.

Importantly, there is also no definitive evidence of a relationship between MS relapses and ART success or pregnancy outcomes, she noted. However, “from a common-sense perspective, most clinicians worry that extreme stress or disability may negatively affect both ART and pregnancy outcomes,” she added.

Dr. Oh agreed that ocrelizumab is an appropriate choice in terms of preventing relapse during ART. “Ocrevus is one of our highest-efficacy DMTs and is only dosed every 6 months. So this allows for ART cycles and conception without worrying about fetal drug exposure and the drug affecting ART cycles,” she said.

She noted the study’s findings “are in keeping with some prior studies, but not others, demonstrating there may be a higher risk of relapse with ART” in patients who are not taking a DMT.

“However, in my mind the most important conclusion from this study is that being on a DMT seems to be protective of relapse risk, which is an important point that will be useful to provide patients with clinical guidance,” Dr. Oh said.

Dr. Graham reported having received consulting fees from Genentech. Dr. Oh reported having received consulting or speaking fees from Alexion, Biogen Idec, BMS, EMD Serono, Genzyme, Novartis, and Roche.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – Women with multiple sclerosis (MS) undergoing assisted reproductive technologies (ART) have an increased relapse risk if they are not treated with disease-modifying therapy (DMT), new research suggests. In a cohort study of women undergoing ART, those who did not receive DMTs had a significantly higher relapse risk than their peers who were treated with the drugs.

In addition, the likelihood of achieving pregnancy through ART while having MS appeared favorable, researchers noted.

“In this modern case series and the largest cohort to date, we identified a lower risk of relapses after ART than previously reported,” Edith L. Graham, MD, of the department of neurology, Northwestern University, Chicago, and colleagues  wrote. “Importantly, continuing DMT during ART may reduce risk of relapse during this period of marked hormonal fluctuations and stressors,” they added.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Study details

Previous research shows a wide range of relapse risk in patients with MS undergoing ART.

To investigate the potential role of DMTs in mitigating relapse risk, the researchers evaluated data on 37 women with either relapsing-remitting MS (n = 31) or clinically isolated syndrome (CIS; n = 6) who underwent ART. The women all had low disability, with a median Expanded Disability Status Scale (EDSS) score of 1.0. All participants had undergone one to five cycles of reproductive therapy between 2010 and 2021.

Most (78%) were receiving ART because of infertility or a need for preimplantation genetic testing, whereas 22% were undergoing the treatment for the preservation of fertility. Average age of the participants was 35 years and average disease duration was 7.4 years.

Among 19 of the 37 patients who were taking DMTs prior to ART, 10 remained on the medication throughout ovarian hyperstimulation.

In those who received DMTs in the 12 months prior to ART, treatment included glatiramer acetate (n = 9), interferons (n = 3), and dimethyl fumarate (n = 1). Three participants received B-cell–depleting agents.

In addition, three women received medication in response to a rebound after discontinuation. Of these, two received fingolimod and one natalizumab.

Five patients (13.5%) experienced MS relapses in the 12 months following ART therapy. Among those experiencing relapse, none were treated with DMTs during the preceding 12 months.

Of the relapses, three occurred within 3 months of the ART treatment, one within 6 months, and one within 12 months.
 

High rate of successful pregnancy

Overall, 24 of 29 women (83%) underwent in vitro fertilization (IVF) with embryo transfer as part of ART achieved pregnancy. The remaining five patients were undergoing egg cryopreservation.

Although 14 of the 24 who achieved pregnancy were on DMTs and 2 of 5 who did not achieve pregnancy were on the therapies, Dr. Graham noted, “these numbers seem too small to draw conclusions.”

In particular, patients may benefit from treatment with rituximab or ocrelizumab 3-6 months prior to ART, “which gives better protection during ART cycle with low risk of fetal exposure,” she said.

“Treatment does not need to be discontinued if undergoing embryo banking only,” Dr. Graham added. “The risk to the fetus occurs only after embryo transfer.”

Although there is a lack of research examining whether MS relapse lowers the chance of pregnancy, Dr. Graham noted, “in theory, relapsing MS may compromise ART success because [patients] may have a narrower window to undergo ART treatments if they are trying to mitigate DMT exposure to the fetus.” 

However, the study’s results generally suggest favorable outcomes with ART among women with MS, she added. “We found that overall ART is actually very successful among people with MS. I was actually very surprised by this high rate of successful pregnancy,” Dr. Graham said.

She noted that as women with MS increasingly undergo IVF as well as egg cryopreservation, research on these issues is gaining importance for clinicians. “This is going to be something that MS specialists need to know more about, particularly the safety of ART in their patients,” said Dr. Graham.

“What’s important is there are no [formal] recommendations along these lines, so this represents an opportunity to get the word out to clinicians that you want to make sure patients with MS are protected throughout the ART cycle and that you’re not discontinuing their DMT too early,” she added.
 

Protective against relapse?

Commenting on the study, Jiwon Oh, MD, PhD, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, noted that, while there are many guidelines/recommendations regarding use of older DMTs peripregnancy, data on many newer therapies is more limited.

“Often, when people do not have definitive evidence, they tend to take a conservative approach, which is why there is likely reluctance to keep patients on DMTs during ART as well as in early pregnancy,” said Dr. Oh, who was not involved in the research.

Importantly, there is also no definitive evidence of a relationship between MS relapses and ART success or pregnancy outcomes, she noted. However, “from a common-sense perspective, most clinicians worry that extreme stress or disability may negatively affect both ART and pregnancy outcomes,” she added.

Dr. Oh agreed that ocrelizumab is an appropriate choice in terms of preventing relapse during ART. “Ocrevus is one of our highest-efficacy DMTs and is only dosed every 6 months. So this allows for ART cycles and conception without worrying about fetal drug exposure and the drug affecting ART cycles,” she said.

She noted the study’s findings “are in keeping with some prior studies, but not others, demonstrating there may be a higher risk of relapse with ART” in patients who are not taking a DMT.

“However, in my mind the most important conclusion from this study is that being on a DMT seems to be protective of relapse risk, which is an important point that will be useful to provide patients with clinical guidance,” Dr. Oh said.

Dr. Graham reported having received consulting fees from Genentech. Dr. Oh reported having received consulting or speaking fees from Alexion, Biogen Idec, BMS, EMD Serono, Genzyme, Novartis, and Roche.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – Women with multiple sclerosis (MS) undergoing assisted reproductive technologies (ART) have an increased relapse risk if they are not treated with disease-modifying therapy (DMT), new research suggests. In a cohort study of women undergoing ART, those who did not receive DMTs had a significantly higher relapse risk than their peers who were treated with the drugs.

In addition, the likelihood of achieving pregnancy through ART while having MS appeared favorable, researchers noted.

“In this modern case series and the largest cohort to date, we identified a lower risk of relapses after ART than previously reported,” Edith L. Graham, MD, of the department of neurology, Northwestern University, Chicago, and colleagues  wrote. “Importantly, continuing DMT during ART may reduce risk of relapse during this period of marked hormonal fluctuations and stressors,” they added.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Study details

Previous research shows a wide range of relapse risk in patients with MS undergoing ART.

To investigate the potential role of DMTs in mitigating relapse risk, the researchers evaluated data on 37 women with either relapsing-remitting MS (n = 31) or clinically isolated syndrome (CIS; n = 6) who underwent ART. The women all had low disability, with a median Expanded Disability Status Scale (EDSS) score of 1.0. All participants had undergone one to five cycles of reproductive therapy between 2010 and 2021.

Most (78%) were receiving ART because of infertility or a need for preimplantation genetic testing, whereas 22% were undergoing the treatment for the preservation of fertility. Average age of the participants was 35 years and average disease duration was 7.4 years.

Among 19 of the 37 patients who were taking DMTs prior to ART, 10 remained on the medication throughout ovarian hyperstimulation.

In those who received DMTs in the 12 months prior to ART, treatment included glatiramer acetate (n = 9), interferons (n = 3), and dimethyl fumarate (n = 1). Three participants received B-cell–depleting agents.

In addition, three women received medication in response to a rebound after discontinuation. Of these, two received fingolimod and one natalizumab.

Five patients (13.5%) experienced MS relapses in the 12 months following ART therapy. Among those experiencing relapse, none were treated with DMTs during the preceding 12 months.

Of the relapses, three occurred within 3 months of the ART treatment, one within 6 months, and one within 12 months.
 

High rate of successful pregnancy

Overall, 24 of 29 women (83%) underwent in vitro fertilization (IVF) with embryo transfer as part of ART achieved pregnancy. The remaining five patients were undergoing egg cryopreservation.

Although 14 of the 24 who achieved pregnancy were on DMTs and 2 of 5 who did not achieve pregnancy were on the therapies, Dr. Graham noted, “these numbers seem too small to draw conclusions.”

In particular, patients may benefit from treatment with rituximab or ocrelizumab 3-6 months prior to ART, “which gives better protection during ART cycle with low risk of fetal exposure,” she said.

“Treatment does not need to be discontinued if undergoing embryo banking only,” Dr. Graham added. “The risk to the fetus occurs only after embryo transfer.”

Although there is a lack of research examining whether MS relapse lowers the chance of pregnancy, Dr. Graham noted, “in theory, relapsing MS may compromise ART success because [patients] may have a narrower window to undergo ART treatments if they are trying to mitigate DMT exposure to the fetus.” 

However, the study’s results generally suggest favorable outcomes with ART among women with MS, she added. “We found that overall ART is actually very successful among people with MS. I was actually very surprised by this high rate of successful pregnancy,” Dr. Graham said.

She noted that as women with MS increasingly undergo IVF as well as egg cryopreservation, research on these issues is gaining importance for clinicians. “This is going to be something that MS specialists need to know more about, particularly the safety of ART in their patients,” said Dr. Graham.

“What’s important is there are no [formal] recommendations along these lines, so this represents an opportunity to get the word out to clinicians that you want to make sure patients with MS are protected throughout the ART cycle and that you’re not discontinuing their DMT too early,” she added.
 

Protective against relapse?

Commenting on the study, Jiwon Oh, MD, PhD, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, noted that, while there are many guidelines/recommendations regarding use of older DMTs peripregnancy, data on many newer therapies is more limited.

“Often, when people do not have definitive evidence, they tend to take a conservative approach, which is why there is likely reluctance to keep patients on DMTs during ART as well as in early pregnancy,” said Dr. Oh, who was not involved in the research.

Importantly, there is also no definitive evidence of a relationship between MS relapses and ART success or pregnancy outcomes, she noted. However, “from a common-sense perspective, most clinicians worry that extreme stress or disability may negatively affect both ART and pregnancy outcomes,” she added.

Dr. Oh agreed that ocrelizumab is an appropriate choice in terms of preventing relapse during ART. “Ocrevus is one of our highest-efficacy DMTs and is only dosed every 6 months. So this allows for ART cycles and conception without worrying about fetal drug exposure and the drug affecting ART cycles,” she said.

She noted the study’s findings “are in keeping with some prior studies, but not others, demonstrating there may be a higher risk of relapse with ART” in patients who are not taking a DMT.

“However, in my mind the most important conclusion from this study is that being on a DMT seems to be protective of relapse risk, which is an important point that will be useful to provide patients with clinical guidance,” Dr. Oh said.

Dr. Graham reported having received consulting fees from Genentech. Dr. Oh reported having received consulting or speaking fees from Alexion, Biogen Idec, BMS, EMD Serono, Genzyme, Novartis, and Roche.

A version of this article first appeared on Medscape.com.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS

Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.

The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.

These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.¹

Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.

There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.

The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.² Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.³ Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.

Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.

What follows is an overview of comorbidities and MS.

MS and the immune system

MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.

The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.⁴

So far, 230 loci have been implicated in modulating the risk of MS development.⁵ That 230 is twice the number found in rheumatoid arthritis⁶ and more than triple the number of genes and loci linked to psoriasis.⁷ The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.⁸

One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.⁹

The comorbidities

As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.¹⁰  One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.^11,12 

But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.^13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.

It is not uncommon for patients with MS to have psoriasis.^7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).

Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.¹⁵ In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.^15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.

Comorbidity specifics

There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.¹⁷ A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.¹⁸

Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.¹⁰ COPD also can increase risk of an earlier death, as can epilepsy.^10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.¹⁹

Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.⁹

In time

While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.²⁰

When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.⁹

Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.¹⁶ At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) ²¹

Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.

An interim analysis of the DAYBREAK open-label extension trial found that the sphingosine-1-phosphate receptor agonist ozanimod achieved sustained control of disease activity in people with relapsing multiple sclerosis (RMS) even during the pandemic. The study began in 2020 and also captured data on COVID-19 infections, and found that most were mild and resembled the profile of COVID-19 infections in the broader MS population.

Ozanimod is approved for the treatment of relapsing MS (RMS) and moderately to severe ulcerative colitis.

The DAYBREAK trial revealed a safety profile that broadly matched what was seen in the pivotal studies, with the exception that one case of progressive multifocal leukoencephalopathy (PML) emerged in the study population.

“So now we do know that ozanimod can cause PML, just as fingolimod can cause PML. I think some of us were hoping that perhaps the extent of immune suppression was going to be somewhat different in ozanimod and that PML might not occur. It’s a rare complication, but one that we now know can occur with this drug,” Bruce Cree, MD, PhD, said in an interview.

Ozanimod is a more selective drug than fingolimod. It affects only cell surface expression of the S1P1 and S1P5 receptors, and not other known S1P receptors. Ozanimod does not require first-dose observation and cardiac monitoring in most patients, and it can be taken at home.

“The two products have not been compared head-to-head. This is all comparison of data from different studies, and one has to take those considerations in mind as important caveats. But generally speaking, the safety profile and tolerability profile of ozanimod seems to be a little bit better, in my opinion, compared to that of fingolimod,” said Dr. Cree, who presented the results of the study at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is professor of neurology at the University of California, San Francisco.
 

Stable efficacy and no worsening of COVID-19 outcomes

Among 2,181 participants in DAYBREAK who were at risk of COVID-19, 8.7% had confirmed or suspected cases of COVID-19 during the study period. All were unvaccinated. Fourteen cases were considered serious, and there were two COVID-19–related deaths, and a third death caused by a pulmonary abscess related to an earlier COVID-19 infection. “When you look at this data and compare it to other datasets, this is not too dissimilar from rates of mortality that we would expect or serious infection that we see in other MS cohorts. So there doesn’t seem to be a striking worsening of COVID outcomes with ozanimod,” said Dr. Cree.

The benefit of the drug appeared to remain stable over multiple years. The annualized relapse rate was low and the relapse rate appeared to decline further over time. “It’s not an absolutely flat line, there is some curvature to it. So that that’s good news as well. And then the objective observation of lesion formation also is attenuated over time. We see a therapeutic effect on new radiographic lesions as well, and very low rates of disability worsening in ozanimod patients,” said Dr. Cree.

Overall, the study included 2,494 patients who entered the open-label extension study of the phase 1-3 trials. The study began in November 2019, and the current data extend through May 10, 2021. A total of 736 patients started out with interferon beta-1a and later switched to 0.92 mg ozanimod, 877 patients started at 0.46 mg ozanimod and switched to 0.92 mg ozanimod, and 881 were on a continuous dose of 0.92 mg ozanimod.

Three-quarters of the patients were relapse free at 36 months, 71% at 48 months. Among those who were on 0.92 mg ozanimod continuously, 64% were relapse-free through 60 months of treatment.

Among the cohort, 7.6% experienced severe treatment-emergent adverse events (TEAEs), 11.9% experienced serious TEAEs, and 3.0% discontinued ozanimod because of TEAEs. Common TEAEs included nasopharyngitis (59.3%), headache (46.1%), upper respiratory tract infection (31.5%), lymphopenia (29.4%), decreased absolute lymphocyte count (ALC, 24.5%), back pain (22.7%), and hypertension (20.7%).

Furthermore, 1.4% of patients developed treatment-emergent malignancies, 0.4% developed macular edema, 2.8% had cardiac TEAEs, and 9.8% had ALC levels below 0.2 x 109/L.
 

Encouraging data

The COVID-19 data were encouraging, according to Patricia Coyle, MD, who was asked to comment on the study. “190 individuals out of 2,181 seems quite reasonable, and they had three deaths. It certainly didn’t look like any excessive numbers of COVID, or excessive numbers of deaths,” said Dr. Coyle, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center.

She noted that other database studies have shown an association between increased risk and anti-CD20 agents, but they haven’t really seen that with the other disease-modifying therapies. “I think this is some long-term data that says that ozanimod appears to be well tolerated without having any surprising late toxicity,” said Dr. Coyle.

The study was funded by Celgene International II. Dr. Cree has consulted for Alexion, Atara, Autobahn, Avotres, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini, and received grant support from Genentech. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

An interim analysis of the DAYBREAK open-label extension trial found that the sphingosine-1-phosphate receptor agonist ozanimod achieved sustained control of disease activity in people with relapsing multiple sclerosis (RMS) even during the pandemic. The study began in 2020 and also captured data on COVID-19 infections, and found that most were mild and resembled the profile of COVID-19 infections in the broader MS population.

Ozanimod is approved for the treatment of relapsing MS (RMS) and moderately to severe ulcerative colitis.

The DAYBREAK trial revealed a safety profile that broadly matched what was seen in the pivotal studies, with the exception that one case of progressive multifocal leukoencephalopathy (PML) emerged in the study population.

“So now we do know that ozanimod can cause PML, just as fingolimod can cause PML. I think some of us were hoping that perhaps the extent of immune suppression was going to be somewhat different in ozanimod and that PML might not occur. It’s a rare complication, but one that we now know can occur with this drug,” Bruce Cree, MD, PhD, said in an interview.

Ozanimod is a more selective drug than fingolimod. It affects only cell surface expression of the S1P1 and S1P5 receptors, and not other known S1P receptors. Ozanimod does not require first-dose observation and cardiac monitoring in most patients, and it can be taken at home.

“The two products have not been compared head-to-head. This is all comparison of data from different studies, and one has to take those considerations in mind as important caveats. But generally speaking, the safety profile and tolerability profile of ozanimod seems to be a little bit better, in my opinion, compared to that of fingolimod,” said Dr. Cree, who presented the results of the study at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is professor of neurology at the University of California, San Francisco.
 

Stable efficacy and no worsening of COVID-19 outcomes

Among 2,181 participants in DAYBREAK who were at risk of COVID-19, 8.7% had confirmed or suspected cases of COVID-19 during the study period. All were unvaccinated. Fourteen cases were considered serious, and there were two COVID-19–related deaths, and a third death caused by a pulmonary abscess related to an earlier COVID-19 infection. “When you look at this data and compare it to other datasets, this is not too dissimilar from rates of mortality that we would expect or serious infection that we see in other MS cohorts. So there doesn’t seem to be a striking worsening of COVID outcomes with ozanimod,” said Dr. Cree.

The benefit of the drug appeared to remain stable over multiple years. The annualized relapse rate was low and the relapse rate appeared to decline further over time. “It’s not an absolutely flat line, there is some curvature to it. So that that’s good news as well. And then the objective observation of lesion formation also is attenuated over time. We see a therapeutic effect on new radiographic lesions as well, and very low rates of disability worsening in ozanimod patients,” said Dr. Cree.

Overall, the study included 2,494 patients who entered the open-label extension study of the phase 1-3 trials. The study began in November 2019, and the current data extend through May 10, 2021. A total of 736 patients started out with interferon beta-1a and later switched to 0.92 mg ozanimod, 877 patients started at 0.46 mg ozanimod and switched to 0.92 mg ozanimod, and 881 were on a continuous dose of 0.92 mg ozanimod.

Three-quarters of the patients were relapse free at 36 months, 71% at 48 months. Among those who were on 0.92 mg ozanimod continuously, 64% were relapse-free through 60 months of treatment.

Among the cohort, 7.6% experienced severe treatment-emergent adverse events (TEAEs), 11.9% experienced serious TEAEs, and 3.0% discontinued ozanimod because of TEAEs. Common TEAEs included nasopharyngitis (59.3%), headache (46.1%), upper respiratory tract infection (31.5%), lymphopenia (29.4%), decreased absolute lymphocyte count (ALC, 24.5%), back pain (22.7%), and hypertension (20.7%).

Furthermore, 1.4% of patients developed treatment-emergent malignancies, 0.4% developed macular edema, 2.8% had cardiac TEAEs, and 9.8% had ALC levels below 0.2 x 109/L.
 

Encouraging data

The COVID-19 data were encouraging, according to Patricia Coyle, MD, who was asked to comment on the study. “190 individuals out of 2,181 seems quite reasonable, and they had three deaths. It certainly didn’t look like any excessive numbers of COVID, or excessive numbers of deaths,” said Dr. Coyle, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center.

She noted that other database studies have shown an association between increased risk and anti-CD20 agents, but they haven’t really seen that with the other disease-modifying therapies. “I think this is some long-term data that says that ozanimod appears to be well tolerated without having any surprising late toxicity,” said Dr. Coyle.

The study was funded by Celgene International II. Dr. Cree has consulted for Alexion, Atara, Autobahn, Avotres, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini, and received grant support from Genentech. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

An interim analysis of the DAYBREAK open-label extension trial found that the sphingosine-1-phosphate receptor agonist ozanimod achieved sustained control of disease activity in people with relapsing multiple sclerosis (RMS) even during the pandemic. The study began in 2020 and also captured data on COVID-19 infections, and found that most were mild and resembled the profile of COVID-19 infections in the broader MS population.

Ozanimod is approved for the treatment of relapsing MS (RMS) and moderately to severe ulcerative colitis.

The DAYBREAK trial revealed a safety profile that broadly matched what was seen in the pivotal studies, with the exception that one case of progressive multifocal leukoencephalopathy (PML) emerged in the study population.

“So now we do know that ozanimod can cause PML, just as fingolimod can cause PML. I think some of us were hoping that perhaps the extent of immune suppression was going to be somewhat different in ozanimod and that PML might not occur. It’s a rare complication, but one that we now know can occur with this drug,” Bruce Cree, MD, PhD, said in an interview.

Ozanimod is a more selective drug than fingolimod. It affects only cell surface expression of the S1P1 and S1P5 receptors, and not other known S1P receptors. Ozanimod does not require first-dose observation and cardiac monitoring in most patients, and it can be taken at home.

“The two products have not been compared head-to-head. This is all comparison of data from different studies, and one has to take those considerations in mind as important caveats. But generally speaking, the safety profile and tolerability profile of ozanimod seems to be a little bit better, in my opinion, compared to that of fingolimod,” said Dr. Cree, who presented the results of the study at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is professor of neurology at the University of California, San Francisco.
 

Stable efficacy and no worsening of COVID-19 outcomes

Among 2,181 participants in DAYBREAK who were at risk of COVID-19, 8.7% had confirmed or suspected cases of COVID-19 during the study period. All were unvaccinated. Fourteen cases were considered serious, and there were two COVID-19–related deaths, and a third death caused by a pulmonary abscess related to an earlier COVID-19 infection. “When you look at this data and compare it to other datasets, this is not too dissimilar from rates of mortality that we would expect or serious infection that we see in other MS cohorts. So there doesn’t seem to be a striking worsening of COVID outcomes with ozanimod,” said Dr. Cree.

The benefit of the drug appeared to remain stable over multiple years. The annualized relapse rate was low and the relapse rate appeared to decline further over time. “It’s not an absolutely flat line, there is some curvature to it. So that that’s good news as well. And then the objective observation of lesion formation also is attenuated over time. We see a therapeutic effect on new radiographic lesions as well, and very low rates of disability worsening in ozanimod patients,” said Dr. Cree.

Overall, the study included 2,494 patients who entered the open-label extension study of the phase 1-3 trials. The study began in November 2019, and the current data extend through May 10, 2021. A total of 736 patients started out with interferon beta-1a and later switched to 0.92 mg ozanimod, 877 patients started at 0.46 mg ozanimod and switched to 0.92 mg ozanimod, and 881 were on a continuous dose of 0.92 mg ozanimod.

Three-quarters of the patients were relapse free at 36 months, 71% at 48 months. Among those who were on 0.92 mg ozanimod continuously, 64% were relapse-free through 60 months of treatment.

Among the cohort, 7.6% experienced severe treatment-emergent adverse events (TEAEs), 11.9% experienced serious TEAEs, and 3.0% discontinued ozanimod because of TEAEs. Common TEAEs included nasopharyngitis (59.3%), headache (46.1%), upper respiratory tract infection (31.5%), lymphopenia (29.4%), decreased absolute lymphocyte count (ALC, 24.5%), back pain (22.7%), and hypertension (20.7%).

Furthermore, 1.4% of patients developed treatment-emergent malignancies, 0.4% developed macular edema, 2.8% had cardiac TEAEs, and 9.8% had ALC levels below 0.2 x 109/L.
 

Encouraging data

The COVID-19 data were encouraging, according to Patricia Coyle, MD, who was asked to comment on the study. “190 individuals out of 2,181 seems quite reasonable, and they had three deaths. It certainly didn’t look like any excessive numbers of COVID, or excessive numbers of deaths,” said Dr. Coyle, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center.

She noted that other database studies have shown an association between increased risk and anti-CD20 agents, but they haven’t really seen that with the other disease-modifying therapies. “I think this is some long-term data that says that ozanimod appears to be well tolerated without having any surprising late toxicity,” said Dr. Coyle.

The study was funded by Celgene International II. Dr. Cree has consulted for Alexion, Atara, Autobahn, Avotres, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini, and received grant support from Genentech. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

Among individuals with multiple sclerosis (MS), disease modifying therapies (DMTs) are associated with a reduced humoral response to SARS-CoV-2 vaccines, according to a new retrospective analysis. The link is particularly strong among B-cell depleting drugs.

“A lot of patients ask us if having MS by itself affects the vaccine response. We did not find that, but it’s about the disease-modifying therapy that a patient is being treated with,” Tirisham Gyang, MD, said in an interview. Dr. Gyang presented the study at a poster session during the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

“These patients (on DMTs) had decreased neutralizing antibody levels to the vaccine after they received it. We also saw a similar marker in drugs that modulate the sphingosine S-1 receptor. These patients also had a lower titer. It wasn’t statistically significant, but we think it’s positive. It was underpowered because there was a small number of patients in that subgroup,” said Dr. Gyang, assistant professor of neurology at The Ohio State University.

The results can inform vaccine strategies among people with MS, but the issue remains complex. “I don’t know that we could do a blanket statement and say, if you wait this amount of time, everybody will be okay. It’s a very individualized approach, and patients need to discuss timing of vaccines with their providers, because we know that waiting is better. It’s preferable to wait until towards the end of the dosing cycle. The other factor is making sure that the MS is well treated,” said Dr. Gyang.

The researchers prospectively followed 83 MS patients at the The Ohio State University Wexner Medical Center. Among the cohort, 71% were female. Fifty-one subjects had serum samples analyzed following mRNA COVID-19 vaccination, and they were compared with 38 health care worker controls.

After vaccination, people with MS had about 2.4-fold lower levels of half-maximal neutralization titer (NT50) values compared with health care worker controls. This appeared to be driven primarily by DMTs. There was a more than ninefold reduction in the neutralizing antibody (nAb) response among 13 patients on B-cell depleting agents, compared with no therapy or other therapies (P < .001). Among of individuals on these agents, 61.5% had no detectable nAb.

The researchers also found an association between postvaccine NT50 values and when the vaccine was received compared with the last infusion of B-cell depleting agents. Every additional day since the previous infusion was associated with a 3.7% increase in NT50 value (P = .0032).

The average length of exposure to B-cell depleting agents was 24 months and the median was 25 months. There was no association between length of time on a B-cell depleting agent and NT50 values after vaccination (Spearman correlation 0.35, P = .24).

Subanalyses by sex and vaccine type revealed no differences in nAb levels.

The study did not look at T-cell responses after vaccination or the effect of T-cell depleting agents, and T cells likely still provide some protection, according to Dr. Gyang. “Even though the vaccine response may not be as robust as it would have been if they were not on the drug, there is still some degree of protection,” she said.
 

Some answers, more questions

The study is important, even though it was presented at the time that the COVID-19 Omicron variant surge was waning. “COVID still remains a major concern. Even though it seems to be on the wane at the moment, that doesn’t mean it will be on the wane next week,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates (Patchogue, N.Y.), who was asked to comment on the study.

He noted that about 21% of patients in the study who received a vaccination had no detectable antibodies. “That’s a problem. You need to pick a medication that works, but not if the medication puts you at risk for other problems, especially in the world of now, where we know there are viral pandemics that occur. And that calls into question: What if you’re immunocompromised and you get a flu vaccine or a tetanus vaccine? How much do we know about the vaccination response to most of these? No one really considers [vaccine response] when choosing a medication,” said Dr. Gudesblatt.

The results broadly confirm what has been seen in other studies, though its focus on the humoral response is a limitation, according to Patricia Coyle, MD, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center. “For example, there have been independent studies with the (anti-CD-20 therapies) that indicate that they have a normal cell-mediated vaccine response to the COVID vaccine, even though the antibody response may be impaired in a significant number of individuals, though as you continue to vaccinate the antibody response seems to get better,” Dr. Coyle said in an interview.

Dr. Gyang has served as consultant for Genentech, Horizon Therapeutics, Greenwich Biosciences and EMD Serono. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

Among individuals with multiple sclerosis (MS), disease modifying therapies (DMTs) are associated with a reduced humoral response to SARS-CoV-2 vaccines, according to a new retrospective analysis. The link is particularly strong among B-cell depleting drugs.

“A lot of patients ask us if having MS by itself affects the vaccine response. We did not find that, but it’s about the disease-modifying therapy that a patient is being treated with,” Tirisham Gyang, MD, said in an interview. Dr. Gyang presented the study at a poster session during the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

“These patients (on DMTs) had decreased neutralizing antibody levels to the vaccine after they received it. We also saw a similar marker in drugs that modulate the sphingosine S-1 receptor. These patients also had a lower titer. It wasn’t statistically significant, but we think it’s positive. It was underpowered because there was a small number of patients in that subgroup,” said Dr. Gyang, assistant professor of neurology at The Ohio State University.

The results can inform vaccine strategies among people with MS, but the issue remains complex. “I don’t know that we could do a blanket statement and say, if you wait this amount of time, everybody will be okay. It’s a very individualized approach, and patients need to discuss timing of vaccines with their providers, because we know that waiting is better. It’s preferable to wait until towards the end of the dosing cycle. The other factor is making sure that the MS is well treated,” said Dr. Gyang.

The researchers prospectively followed 83 MS patients at the The Ohio State University Wexner Medical Center. Among the cohort, 71% were female. Fifty-one subjects had serum samples analyzed following mRNA COVID-19 vaccination, and they were compared with 38 health care worker controls.

After vaccination, people with MS had about 2.4-fold lower levels of half-maximal neutralization titer (NT50) values compared with health care worker controls. This appeared to be driven primarily by DMTs. There was a more than ninefold reduction in the neutralizing antibody (nAb) response among 13 patients on B-cell depleting agents, compared with no therapy or other therapies (P < .001). Among of individuals on these agents, 61.5% had no detectable nAb.

The researchers also found an association between postvaccine NT50 values and when the vaccine was received compared with the last infusion of B-cell depleting agents. Every additional day since the previous infusion was associated with a 3.7% increase in NT50 value (P = .0032).

The average length of exposure to B-cell depleting agents was 24 months and the median was 25 months. There was no association between length of time on a B-cell depleting agent and NT50 values after vaccination (Spearman correlation 0.35, P = .24).

Subanalyses by sex and vaccine type revealed no differences in nAb levels.

The study did not look at T-cell responses after vaccination or the effect of T-cell depleting agents, and T cells likely still provide some protection, according to Dr. Gyang. “Even though the vaccine response may not be as robust as it would have been if they were not on the drug, there is still some degree of protection,” she said.
 

Some answers, more questions

The study is important, even though it was presented at the time that the COVID-19 Omicron variant surge was waning. “COVID still remains a major concern. Even though it seems to be on the wane at the moment, that doesn’t mean it will be on the wane next week,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates (Patchogue, N.Y.), who was asked to comment on the study.

He noted that about 21% of patients in the study who received a vaccination had no detectable antibodies. “That’s a problem. You need to pick a medication that works, but not if the medication puts you at risk for other problems, especially in the world of now, where we know there are viral pandemics that occur. And that calls into question: What if you’re immunocompromised and you get a flu vaccine or a tetanus vaccine? How much do we know about the vaccination response to most of these? No one really considers [vaccine response] when choosing a medication,” said Dr. Gudesblatt.

The results broadly confirm what has been seen in other studies, though its focus on the humoral response is a limitation, according to Patricia Coyle, MD, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center. “For example, there have been independent studies with the (anti-CD-20 therapies) that indicate that they have a normal cell-mediated vaccine response to the COVID vaccine, even though the antibody response may be impaired in a significant number of individuals, though as you continue to vaccinate the antibody response seems to get better,” Dr. Coyle said in an interview.

Dr. Gyang has served as consultant for Genentech, Horizon Therapeutics, Greenwich Biosciences and EMD Serono. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

Among individuals with multiple sclerosis (MS), disease modifying therapies (DMTs) are associated with a reduced humoral response to SARS-CoV-2 vaccines, according to a new retrospective analysis. The link is particularly strong among B-cell depleting drugs.

“A lot of patients ask us if having MS by itself affects the vaccine response. We did not find that, but it’s about the disease-modifying therapy that a patient is being treated with,” Tirisham Gyang, MD, said in an interview. Dr. Gyang presented the study at a poster session during the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

“These patients (on DMTs) had decreased neutralizing antibody levels to the vaccine after they received it. We also saw a similar marker in drugs that modulate the sphingosine S-1 receptor. These patients also had a lower titer. It wasn’t statistically significant, but we think it’s positive. It was underpowered because there was a small number of patients in that subgroup,” said Dr. Gyang, assistant professor of neurology at The Ohio State University.

The results can inform vaccine strategies among people with MS, but the issue remains complex. “I don’t know that we could do a blanket statement and say, if you wait this amount of time, everybody will be okay. It’s a very individualized approach, and patients need to discuss timing of vaccines with their providers, because we know that waiting is better. It’s preferable to wait until towards the end of the dosing cycle. The other factor is making sure that the MS is well treated,” said Dr. Gyang.

The researchers prospectively followed 83 MS patients at the The Ohio State University Wexner Medical Center. Among the cohort, 71% were female. Fifty-one subjects had serum samples analyzed following mRNA COVID-19 vaccination, and they were compared with 38 health care worker controls.

After vaccination, people with MS had about 2.4-fold lower levels of half-maximal neutralization titer (NT50) values compared with health care worker controls. This appeared to be driven primarily by DMTs. There was a more than ninefold reduction in the neutralizing antibody (nAb) response among 13 patients on B-cell depleting agents, compared with no therapy or other therapies (P < .001). Among of individuals on these agents, 61.5% had no detectable nAb.

The researchers also found an association between postvaccine NT50 values and when the vaccine was received compared with the last infusion of B-cell depleting agents. Every additional day since the previous infusion was associated with a 3.7% increase in NT50 value (P = .0032).

The average length of exposure to B-cell depleting agents was 24 months and the median was 25 months. There was no association between length of time on a B-cell depleting agent and NT50 values after vaccination (Spearman correlation 0.35, P = .24).

Subanalyses by sex and vaccine type revealed no differences in nAb levels.

The study did not look at T-cell responses after vaccination or the effect of T-cell depleting agents, and T cells likely still provide some protection, according to Dr. Gyang. “Even though the vaccine response may not be as robust as it would have been if they were not on the drug, there is still some degree of protection,” she said.
 

Some answers, more questions

The study is important, even though it was presented at the time that the COVID-19 Omicron variant surge was waning. “COVID still remains a major concern. Even though it seems to be on the wane at the moment, that doesn’t mean it will be on the wane next week,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates (Patchogue, N.Y.), who was asked to comment on the study.

He noted that about 21% of patients in the study who received a vaccination had no detectable antibodies. “That’s a problem. You need to pick a medication that works, but not if the medication puts you at risk for other problems, especially in the world of now, where we know there are viral pandemics that occur. And that calls into question: What if you’re immunocompromised and you get a flu vaccine or a tetanus vaccine? How much do we know about the vaccination response to most of these? No one really considers [vaccine response] when choosing a medication,” said Dr. Gudesblatt.

The results broadly confirm what has been seen in other studies, though its focus on the humoral response is a limitation, according to Patricia Coyle, MD, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center. “For example, there have been independent studies with the (anti-CD-20 therapies) that indicate that they have a normal cell-mediated vaccine response to the COVID vaccine, even though the antibody response may be impaired in a significant number of individuals, though as you continue to vaccinate the antibody response seems to get better,” Dr. Coyle said in an interview.

Dr. Gyang has served as consultant for Genentech, Horizon Therapeutics, Greenwich Biosciences and EMD Serono. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

WEST PALM BEACH, FLA. – The presence of paramagnetic rim lesions (PRLs) on MRI may help in the diagnosis of multiple sclerosis (MS), as well as in predicting more severe disease course, new research suggests.

Results from two studies add to the mounting evidence underscoring the importance of the imaging features, researchers noted. “Our data suggest that the presence and number of iron rim lesions hold a prognostic value for long-term disability in MS, especially the presence of four or more rim lesions,” said Amjad I. AlTokhis, School of Medicine, University of Nottingham, United Kingdom, and Division of Clinical Neuroscience, Nottingham University Hospitals NHS Trust, who was the lead author of both studies.

Importantly, the effect of the rim lesions on disability was greater than that of established prognostic biomarkers of T2 white matter lesion count and volume, she noted.

“This could support the use of iron rim lesions as an imaging biomarker for disease severity and worse prognosis,” said Dr. AlTokhis. “These findings also support that iron rim lesions might be clinically useful not only diagnostically but also for disease progression and predicting future disability in MS,” she added.

The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.
 

Sign of aggressive disease?

Dozens of studies have linked rim lesions, which are also known as iron rim lesions because of their composition of iron-laden macrophages/microglia, to more severe disease course in MS, as well as to having potential as an important imaging biomarker for diagnosis. However, studies have often been limited to smaller longitudinal cohorts.

In the first study, Dr. AlTokhis and colleagues enrolled 91 patients with MS (56 women) between 2008 and 2013 for whom 7 Tesla (7T) MRI was available with SWI-filtered phase sequencing.

At baseline, among 42 patients with clinically isolated syndrome, 50% had one or more of the rim lesions. The corresponding rates were 38% among 34 patients with relapsing-remitting MS, 38% among 18 patients with primary-progressive MS, and as high as 71% among 17 patients with secondary-progressive MS (P < .05 vs. primary progressive MS and clinically isolated syndrome).

At a median follow-up of 9 years, 18 of the patients with clinically isolated syndrome and relapsing-remitting MS progressed to secondary progressive MS; and among them, 56% had at least one rim lesion.

Of 24 who did not progress to secondary progressive MS, only 33% had at least one rim lesion.

The median baseline level of disease severity in the entire cohort, as measured by Age-Related Multiple Sclerosis Score (ARMSS), was 5.4. However, the median score among patients with rim lesions was higher, compared with those without the lesions (ARMSS, 6.7 vs. 5.0).

After the median 9-year follow-up, disease severity remained higher among those with versus those without the lesions (ARMSS, 7.3 vs. 6.3).

Patients with rim lesions had more white matter lesions overall; and a further analysis surprisingly showed that the number of rim lesions was indeed associated with long-term disability (P = .005).

“Detecting four or more iron rim lesions could be a sign of more aggressive disease and disability – thus, possibly useful in earlier treatment and a potential target for therapies,” Dr. AlTokhis said.

“Also, for clinical practicality, [the number of] iron rim lesions had the most direct effect on disability compared to white matter lesion count and volume, supporting its role as an independent prognostic imaging biomarker,” she added.

Dr. AlTokhis noted that “detecting and counting rim lesions is much easier than assessing all white matter lesions, adding to the clinical utility of this sign.”
 

Diagnostic value

The second study, presented at the meeting by coinvestigator Brian Renner, MD, Department of Neurology at Cedars Sinai, Los Angeles, reported on the significance of the rim lesions in MS diagnosis. It included 95 patients who had presented for new evaluation on suspicion of MS at 10 centers in the North American Imaging in MS Cooperative (NAIMS).

Of these participants, 44 (46%) were positively diagnosed according to McDonald 2017 criteria (MC2017) for MS, while 37 (39%) were given an alternative diagnosis to MS. Fourteen were considered at risk for MS with diagnoses of clinically isolating syndrome or radiologically isolating syndrome.

Overall, among the 44 with an MS diagnosis, 34 had one or more rim lesions; among the 51 who did not meet an MS diagnosis, only six had one or more of the rim lesions. One or more rim lesions were further observed in three patients with radiologically isolating syndrome and one patient with clinically isolating syndrome.

Among those with one or more of the rim lesions, a diagnosis of MS with MC2017 MS criteria was identified with a high sensitivity of 80%, high specificity of 88%, accuracy of 84%, and an AUC of 81%.

“We’ve shown that paramagnetic rim lesions are highly specific for MS, and the sensitivity of rim lesions for MS is higher than previously reported, despite similar techniques in rating, processing, and evaluation – which was likely related to the nature of the cohort,” Dr. Renner said.
 

Promising data

During the NAIMS symposium, Christopher C. Hemond, MD, assistant professor or neurology at the University of Massachusetts Medical School, Worcester, noted to meeting attendees that the rim lesions were seen across the entire course of the MS disease spectrum, spanning from radiologically isolating syndrome to secondary progressive MS.

“We know paramagnetic rim lesions are visible at all disease stages. They are uniquely larger and more destructive than their rimless peers and are associated with stronger disease severity,” said Dr. Hemond, who was not involved with the research.

“There is promising data at this point suggesting that [the rim lesions] may represent a biomarker predictive of future disability accumulation,” he added.

Dr. Hemond noted that, unlike in Dr. Renner’s study, the bulk of previous studies have indicated that rim lesions “are associated with a high specificity but only modest sensitivity, in the mid-50% range, for the diagnosis of MS in comparison to some conditions that mimic MS.”

Commenting on the findings, Dr. Hemond noted the results from Dr. Renner’s ongoing study “are critical in building confidence in the translational use of this biomarker to assist in ruling in a diagnosis of MS,” while Dr. AlTokis’ study “adds to and is consistent with the growing literature of pathological associations of paramagnetic rim lesions in MS.”

Dr. Hemond added that the NAIMS cooperative plans to publish guidance in the area in the coming months.

“Although paramagnetic rim lesions have strong pathological associations in MS, it remains unclear if the presence of these lesions should change MS clinical management at the present time,” he said.

During the NAIMS session, Francesca Bagnato, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn., noted the growing importance of the role of rim lesions in clinical research. “It is clear that these paramagnetic rim lesions are going to be the new biomarker for the next generation of clinical trials,” she said.

Dr. Renner’s study received funding from the Race to Erase MS Foundation. Dr. AlTokhis, Dr. Renner, and Dr. Hemond have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – The presence of paramagnetic rim lesions (PRLs) on MRI may help in the diagnosis of multiple sclerosis (MS), as well as in predicting more severe disease course, new research suggests.

Results from two studies add to the mounting evidence underscoring the importance of the imaging features, researchers noted. “Our data suggest that the presence and number of iron rim lesions hold a prognostic value for long-term disability in MS, especially the presence of four or more rim lesions,” said Amjad I. AlTokhis, School of Medicine, University of Nottingham, United Kingdom, and Division of Clinical Neuroscience, Nottingham University Hospitals NHS Trust, who was the lead author of both studies.

Importantly, the effect of the rim lesions on disability was greater than that of established prognostic biomarkers of T2 white matter lesion count and volume, she noted.

“This could support the use of iron rim lesions as an imaging biomarker for disease severity and worse prognosis,” said Dr. AlTokhis. “These findings also support that iron rim lesions might be clinically useful not only diagnostically but also for disease progression and predicting future disability in MS,” she added.

The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.
 

Sign of aggressive disease?

Dozens of studies have linked rim lesions, which are also known as iron rim lesions because of their composition of iron-laden macrophages/microglia, to more severe disease course in MS, as well as to having potential as an important imaging biomarker for diagnosis. However, studies have often been limited to smaller longitudinal cohorts.

In the first study, Dr. AlTokhis and colleagues enrolled 91 patients with MS (56 women) between 2008 and 2013 for whom 7 Tesla (7T) MRI was available with SWI-filtered phase sequencing.

At baseline, among 42 patients with clinically isolated syndrome, 50% had one or more of the rim lesions. The corresponding rates were 38% among 34 patients with relapsing-remitting MS, 38% among 18 patients with primary-progressive MS, and as high as 71% among 17 patients with secondary-progressive MS (P < .05 vs. primary progressive MS and clinically isolated syndrome).

At a median follow-up of 9 years, 18 of the patients with clinically isolated syndrome and relapsing-remitting MS progressed to secondary progressive MS; and among them, 56% had at least one rim lesion.

Of 24 who did not progress to secondary progressive MS, only 33% had at least one rim lesion.

The median baseline level of disease severity in the entire cohort, as measured by Age-Related Multiple Sclerosis Score (ARMSS), was 5.4. However, the median score among patients with rim lesions was higher, compared with those without the lesions (ARMSS, 6.7 vs. 5.0).

After the median 9-year follow-up, disease severity remained higher among those with versus those without the lesions (ARMSS, 7.3 vs. 6.3).

Patients with rim lesions had more white matter lesions overall; and a further analysis surprisingly showed that the number of rim lesions was indeed associated with long-term disability (P = .005).

“Detecting four or more iron rim lesions could be a sign of more aggressive disease and disability – thus, possibly useful in earlier treatment and a potential target for therapies,” Dr. AlTokhis said.

“Also, for clinical practicality, [the number of] iron rim lesions had the most direct effect on disability compared to white matter lesion count and volume, supporting its role as an independent prognostic imaging biomarker,” she added.

Dr. AlTokhis noted that “detecting and counting rim lesions is much easier than assessing all white matter lesions, adding to the clinical utility of this sign.”
 

Diagnostic value

The second study, presented at the meeting by coinvestigator Brian Renner, MD, Department of Neurology at Cedars Sinai, Los Angeles, reported on the significance of the rim lesions in MS diagnosis. It included 95 patients who had presented for new evaluation on suspicion of MS at 10 centers in the North American Imaging in MS Cooperative (NAIMS).

Of these participants, 44 (46%) were positively diagnosed according to McDonald 2017 criteria (MC2017) for MS, while 37 (39%) were given an alternative diagnosis to MS. Fourteen were considered at risk for MS with diagnoses of clinically isolating syndrome or radiologically isolating syndrome.

Overall, among the 44 with an MS diagnosis, 34 had one or more rim lesions; among the 51 who did not meet an MS diagnosis, only six had one or more of the rim lesions. One or more rim lesions were further observed in three patients with radiologically isolating syndrome and one patient with clinically isolating syndrome.

Among those with one or more of the rim lesions, a diagnosis of MS with MC2017 MS criteria was identified with a high sensitivity of 80%, high specificity of 88%, accuracy of 84%, and an AUC of 81%.

“We’ve shown that paramagnetic rim lesions are highly specific for MS, and the sensitivity of rim lesions for MS is higher than previously reported, despite similar techniques in rating, processing, and evaluation – which was likely related to the nature of the cohort,” Dr. Renner said.
 

Promising data

During the NAIMS symposium, Christopher C. Hemond, MD, assistant professor or neurology at the University of Massachusetts Medical School, Worcester, noted to meeting attendees that the rim lesions were seen across the entire course of the MS disease spectrum, spanning from radiologically isolating syndrome to secondary progressive MS.

“We know paramagnetic rim lesions are visible at all disease stages. They are uniquely larger and more destructive than their rimless peers and are associated with stronger disease severity,” said Dr. Hemond, who was not involved with the research.

“There is promising data at this point suggesting that [the rim lesions] may represent a biomarker predictive of future disability accumulation,” he added.

Dr. Hemond noted that, unlike in Dr. Renner’s study, the bulk of previous studies have indicated that rim lesions “are associated with a high specificity but only modest sensitivity, in the mid-50% range, for the diagnosis of MS in comparison to some conditions that mimic MS.”

Commenting on the findings, Dr. Hemond noted the results from Dr. Renner’s ongoing study “are critical in building confidence in the translational use of this biomarker to assist in ruling in a diagnosis of MS,” while Dr. AlTokis’ study “adds to and is consistent with the growing literature of pathological associations of paramagnetic rim lesions in MS.”

Dr. Hemond added that the NAIMS cooperative plans to publish guidance in the area in the coming months.

“Although paramagnetic rim lesions have strong pathological associations in MS, it remains unclear if the presence of these lesions should change MS clinical management at the present time,” he said.

During the NAIMS session, Francesca Bagnato, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn., noted the growing importance of the role of rim lesions in clinical research. “It is clear that these paramagnetic rim lesions are going to be the new biomarker for the next generation of clinical trials,” she said.

Dr. Renner’s study received funding from the Race to Erase MS Foundation. Dr. AlTokhis, Dr. Renner, and Dr. Hemond have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – The presence of paramagnetic rim lesions (PRLs) on MRI may help in the diagnosis of multiple sclerosis (MS), as well as in predicting more severe disease course, new research suggests.

Results from two studies add to the mounting evidence underscoring the importance of the imaging features, researchers noted. “Our data suggest that the presence and number of iron rim lesions hold a prognostic value for long-term disability in MS, especially the presence of four or more rim lesions,” said Amjad I. AlTokhis, School of Medicine, University of Nottingham, United Kingdom, and Division of Clinical Neuroscience, Nottingham University Hospitals NHS Trust, who was the lead author of both studies.

Importantly, the effect of the rim lesions on disability was greater than that of established prognostic biomarkers of T2 white matter lesion count and volume, she noted.

“This could support the use of iron rim lesions as an imaging biomarker for disease severity and worse prognosis,” said Dr. AlTokhis. “These findings also support that iron rim lesions might be clinically useful not only diagnostically but also for disease progression and predicting future disability in MS,” she added.

The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.
 

Sign of aggressive disease?

Dozens of studies have linked rim lesions, which are also known as iron rim lesions because of their composition of iron-laden macrophages/microglia, to more severe disease course in MS, as well as to having potential as an important imaging biomarker for diagnosis. However, studies have often been limited to smaller longitudinal cohorts.

In the first study, Dr. AlTokhis and colleagues enrolled 91 patients with MS (56 women) between 2008 and 2013 for whom 7 Tesla (7T) MRI was available with SWI-filtered phase sequencing.

At baseline, among 42 patients with clinically isolated syndrome, 50% had one or more of the rim lesions. The corresponding rates were 38% among 34 patients with relapsing-remitting MS, 38% among 18 patients with primary-progressive MS, and as high as 71% among 17 patients with secondary-progressive MS (P < .05 vs. primary progressive MS and clinically isolated syndrome).

At a median follow-up of 9 years, 18 of the patients with clinically isolated syndrome and relapsing-remitting MS progressed to secondary progressive MS; and among them, 56% had at least one rim lesion.

Of 24 who did not progress to secondary progressive MS, only 33% had at least one rim lesion.

The median baseline level of disease severity in the entire cohort, as measured by Age-Related Multiple Sclerosis Score (ARMSS), was 5.4. However, the median score among patients with rim lesions was higher, compared with those without the lesions (ARMSS, 6.7 vs. 5.0).

After the median 9-year follow-up, disease severity remained higher among those with versus those without the lesions (ARMSS, 7.3 vs. 6.3).

Patients with rim lesions had more white matter lesions overall; and a further analysis surprisingly showed that the number of rim lesions was indeed associated with long-term disability (P = .005).

“Detecting four or more iron rim lesions could be a sign of more aggressive disease and disability – thus, possibly useful in earlier treatment and a potential target for therapies,” Dr. AlTokhis said.

“Also, for clinical practicality, [the number of] iron rim lesions had the most direct effect on disability compared to white matter lesion count and volume, supporting its role as an independent prognostic imaging biomarker,” she added.

Dr. AlTokhis noted that “detecting and counting rim lesions is much easier than assessing all white matter lesions, adding to the clinical utility of this sign.”
 

Diagnostic value

The second study, presented at the meeting by coinvestigator Brian Renner, MD, Department of Neurology at Cedars Sinai, Los Angeles, reported on the significance of the rim lesions in MS diagnosis. It included 95 patients who had presented for new evaluation on suspicion of MS at 10 centers in the North American Imaging in MS Cooperative (NAIMS).

Of these participants, 44 (46%) were positively diagnosed according to McDonald 2017 criteria (MC2017) for MS, while 37 (39%) were given an alternative diagnosis to MS. Fourteen were considered at risk for MS with diagnoses of clinically isolating syndrome or radiologically isolating syndrome.

Overall, among the 44 with an MS diagnosis, 34 had one or more rim lesions; among the 51 who did not meet an MS diagnosis, only six had one or more of the rim lesions. One or more rim lesions were further observed in three patients with radiologically isolating syndrome and one patient with clinically isolating syndrome.

Among those with one or more of the rim lesions, a diagnosis of MS with MC2017 MS criteria was identified with a high sensitivity of 80%, high specificity of 88%, accuracy of 84%, and an AUC of 81%.

“We’ve shown that paramagnetic rim lesions are highly specific for MS, and the sensitivity of rim lesions for MS is higher than previously reported, despite similar techniques in rating, processing, and evaluation – which was likely related to the nature of the cohort,” Dr. Renner said.
 

Promising data

During the NAIMS symposium, Christopher C. Hemond, MD, assistant professor or neurology at the University of Massachusetts Medical School, Worcester, noted to meeting attendees that the rim lesions were seen across the entire course of the MS disease spectrum, spanning from radiologically isolating syndrome to secondary progressive MS.

“We know paramagnetic rim lesions are visible at all disease stages. They are uniquely larger and more destructive than their rimless peers and are associated with stronger disease severity,” said Dr. Hemond, who was not involved with the research.

“There is promising data at this point suggesting that [the rim lesions] may represent a biomarker predictive of future disability accumulation,” he added.

Dr. Hemond noted that, unlike in Dr. Renner’s study, the bulk of previous studies have indicated that rim lesions “are associated with a high specificity but only modest sensitivity, in the mid-50% range, for the diagnosis of MS in comparison to some conditions that mimic MS.”

Commenting on the findings, Dr. Hemond noted the results from Dr. Renner’s ongoing study “are critical in building confidence in the translational use of this biomarker to assist in ruling in a diagnosis of MS,” while Dr. AlTokis’ study “adds to and is consistent with the growing literature of pathological associations of paramagnetic rim lesions in MS.”

Dr. Hemond added that the NAIMS cooperative plans to publish guidance in the area in the coming months.

“Although paramagnetic rim lesions have strong pathological associations in MS, it remains unclear if the presence of these lesions should change MS clinical management at the present time,” he said.

During the NAIMS session, Francesca Bagnato, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn., noted the growing importance of the role of rim lesions in clinical research. “It is clear that these paramagnetic rim lesions are going to be the new biomarker for the next generation of clinical trials,” she said.

Dr. Renner’s study received funding from the Race to Erase MS Foundation. Dr. AlTokhis, Dr. Renner, and Dr. Hemond have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – Spinal cord atrophy, as detected on calibrated brain MRI scans, significantly correlates with silent progression of multiple sclerosis (MS) to progressive MS, new research shows. Study results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators noted.

“We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion,” said lead author Antje Bischof, MD, department of neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.

“Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy,” she added.

Dr. Bischof presented the findings at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Relatively new concept

Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.

However, a relapse-free “silent progression” of MS, described in previous research as occurring in as many as one-third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.

“Because the concept of silent progression is relatively new and directly challenges the long-accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice,” said coinvestigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco).

To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.

They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.

To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.

Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.
 

‘Strongest predictor’

The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).

Those who converted from RRMS to SPMS showed spinal atrophy rates of –2.19% per year, versus –0.88% per year among those who did not convert (P < .001).

“C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients,” Dr. Bischof said.

Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.

Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).

“These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression,” Dr. Bischof said. “Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures,” she said.
 

Standard of care?

While the unique MRI techniques used in the study may not be easily obtained in standard practice, Dr. Cree noted that efforts are underway to facilitate the process. “Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway,” he said.

Dr. Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care. “I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients,” he said.

“Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates,” Dr. Cree added.
 

Treatment implications

Commenting on the findings, ACTRIMS program cochair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal–Dr John Trotter MS Chair in Neuroimmunology, Washington University, St. Louis, noted that the study is important for two key reasons.

“We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient,” said Dr. Cross, who was not involved with the research.

Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. “Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS” is important, Dr. Cross said.

“We don’t want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years,” she added.

Also commenting on the findings, Benjamin Segal, MD, director of the University of Michigan’s Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights. “These findings are striking in that they underscore the fact that even patients with relapsing-remitting MS undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS,” Dr. Segal said.

He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, “is not so surprising, since clinical decline was measured using the EDSS scale – which emphasizes ambulation over other functions,” such as cognition.

“It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time,” Dr. Segal added.

Dr. Bischof and Dr. Segal have reported no relevant financial relationships. Dr. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – Spinal cord atrophy, as detected on calibrated brain MRI scans, significantly correlates with silent progression of multiple sclerosis (MS) to progressive MS, new research shows. Study results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators noted.

“We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion,” said lead author Antje Bischof, MD, department of neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.

“Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy,” she added.

Dr. Bischof presented the findings at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Relatively new concept

Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.

However, a relapse-free “silent progression” of MS, described in previous research as occurring in as many as one-third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.

“Because the concept of silent progression is relatively new and directly challenges the long-accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice,” said coinvestigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco).

To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.

They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.

To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.

Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.
 

‘Strongest predictor’

The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).

Those who converted from RRMS to SPMS showed spinal atrophy rates of –2.19% per year, versus –0.88% per year among those who did not convert (P < .001).

“C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients,” Dr. Bischof said.

Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.

Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).

“These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression,” Dr. Bischof said. “Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures,” she said.
 

Standard of care?

While the unique MRI techniques used in the study may not be easily obtained in standard practice, Dr. Cree noted that efforts are underway to facilitate the process. “Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway,” he said.

Dr. Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care. “I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients,” he said.

“Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates,” Dr. Cree added.
 

Treatment implications

Commenting on the findings, ACTRIMS program cochair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal–Dr John Trotter MS Chair in Neuroimmunology, Washington University, St. Louis, noted that the study is important for two key reasons.

“We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient,” said Dr. Cross, who was not involved with the research.

Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. “Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS” is important, Dr. Cross said.

“We don’t want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years,” she added.

Also commenting on the findings, Benjamin Segal, MD, director of the University of Michigan’s Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights. “These findings are striking in that they underscore the fact that even patients with relapsing-remitting MS undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS,” Dr. Segal said.

He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, “is not so surprising, since clinical decline was measured using the EDSS scale – which emphasizes ambulation over other functions,” such as cognition.

“It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time,” Dr. Segal added.

Dr. Bischof and Dr. Segal have reported no relevant financial relationships. Dr. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLA. – Spinal cord atrophy, as detected on calibrated brain MRI scans, significantly correlates with silent progression of multiple sclerosis (MS) to progressive MS, new research shows. Study results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators noted.

“We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion,” said lead author Antje Bischof, MD, department of neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.

“Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy,” she added.

Dr. Bischof presented the findings at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Relatively new concept

Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.

However, a relapse-free “silent progression” of MS, described in previous research as occurring in as many as one-third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.

“Because the concept of silent progression is relatively new and directly challenges the long-accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice,” said coinvestigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco).

To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.

They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.

To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.

Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.
 

‘Strongest predictor’

The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).

Those who converted from RRMS to SPMS showed spinal atrophy rates of –2.19% per year, versus –0.88% per year among those who did not convert (P < .001).

“C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients,” Dr. Bischof said.

Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.

Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).

“These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression,” Dr. Bischof said. “Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures,” she said.
 

Standard of care?

While the unique MRI techniques used in the study may not be easily obtained in standard practice, Dr. Cree noted that efforts are underway to facilitate the process. “Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway,” he said.

Dr. Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care. “I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients,” he said.

“Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates,” Dr. Cree added.
 

Treatment implications

Commenting on the findings, ACTRIMS program cochair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal–Dr John Trotter MS Chair in Neuroimmunology, Washington University, St. Louis, noted that the study is important for two key reasons.

“We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient,” said Dr. Cross, who was not involved with the research.

Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. “Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS” is important, Dr. Cross said.

“We don’t want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years,” she added.

Also commenting on the findings, Benjamin Segal, MD, director of the University of Michigan’s Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights. “These findings are striking in that they underscore the fact that even patients with relapsing-remitting MS undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS,” Dr. Segal said.

He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, “is not so surprising, since clinical decline was measured using the EDSS scale – which emphasizes ambulation over other functions,” such as cognition.

“It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time,” Dr. Segal added.

Dr. Bischof and Dr. Segal have reported no relevant financial relationships. Dr. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.

A version of this article first appeared on Medscape.com.

Key clinical point: Patients with multiple sclerosis (pwMS) who participated in a web-based mindfulness-based intervention (MBI) showed significant improvements in depressive symptoms and health-related quality of life (HRQoL).

Major finding: The MBI group showed a significant improvement in depressive symptoms compared with the waitlist (Cohen’s d 0.39; 95% CI, 0.034-0.742), with patients with recurrent depressive symptoms benefitting the most (P = .034). MBI had a positive effect on HRQoL regardless of previous depressive history (P = .009).

Study details: The findings come from a randomized controlled trial involving 132 pwMS with or without a history of recurrent depression, and who received either an internet-delivered MBI (n = 69) or were assigned to a waitlist (n = 63).

Disclosures: This study was supported by the National Health and Medical Research Council and Multiple Sclerosis Research, Australia. The authors declared no conflict of interests.

Source: Sesel AL et al. Mult Scler. 2022 (Feb 7). Doi:  10.1177/13524585211068002.

Key clinical point: Patients with multiple sclerosis (pwMS) who participated in a web-based mindfulness-based intervention (MBI) showed significant improvements in depressive symptoms and health-related quality of life (HRQoL).

Major finding: The MBI group showed a significant improvement in depressive symptoms compared with the waitlist (Cohen’s d 0.39; 95% CI, 0.034-0.742), with patients with recurrent depressive symptoms benefitting the most (P = .034). MBI had a positive effect on HRQoL regardless of previous depressive history (P = .009).

Study details: The findings come from a randomized controlled trial involving 132 pwMS with or without a history of recurrent depression, and who received either an internet-delivered MBI (n = 69) or were assigned to a waitlist (n = 63).

Disclosures: This study was supported by the National Health and Medical Research Council and Multiple Sclerosis Research, Australia. The authors declared no conflict of interests.

Source: Sesel AL et al. Mult Scler. 2022 (Feb 7). Doi:  10.1177/13524585211068002.

Key clinical point: Patients with multiple sclerosis (pwMS) who participated in a web-based mindfulness-based intervention (MBI) showed significant improvements in depressive symptoms and health-related quality of life (HRQoL).

Major finding: The MBI group showed a significant improvement in depressive symptoms compared with the waitlist (Cohen’s d 0.39; 95% CI, 0.034-0.742), with patients with recurrent depressive symptoms benefitting the most (P = .034). MBI had a positive effect on HRQoL regardless of previous depressive history (P = .009).

Study details: The findings come from a randomized controlled trial involving 132 pwMS with or without a history of recurrent depression, and who received either an internet-delivered MBI (n = 69) or were assigned to a waitlist (n = 63).

Disclosures: This study was supported by the National Health and Medical Research Council and Multiple Sclerosis Research, Australia. The authors declared no conflict of interests.

Source: Sesel AL et al. Mult Scler. 2022 (Feb 7). Doi:  10.1177/13524585211068002.