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Ocrelizumab benefit confirmed in older patients with MS
MILAN – they say.
The researchers studied about 700 patients with MS aged 60 years and older from an international database, comparing outcomes with the anti-CD20 monoclonal antibody ocrelizumab versus those for interferon/glatiramer acetate (BRACE). They found ocrelizumab significantly reduced the annual rate of relapses, although after adjustments, patients overall faced a relapse rate of less than 0.1 per year. There were also no significant differences in either disability progression or improvement between the two treatments.
“We believe this study is unique in that ocrelizumab demonstrates a very clear differential treatment benefit in this age group,” said study presenter Yi Chao Foong, MD, department of neuroscience, Monash University, Melbourne. “However, this has to be balanced against the fact that overall relapse activity is extremely low in people with MS over the age of 60. We believe that this study adds valuable, real-world data for nuanced benefit versus risk DMT discussions with for older adults with MS.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Lack of data in older patients
Dr. Fong explained the comparative efficacy of disease-modifying therapies (DMTs) has not been demonstrated in older people with MS, as all landmark trials to date have excluded people older than age 60 years. He underlined, however, that the inflammatory aspect of MS reduces with age, when neurodegenerative processes begin to predominate.
“This, combined with increased risk of acute infections in older adults have raised concerns over the benefit ratios of DMTs in this age group,” Dr. Fong said.
This has led to several de-escalation studies in older patients already on treatment for MS, but with “varied results.”
One study, published earlier in 2023, was unable to conclude whether DMT discontinuation was noninferior to continuation in older patients with no recent relapse or new MRI activity.
To investigate further, the Australian team used the MSBase database to study patients with a confirmed MS diagnosis who had started or switched to ocrelizumab or BRACE when older than 60 years of age.
They were also required to have undergone an Expanded Disability Status Scale (EDSS) assessment around the time of the initiation of DMT. In all, 675 patients met the inclusion criteria, of whom 248 started with ocrelizumab and 427 with BRACE.
The treatment groups were well balanced, although baseline EDSS scores were higher in patients given ocrelizumab, at 5.22 versus 3.89 with BRACE (P = .05), and they had a lower relapse rate prior in the year (P = .01) and 2 years (P = .02) prior to baseline.
Only relapse rates reduced
With more than 571 patient-years of follow-up, there were eight relapses in patients treated with ocrelizumab, compared with 182 relapses during 2238 patient-years among those given BRACE.
The team then performed propensity matching based on patient age, disease duration, sex, baseline EDSS, prior relapses, and prior DMTs.
They found that, over a median follow-up of 2.47 years for ocrelizumab and 4.48 years for BRACE, there was a lower rate of relapse with ocrelizumab, at a weighted annualized relapse rate of 0.01 versus 0.08 (P < .0001). This, they calculated, equated to an ARR ratio in favor of ocrelizumab of 0.15 (P < .01).
The time to first relapse was also longer for ocrelizumab versus BRACE, at a weighted hazard ratio for relapse of 0.11 (P < .001) and with, as Dr. Fong highlighted, separation of the curves at 5 months.
Over a follow-up duration of 3.6 years, there was, however, no significant difference in confirmed disability progression between the two treatments (P = .31), with similar results seen for confirmed disability improvement (P = .92).
Dr. Fong noted the study was limited by an inherent treatment indication bias, affecting the sensitivity analysis and weighing, while assessment of confirmed disability progression and confirmed disability improvement was hampered by the relatively short follow-up period and the lack of data on comorbidities.
He also highlighted the lack of safety data for the study population, as well as the lack of MRI.
Muddling the data
Approached for comment, Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, pointed out the study is based on retrospective data.
“The main question that we normally come up against in clinical practice, once people are older, is: What do you do with their treatment?” he asked.
This, Dr. Bhargava said, was the question that was addressed in the previous de-escalation studies.
The current study “actually answered a completely different question: If you were starting or changing a treatment after 60, which one would be better to choose?” This is a “much rarer scenario,” he said.
The results nevertheless showed what is seen in younger patients; in other words, “a more efficacious treatment is more effective at reducing relapses than a less efficacious treatment, even though overall the number of relapses is quite low,” Dr. Bhargava said.
“The other problem,” he added, is the study included “not just relapsing but also progressive patients, so that kind of muddles the data a little bit.”
Consequently, “it’s hard to really make a definitive conclusion” from the results, Dr. Bhargava concluded.
No funding was declared. Dr. Fong declares relationships with Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia, and the Australian and New Zealand Association of Neurologists. Several coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – they say.
The researchers studied about 700 patients with MS aged 60 years and older from an international database, comparing outcomes with the anti-CD20 monoclonal antibody ocrelizumab versus those for interferon/glatiramer acetate (BRACE). They found ocrelizumab significantly reduced the annual rate of relapses, although after adjustments, patients overall faced a relapse rate of less than 0.1 per year. There were also no significant differences in either disability progression or improvement between the two treatments.
“We believe this study is unique in that ocrelizumab demonstrates a very clear differential treatment benefit in this age group,” said study presenter Yi Chao Foong, MD, department of neuroscience, Monash University, Melbourne. “However, this has to be balanced against the fact that overall relapse activity is extremely low in people with MS over the age of 60. We believe that this study adds valuable, real-world data for nuanced benefit versus risk DMT discussions with for older adults with MS.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Lack of data in older patients
Dr. Fong explained the comparative efficacy of disease-modifying therapies (DMTs) has not been demonstrated in older people with MS, as all landmark trials to date have excluded people older than age 60 years. He underlined, however, that the inflammatory aspect of MS reduces with age, when neurodegenerative processes begin to predominate.
“This, combined with increased risk of acute infections in older adults have raised concerns over the benefit ratios of DMTs in this age group,” Dr. Fong said.
This has led to several de-escalation studies in older patients already on treatment for MS, but with “varied results.”
One study, published earlier in 2023, was unable to conclude whether DMT discontinuation was noninferior to continuation in older patients with no recent relapse or new MRI activity.
To investigate further, the Australian team used the MSBase database to study patients with a confirmed MS diagnosis who had started or switched to ocrelizumab or BRACE when older than 60 years of age.
They were also required to have undergone an Expanded Disability Status Scale (EDSS) assessment around the time of the initiation of DMT. In all, 675 patients met the inclusion criteria, of whom 248 started with ocrelizumab and 427 with BRACE.
The treatment groups were well balanced, although baseline EDSS scores were higher in patients given ocrelizumab, at 5.22 versus 3.89 with BRACE (P = .05), and they had a lower relapse rate prior in the year (P = .01) and 2 years (P = .02) prior to baseline.
Only relapse rates reduced
With more than 571 patient-years of follow-up, there were eight relapses in patients treated with ocrelizumab, compared with 182 relapses during 2238 patient-years among those given BRACE.
The team then performed propensity matching based on patient age, disease duration, sex, baseline EDSS, prior relapses, and prior DMTs.
They found that, over a median follow-up of 2.47 years for ocrelizumab and 4.48 years for BRACE, there was a lower rate of relapse with ocrelizumab, at a weighted annualized relapse rate of 0.01 versus 0.08 (P < .0001). This, they calculated, equated to an ARR ratio in favor of ocrelizumab of 0.15 (P < .01).
The time to first relapse was also longer for ocrelizumab versus BRACE, at a weighted hazard ratio for relapse of 0.11 (P < .001) and with, as Dr. Fong highlighted, separation of the curves at 5 months.
Over a follow-up duration of 3.6 years, there was, however, no significant difference in confirmed disability progression between the two treatments (P = .31), with similar results seen for confirmed disability improvement (P = .92).
Dr. Fong noted the study was limited by an inherent treatment indication bias, affecting the sensitivity analysis and weighing, while assessment of confirmed disability progression and confirmed disability improvement was hampered by the relatively short follow-up period and the lack of data on comorbidities.
He also highlighted the lack of safety data for the study population, as well as the lack of MRI.
Muddling the data
Approached for comment, Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, pointed out the study is based on retrospective data.
“The main question that we normally come up against in clinical practice, once people are older, is: What do you do with their treatment?” he asked.
This, Dr. Bhargava said, was the question that was addressed in the previous de-escalation studies.
The current study “actually answered a completely different question: If you were starting or changing a treatment after 60, which one would be better to choose?” This is a “much rarer scenario,” he said.
The results nevertheless showed what is seen in younger patients; in other words, “a more efficacious treatment is more effective at reducing relapses than a less efficacious treatment, even though overall the number of relapses is quite low,” Dr. Bhargava said.
“The other problem,” he added, is the study included “not just relapsing but also progressive patients, so that kind of muddles the data a little bit.”
Consequently, “it’s hard to really make a definitive conclusion” from the results, Dr. Bhargava concluded.
No funding was declared. Dr. Fong declares relationships with Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia, and the Australian and New Zealand Association of Neurologists. Several coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – they say.
The researchers studied about 700 patients with MS aged 60 years and older from an international database, comparing outcomes with the anti-CD20 monoclonal antibody ocrelizumab versus those for interferon/glatiramer acetate (BRACE). They found ocrelizumab significantly reduced the annual rate of relapses, although after adjustments, patients overall faced a relapse rate of less than 0.1 per year. There were also no significant differences in either disability progression or improvement between the two treatments.
“We believe this study is unique in that ocrelizumab demonstrates a very clear differential treatment benefit in this age group,” said study presenter Yi Chao Foong, MD, department of neuroscience, Monash University, Melbourne. “However, this has to be balanced against the fact that overall relapse activity is extremely low in people with MS over the age of 60. We believe that this study adds valuable, real-world data for nuanced benefit versus risk DMT discussions with for older adults with MS.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Lack of data in older patients
Dr. Fong explained the comparative efficacy of disease-modifying therapies (DMTs) has not been demonstrated in older people with MS, as all landmark trials to date have excluded people older than age 60 years. He underlined, however, that the inflammatory aspect of MS reduces with age, when neurodegenerative processes begin to predominate.
“This, combined with increased risk of acute infections in older adults have raised concerns over the benefit ratios of DMTs in this age group,” Dr. Fong said.
This has led to several de-escalation studies in older patients already on treatment for MS, but with “varied results.”
One study, published earlier in 2023, was unable to conclude whether DMT discontinuation was noninferior to continuation in older patients with no recent relapse or new MRI activity.
To investigate further, the Australian team used the MSBase database to study patients with a confirmed MS diagnosis who had started or switched to ocrelizumab or BRACE when older than 60 years of age.
They were also required to have undergone an Expanded Disability Status Scale (EDSS) assessment around the time of the initiation of DMT. In all, 675 patients met the inclusion criteria, of whom 248 started with ocrelizumab and 427 with BRACE.
The treatment groups were well balanced, although baseline EDSS scores were higher in patients given ocrelizumab, at 5.22 versus 3.89 with BRACE (P = .05), and they had a lower relapse rate prior in the year (P = .01) and 2 years (P = .02) prior to baseline.
Only relapse rates reduced
With more than 571 patient-years of follow-up, there were eight relapses in patients treated with ocrelizumab, compared with 182 relapses during 2238 patient-years among those given BRACE.
The team then performed propensity matching based on patient age, disease duration, sex, baseline EDSS, prior relapses, and prior DMTs.
They found that, over a median follow-up of 2.47 years for ocrelizumab and 4.48 years for BRACE, there was a lower rate of relapse with ocrelizumab, at a weighted annualized relapse rate of 0.01 versus 0.08 (P < .0001). This, they calculated, equated to an ARR ratio in favor of ocrelizumab of 0.15 (P < .01).
The time to first relapse was also longer for ocrelizumab versus BRACE, at a weighted hazard ratio for relapse of 0.11 (P < .001) and with, as Dr. Fong highlighted, separation of the curves at 5 months.
Over a follow-up duration of 3.6 years, there was, however, no significant difference in confirmed disability progression between the two treatments (P = .31), with similar results seen for confirmed disability improvement (P = .92).
Dr. Fong noted the study was limited by an inherent treatment indication bias, affecting the sensitivity analysis and weighing, while assessment of confirmed disability progression and confirmed disability improvement was hampered by the relatively short follow-up period and the lack of data on comorbidities.
He also highlighted the lack of safety data for the study population, as well as the lack of MRI.
Muddling the data
Approached for comment, Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, pointed out the study is based on retrospective data.
“The main question that we normally come up against in clinical practice, once people are older, is: What do you do with their treatment?” he asked.
This, Dr. Bhargava said, was the question that was addressed in the previous de-escalation studies.
The current study “actually answered a completely different question: If you were starting or changing a treatment after 60, which one would be better to choose?” This is a “much rarer scenario,” he said.
The results nevertheless showed what is seen in younger patients; in other words, “a more efficacious treatment is more effective at reducing relapses than a less efficacious treatment, even though overall the number of relapses is quite low,” Dr. Bhargava said.
“The other problem,” he added, is the study included “not just relapsing but also progressive patients, so that kind of muddles the data a little bit.”
Consequently, “it’s hard to really make a definitive conclusion” from the results, Dr. Bhargava concluded.
No funding was declared. Dr. Fong declares relationships with Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia, and the Australian and New Zealand Association of Neurologists. Several coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
AT ECTRIMS 2023
Obesity linked to multiple ills in MS study
MILAN – Swedish researchers reported at the 9th Joint ECTRIMS-ACTRIMS meeting.
In a group of 3,249 subjects tracked for up to 5 years (74% female; mean age, 37.8 years), patients who were obese at diagnosis were 1.41 times more likely than normal-weight patients to reach an Expanded Disability Status Scale (EDSS) score of 3. About 35% of 355 obese subjects (body mass index > 30 kg/m2) reached that level versus 29% of 713 overweight patients (BMI, 25-30) and 28% of 1,475 normal-weight patients (BMI, 18.5-24.99).
Among subjects whose BMI category didn’t change over follow-up, those who were obese at diagnosis were more likely to develop cognitive worsening than those who weren’t obese (hazard ratio, 1.47, 95% confidence interval, 1.08-2.01).
Lars Alfredsson, PhD, a professor at the Karolinska Institutet, Stockholm, who presented the study findings, said in an interview that they fill a gap in knowledge about obesity and MS. “It is known that obesity around the age of 20 or in adolescence is a risk factor for developing MS. But much less is known in regard to progression, and the studies have been very inconclusive.”
The researchers tracked patients via the Swedish MS registry: 1,475 of normal weight, 713 overweight, and 355 obese. Before adjustment for factors such as age, gender, and baseline EDSS, obese subjects were 1.51 times more likely to reach EDSS score 3 than normal-weight subjects.
Obese subjects whose BMI level didn’t change over time were 1.70 times more likely than the nonobese to develop physical worsening as measured by an increased Multiple Sclerosis Impact Scale physical score of 7.5 points or more, and they were 1.36 times more likely to have psychological worsening as measured by increased MSIS-28 psychological score of 7.5 points or more.
Also, among subjects whose BMI didn’t change over time, the likelihood of cognitive disability worsening was 1.47 times higher among obese participants versus nonobese participants. Worsening was defined as an increased Symbol Digit Modalities Test score of 8 points or more.
The level of excess cognitive decline “will affect people significantly,” Dr. Alfredsson said.
While obesity can counterintuitively provide a protective effect in some diseases, he said there’s no sign of such an effect in the subjects.
As for limitations, Dr. Alfredsson noted in his presentation that BMI data is self-reported, and it’s possible that the researchers didn’t adjust their statistics to reflect important confounders.
A 2023 German study of outcomes in MS patients with obesity came to similar conclusions. It tracked 1,066 subjects for up to 6 years and found that “median time to reach EDSS 3 was 0.99 years for patients with BMI of 30 or higher and 1.46 years for nonobese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI of at least 30, compared with patients with BMI less than 30 after adjustment for sex, age, smoking (HR, 1.87; 95% CI, 1.3-2.6; P < .001), and independent of disease-modifying therapies.”
However, the German researchers found no link between obesity and higher levels of relapse, contrast-enhancing MRI lesions, or MRI T2 lesion burden.
Interpretation and commentary
Could obesity be causing worse outcomes? The new study doesn’t provide insight into cause and effect. However, obesity may speed up progression via low-grade inflammation, Dr. Alfredsson said.
What can clinicians do with the information from the study? If patients are obese, it can be a good idea to more carefully monitor them and use reliable tools to improve their progression, Dr. Alfredsson said.
In an interview, Michael D. Kornberg, MD, PhD, an assistant professor of neurology at Johns Hopkins University, Baltimore, who was not involved with the study, agreed with Dr. Alfredsson that other research has linked obesity early in life to higher rates of MS. He added that “a number of studies have shown that comorbidities in general are usually associated with a higher rate of disability.”
Dr. Kornberg said the new research is important, and he noted that it has a “robust” cohort because of its larger size.
Could patients with MS reverse the risk of progression and other poor outcomes by losing weight? “It’s hard to say,” Dr. Kornberg said. “We have to be cautious when we assume causation. There’s a plausible rationale that obesity might worsen progression in MS, but it could just be a marker of some other factor that reflects a different phenotype of MS.”
He doesn’t think it’s likely that weight loss would “dramatically reverse the biology of MS,” but he said reversing the obesity epidemic would still be a good thing. An interventional study could examine the effects of weight-loss intervention on disability measures, he said, “and that’s the next step.”
Also contacted for commentary, Adil Harroud, MD, a neurologist at McGill University who studies obesity in MS, said research suggests that “obesity seems to exacerbate MS disability. While some studies show no effect, the majority indicate a detrimental impact.”
However, “the effect of obesity on MS progression remains unclear. Animal studies suggest that shifts in immune cell subsets and functions may play a role, but the relevance to humans is yet to be determined,” he said.
Dr. Harroud, who did not take part in the new study, said it’s “one of the largest examining the impact of obesity on MS disability.” He added that “the cohort was relatively early in their disease course, suggesting that obesity impacts even the early stages of MS. This underscores the importance of obesity as a modifiable risk factor for disability accumulation.”
As for why obesity affects MS, he said one theory is that obesity plays a role through its impact on vitamin D levels. “However, using a genetic approach, we have demonstrated that, at least for MS risk, the effect of obesity is independent of vitamin D. This is also likely true for MS progression, as recent trials of vitamin D supplementation have not shown a meaningful impact on MS outcomes.”
According to Dr. Harroud, “other theories suggest that obesity leads to a pro-inflammatory immune shift. Additionally, it has been proposed that obesity may influence the response to disease-modifying therapy by reducing drug bioavailability, potentially necessitating weight-based dosing for some therapies.”
Dr. Alfredsson reported receiving grants from the Swedish Research Council, the Swedish Research Council for Health Working Life and Welfare, and the Swedish Brain Foundation and personal fees from Teva and Biogene Idec. Some of the other study authors reported various disclosures. Dr. Kornberg and Dr. Harroud reported no relevant disclosures.
This article was updated 10/20/23.
MILAN – Swedish researchers reported at the 9th Joint ECTRIMS-ACTRIMS meeting.
In a group of 3,249 subjects tracked for up to 5 years (74% female; mean age, 37.8 years), patients who were obese at diagnosis were 1.41 times more likely than normal-weight patients to reach an Expanded Disability Status Scale (EDSS) score of 3. About 35% of 355 obese subjects (body mass index > 30 kg/m2) reached that level versus 29% of 713 overweight patients (BMI, 25-30) and 28% of 1,475 normal-weight patients (BMI, 18.5-24.99).
Among subjects whose BMI category didn’t change over follow-up, those who were obese at diagnosis were more likely to develop cognitive worsening than those who weren’t obese (hazard ratio, 1.47, 95% confidence interval, 1.08-2.01).
Lars Alfredsson, PhD, a professor at the Karolinska Institutet, Stockholm, who presented the study findings, said in an interview that they fill a gap in knowledge about obesity and MS. “It is known that obesity around the age of 20 or in adolescence is a risk factor for developing MS. But much less is known in regard to progression, and the studies have been very inconclusive.”
The researchers tracked patients via the Swedish MS registry: 1,475 of normal weight, 713 overweight, and 355 obese. Before adjustment for factors such as age, gender, and baseline EDSS, obese subjects were 1.51 times more likely to reach EDSS score 3 than normal-weight subjects.
Obese subjects whose BMI level didn’t change over time were 1.70 times more likely than the nonobese to develop physical worsening as measured by an increased Multiple Sclerosis Impact Scale physical score of 7.5 points or more, and they were 1.36 times more likely to have psychological worsening as measured by increased MSIS-28 psychological score of 7.5 points or more.
Also, among subjects whose BMI didn’t change over time, the likelihood of cognitive disability worsening was 1.47 times higher among obese participants versus nonobese participants. Worsening was defined as an increased Symbol Digit Modalities Test score of 8 points or more.
The level of excess cognitive decline “will affect people significantly,” Dr. Alfredsson said.
While obesity can counterintuitively provide a protective effect in some diseases, he said there’s no sign of such an effect in the subjects.
As for limitations, Dr. Alfredsson noted in his presentation that BMI data is self-reported, and it’s possible that the researchers didn’t adjust their statistics to reflect important confounders.
A 2023 German study of outcomes in MS patients with obesity came to similar conclusions. It tracked 1,066 subjects for up to 6 years and found that “median time to reach EDSS 3 was 0.99 years for patients with BMI of 30 or higher and 1.46 years for nonobese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI of at least 30, compared with patients with BMI less than 30 after adjustment for sex, age, smoking (HR, 1.87; 95% CI, 1.3-2.6; P < .001), and independent of disease-modifying therapies.”
However, the German researchers found no link between obesity and higher levels of relapse, contrast-enhancing MRI lesions, or MRI T2 lesion burden.
Interpretation and commentary
Could obesity be causing worse outcomes? The new study doesn’t provide insight into cause and effect. However, obesity may speed up progression via low-grade inflammation, Dr. Alfredsson said.
What can clinicians do with the information from the study? If patients are obese, it can be a good idea to more carefully monitor them and use reliable tools to improve their progression, Dr. Alfredsson said.
In an interview, Michael D. Kornberg, MD, PhD, an assistant professor of neurology at Johns Hopkins University, Baltimore, who was not involved with the study, agreed with Dr. Alfredsson that other research has linked obesity early in life to higher rates of MS. He added that “a number of studies have shown that comorbidities in general are usually associated with a higher rate of disability.”
Dr. Kornberg said the new research is important, and he noted that it has a “robust” cohort because of its larger size.
Could patients with MS reverse the risk of progression and other poor outcomes by losing weight? “It’s hard to say,” Dr. Kornberg said. “We have to be cautious when we assume causation. There’s a plausible rationale that obesity might worsen progression in MS, but it could just be a marker of some other factor that reflects a different phenotype of MS.”
He doesn’t think it’s likely that weight loss would “dramatically reverse the biology of MS,” but he said reversing the obesity epidemic would still be a good thing. An interventional study could examine the effects of weight-loss intervention on disability measures, he said, “and that’s the next step.”
Also contacted for commentary, Adil Harroud, MD, a neurologist at McGill University who studies obesity in MS, said research suggests that “obesity seems to exacerbate MS disability. While some studies show no effect, the majority indicate a detrimental impact.”
However, “the effect of obesity on MS progression remains unclear. Animal studies suggest that shifts in immune cell subsets and functions may play a role, but the relevance to humans is yet to be determined,” he said.
Dr. Harroud, who did not take part in the new study, said it’s “one of the largest examining the impact of obesity on MS disability.” He added that “the cohort was relatively early in their disease course, suggesting that obesity impacts even the early stages of MS. This underscores the importance of obesity as a modifiable risk factor for disability accumulation.”
As for why obesity affects MS, he said one theory is that obesity plays a role through its impact on vitamin D levels. “However, using a genetic approach, we have demonstrated that, at least for MS risk, the effect of obesity is independent of vitamin D. This is also likely true for MS progression, as recent trials of vitamin D supplementation have not shown a meaningful impact on MS outcomes.”
According to Dr. Harroud, “other theories suggest that obesity leads to a pro-inflammatory immune shift. Additionally, it has been proposed that obesity may influence the response to disease-modifying therapy by reducing drug bioavailability, potentially necessitating weight-based dosing for some therapies.”
Dr. Alfredsson reported receiving grants from the Swedish Research Council, the Swedish Research Council for Health Working Life and Welfare, and the Swedish Brain Foundation and personal fees from Teva and Biogene Idec. Some of the other study authors reported various disclosures. Dr. Kornberg and Dr. Harroud reported no relevant disclosures.
This article was updated 10/20/23.
MILAN – Swedish researchers reported at the 9th Joint ECTRIMS-ACTRIMS meeting.
In a group of 3,249 subjects tracked for up to 5 years (74% female; mean age, 37.8 years), patients who were obese at diagnosis were 1.41 times more likely than normal-weight patients to reach an Expanded Disability Status Scale (EDSS) score of 3. About 35% of 355 obese subjects (body mass index > 30 kg/m2) reached that level versus 29% of 713 overweight patients (BMI, 25-30) and 28% of 1,475 normal-weight patients (BMI, 18.5-24.99).
Among subjects whose BMI category didn’t change over follow-up, those who were obese at diagnosis were more likely to develop cognitive worsening than those who weren’t obese (hazard ratio, 1.47, 95% confidence interval, 1.08-2.01).
Lars Alfredsson, PhD, a professor at the Karolinska Institutet, Stockholm, who presented the study findings, said in an interview that they fill a gap in knowledge about obesity and MS. “It is known that obesity around the age of 20 or in adolescence is a risk factor for developing MS. But much less is known in regard to progression, and the studies have been very inconclusive.”
The researchers tracked patients via the Swedish MS registry: 1,475 of normal weight, 713 overweight, and 355 obese. Before adjustment for factors such as age, gender, and baseline EDSS, obese subjects were 1.51 times more likely to reach EDSS score 3 than normal-weight subjects.
Obese subjects whose BMI level didn’t change over time were 1.70 times more likely than the nonobese to develop physical worsening as measured by an increased Multiple Sclerosis Impact Scale physical score of 7.5 points or more, and they were 1.36 times more likely to have psychological worsening as measured by increased MSIS-28 psychological score of 7.5 points or more.
Also, among subjects whose BMI didn’t change over time, the likelihood of cognitive disability worsening was 1.47 times higher among obese participants versus nonobese participants. Worsening was defined as an increased Symbol Digit Modalities Test score of 8 points or more.
The level of excess cognitive decline “will affect people significantly,” Dr. Alfredsson said.
While obesity can counterintuitively provide a protective effect in some diseases, he said there’s no sign of such an effect in the subjects.
As for limitations, Dr. Alfredsson noted in his presentation that BMI data is self-reported, and it’s possible that the researchers didn’t adjust their statistics to reflect important confounders.
A 2023 German study of outcomes in MS patients with obesity came to similar conclusions. It tracked 1,066 subjects for up to 6 years and found that “median time to reach EDSS 3 was 0.99 years for patients with BMI of 30 or higher and 1.46 years for nonobese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI of at least 30, compared with patients with BMI less than 30 after adjustment for sex, age, smoking (HR, 1.87; 95% CI, 1.3-2.6; P < .001), and independent of disease-modifying therapies.”
However, the German researchers found no link between obesity and higher levels of relapse, contrast-enhancing MRI lesions, or MRI T2 lesion burden.
Interpretation and commentary
Could obesity be causing worse outcomes? The new study doesn’t provide insight into cause and effect. However, obesity may speed up progression via low-grade inflammation, Dr. Alfredsson said.
What can clinicians do with the information from the study? If patients are obese, it can be a good idea to more carefully monitor them and use reliable tools to improve their progression, Dr. Alfredsson said.
In an interview, Michael D. Kornberg, MD, PhD, an assistant professor of neurology at Johns Hopkins University, Baltimore, who was not involved with the study, agreed with Dr. Alfredsson that other research has linked obesity early in life to higher rates of MS. He added that “a number of studies have shown that comorbidities in general are usually associated with a higher rate of disability.”
Dr. Kornberg said the new research is important, and he noted that it has a “robust” cohort because of its larger size.
Could patients with MS reverse the risk of progression and other poor outcomes by losing weight? “It’s hard to say,” Dr. Kornberg said. “We have to be cautious when we assume causation. There’s a plausible rationale that obesity might worsen progression in MS, but it could just be a marker of some other factor that reflects a different phenotype of MS.”
He doesn’t think it’s likely that weight loss would “dramatically reverse the biology of MS,” but he said reversing the obesity epidemic would still be a good thing. An interventional study could examine the effects of weight-loss intervention on disability measures, he said, “and that’s the next step.”
Also contacted for commentary, Adil Harroud, MD, a neurologist at McGill University who studies obesity in MS, said research suggests that “obesity seems to exacerbate MS disability. While some studies show no effect, the majority indicate a detrimental impact.”
However, “the effect of obesity on MS progression remains unclear. Animal studies suggest that shifts in immune cell subsets and functions may play a role, but the relevance to humans is yet to be determined,” he said.
Dr. Harroud, who did not take part in the new study, said it’s “one of the largest examining the impact of obesity on MS disability.” He added that “the cohort was relatively early in their disease course, suggesting that obesity impacts even the early stages of MS. This underscores the importance of obesity as a modifiable risk factor for disability accumulation.”
As for why obesity affects MS, he said one theory is that obesity plays a role through its impact on vitamin D levels. “However, using a genetic approach, we have demonstrated that, at least for MS risk, the effect of obesity is independent of vitamin D. This is also likely true for MS progression, as recent trials of vitamin D supplementation have not shown a meaningful impact on MS outcomes.”
According to Dr. Harroud, “other theories suggest that obesity leads to a pro-inflammatory immune shift. Additionally, it has been proposed that obesity may influence the response to disease-modifying therapy by reducing drug bioavailability, potentially necessitating weight-based dosing for some therapies.”
Dr. Alfredsson reported receiving grants from the Swedish Research Council, the Swedish Research Council for Health Working Life and Welfare, and the Swedish Brain Foundation and personal fees from Teva and Biogene Idec. Some of the other study authors reported various disclosures. Dr. Kornberg and Dr. Harroud reported no relevant disclosures.
This article was updated 10/20/23.
AT ECTRIMS 2023
DMT discontinuation trial halted; MS returned in 17.8%
MILAN –
In the multicenter, randomized, controlled, noninferiority DOT-MS trial, inflammatory activity came back in 17.8% of 45 participants who discontinued DMT, researchers reported at the 9th Joint ECTRIMS-ACTRIMS Meeting.
“Because the number of participants with active disease – relapse or MRI activity – was higher in the discontinuation group, and this difference between the groups exceeded our predefined threshold, we prematurely terminated the trial in its current form,” said Eline Coerver, a graduate student with VU University Amsterdam, in an interview.
Previous studies have offered a mixed picture about whether stopping DMT is a good idea when patients with MS are doing well.
“Observational studies suggest that discontinuation of first-line DMTs, or platform therapies, might be safe in patients with MS who have been stable for a long period of time, meaning they did not have any clinical relapses or inflammatory MRI activity – new or contrast-enhancing lesions on MRI,” Ms. Coerver said. “These studies also suggest that patients with higher age have a lower risk of disease activity after DMT discontinuation.”
Discontinuation of DMTs can spare patients from side effects and the cost of the drugs. However, a phase 4 trial published earlier this year in The Lancet Neurology could not determine that stopping DMTs is noninferior to continuing treatment in patients with MS aged 55 and older.
“Six (4.7%) of 128 participants in the continue group and 16 (12.2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years,” the researchers reported.
For the new study, Ms. Coerver and colleagues recruited patients with relapse-onset MS aged 18 years or older who hadn’t had any relapses or substantial MRI activity in the last 5 years. The subjects were randomly assigned to discontinue DMT (interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate) or continue taking the therapy for 2 years.
At pre-set interim analyses, the researchers would look for signs of inflammatory disease activity, which they defined as a confirmed relapse or three or more new T2-lesions or two or more contrast-enhancing lesions detected via MRI.
At the time of cessation in March 2023 (median follow-up = 12.0 months, interquartile range 7.0-20.0), the study had recruited 89 subjects: 67.4% female, mean age 53 (SD, 7.8). Just over half (50.6%) were randomized to discontinue treatment. Of the 45 in the discontinuation group, 8 (17.8%) developed inflammatory activity (7 significant MRI activity, 2 relapses) versus none of the 44 who continued therapy.
Interpreting the results
Two MS clinicians who are familiar with the study findings but weren’t involved with the research were reached for comment.
Katherine Knox, MD, a physiatrist and associate professor who specializes in MS care at the University of Saskatchewan, Saskatoon, said in an interview that the new study is useful “because it affirms that an appropriate stopping recommendation cannot be made primarily on the basis of a standard number of years without disease activity.”
In regard to the percentage of patients who had a recurrence of inflammatory activity (17.8%), Dr. Knox said “ideally patients can be triaged for stopping therapy appropriately with a much lower risk for return of disease activity based on their individual risk factors – i.e., under 2%.”
Michael J. Olek, DO, associate professor of neurology at Touro University Nevada, Henderson, took a different view. He said he does not discontinue medication in patients with MS even if they’re stable for 5 years.
“I am waiting for trials that show that discontinuing medication is OK for the patient. To date, there are no studies showing that stopping medication is a good idea,” he said. “The immune systems slows as people age, so there may be a point in a person’s lifetime when medication used to slow the immune system is no longer needed. But until then I will continue medication for all multiple sclerosis patients.”
Moving forward, study lead author Ms. Coerver said “there are large differences between patients, and there is still room for discussion regarding what percentage of disease activity can be accepted after DMT discontinuation. The most important point is to inform patients about the risks of discontinuation so that each individual patient can make a well-informed decision.”
The study was funded by the Netherlands Organization for Health Research and Development and Stichting MS Research. Ms. Coerver reports no disclosures; some other study authors report various disclosures. Dr. Olek reports no disclosures. Dr. Knox discloses research funding from the Saskatchewan Ministry of Health to evaluate and monitor long-term outcomes in MS.
MILAN –
In the multicenter, randomized, controlled, noninferiority DOT-MS trial, inflammatory activity came back in 17.8% of 45 participants who discontinued DMT, researchers reported at the 9th Joint ECTRIMS-ACTRIMS Meeting.
“Because the number of participants with active disease – relapse or MRI activity – was higher in the discontinuation group, and this difference between the groups exceeded our predefined threshold, we prematurely terminated the trial in its current form,” said Eline Coerver, a graduate student with VU University Amsterdam, in an interview.
Previous studies have offered a mixed picture about whether stopping DMT is a good idea when patients with MS are doing well.
“Observational studies suggest that discontinuation of first-line DMTs, or platform therapies, might be safe in patients with MS who have been stable for a long period of time, meaning they did not have any clinical relapses or inflammatory MRI activity – new or contrast-enhancing lesions on MRI,” Ms. Coerver said. “These studies also suggest that patients with higher age have a lower risk of disease activity after DMT discontinuation.”
Discontinuation of DMTs can spare patients from side effects and the cost of the drugs. However, a phase 4 trial published earlier this year in The Lancet Neurology could not determine that stopping DMTs is noninferior to continuing treatment in patients with MS aged 55 and older.
“Six (4.7%) of 128 participants in the continue group and 16 (12.2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years,” the researchers reported.
For the new study, Ms. Coerver and colleagues recruited patients with relapse-onset MS aged 18 years or older who hadn’t had any relapses or substantial MRI activity in the last 5 years. The subjects were randomly assigned to discontinue DMT (interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate) or continue taking the therapy for 2 years.
At pre-set interim analyses, the researchers would look for signs of inflammatory disease activity, which they defined as a confirmed relapse or three or more new T2-lesions or two or more contrast-enhancing lesions detected via MRI.
At the time of cessation in March 2023 (median follow-up = 12.0 months, interquartile range 7.0-20.0), the study had recruited 89 subjects: 67.4% female, mean age 53 (SD, 7.8). Just over half (50.6%) were randomized to discontinue treatment. Of the 45 in the discontinuation group, 8 (17.8%) developed inflammatory activity (7 significant MRI activity, 2 relapses) versus none of the 44 who continued therapy.
Interpreting the results
Two MS clinicians who are familiar with the study findings but weren’t involved with the research were reached for comment.
Katherine Knox, MD, a physiatrist and associate professor who specializes in MS care at the University of Saskatchewan, Saskatoon, said in an interview that the new study is useful “because it affirms that an appropriate stopping recommendation cannot be made primarily on the basis of a standard number of years without disease activity.”
In regard to the percentage of patients who had a recurrence of inflammatory activity (17.8%), Dr. Knox said “ideally patients can be triaged for stopping therapy appropriately with a much lower risk for return of disease activity based on their individual risk factors – i.e., under 2%.”
Michael J. Olek, DO, associate professor of neurology at Touro University Nevada, Henderson, took a different view. He said he does not discontinue medication in patients with MS even if they’re stable for 5 years.
“I am waiting for trials that show that discontinuing medication is OK for the patient. To date, there are no studies showing that stopping medication is a good idea,” he said. “The immune systems slows as people age, so there may be a point in a person’s lifetime when medication used to slow the immune system is no longer needed. But until then I will continue medication for all multiple sclerosis patients.”
Moving forward, study lead author Ms. Coerver said “there are large differences between patients, and there is still room for discussion regarding what percentage of disease activity can be accepted after DMT discontinuation. The most important point is to inform patients about the risks of discontinuation so that each individual patient can make a well-informed decision.”
The study was funded by the Netherlands Organization for Health Research and Development and Stichting MS Research. Ms. Coerver reports no disclosures; some other study authors report various disclosures. Dr. Olek reports no disclosures. Dr. Knox discloses research funding from the Saskatchewan Ministry of Health to evaluate and monitor long-term outcomes in MS.
MILAN –
In the multicenter, randomized, controlled, noninferiority DOT-MS trial, inflammatory activity came back in 17.8% of 45 participants who discontinued DMT, researchers reported at the 9th Joint ECTRIMS-ACTRIMS Meeting.
“Because the number of participants with active disease – relapse or MRI activity – was higher in the discontinuation group, and this difference between the groups exceeded our predefined threshold, we prematurely terminated the trial in its current form,” said Eline Coerver, a graduate student with VU University Amsterdam, in an interview.
Previous studies have offered a mixed picture about whether stopping DMT is a good idea when patients with MS are doing well.
“Observational studies suggest that discontinuation of first-line DMTs, or platform therapies, might be safe in patients with MS who have been stable for a long period of time, meaning they did not have any clinical relapses or inflammatory MRI activity – new or contrast-enhancing lesions on MRI,” Ms. Coerver said. “These studies also suggest that patients with higher age have a lower risk of disease activity after DMT discontinuation.”
Discontinuation of DMTs can spare patients from side effects and the cost of the drugs. However, a phase 4 trial published earlier this year in The Lancet Neurology could not determine that stopping DMTs is noninferior to continuing treatment in patients with MS aged 55 and older.
“Six (4.7%) of 128 participants in the continue group and 16 (12.2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years,” the researchers reported.
For the new study, Ms. Coerver and colleagues recruited patients with relapse-onset MS aged 18 years or older who hadn’t had any relapses or substantial MRI activity in the last 5 years. The subjects were randomly assigned to discontinue DMT (interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate) or continue taking the therapy for 2 years.
At pre-set interim analyses, the researchers would look for signs of inflammatory disease activity, which they defined as a confirmed relapse or three or more new T2-lesions or two or more contrast-enhancing lesions detected via MRI.
At the time of cessation in March 2023 (median follow-up = 12.0 months, interquartile range 7.0-20.0), the study had recruited 89 subjects: 67.4% female, mean age 53 (SD, 7.8). Just over half (50.6%) were randomized to discontinue treatment. Of the 45 in the discontinuation group, 8 (17.8%) developed inflammatory activity (7 significant MRI activity, 2 relapses) versus none of the 44 who continued therapy.
Interpreting the results
Two MS clinicians who are familiar with the study findings but weren’t involved with the research were reached for comment.
Katherine Knox, MD, a physiatrist and associate professor who specializes in MS care at the University of Saskatchewan, Saskatoon, said in an interview that the new study is useful “because it affirms that an appropriate stopping recommendation cannot be made primarily on the basis of a standard number of years without disease activity.”
In regard to the percentage of patients who had a recurrence of inflammatory activity (17.8%), Dr. Knox said “ideally patients can be triaged for stopping therapy appropriately with a much lower risk for return of disease activity based on their individual risk factors – i.e., under 2%.”
Michael J. Olek, DO, associate professor of neurology at Touro University Nevada, Henderson, took a different view. He said he does not discontinue medication in patients with MS even if they’re stable for 5 years.
“I am waiting for trials that show that discontinuing medication is OK for the patient. To date, there are no studies showing that stopping medication is a good idea,” he said. “The immune systems slows as people age, so there may be a point in a person’s lifetime when medication used to slow the immune system is no longer needed. But until then I will continue medication for all multiple sclerosis patients.”
Moving forward, study lead author Ms. Coerver said “there are large differences between patients, and there is still room for discussion regarding what percentage of disease activity can be accepted after DMT discontinuation. The most important point is to inform patients about the risks of discontinuation so that each individual patient can make a well-informed decision.”
The study was funded by the Netherlands Organization for Health Research and Development and Stichting MS Research. Ms. Coerver reports no disclosures; some other study authors report various disclosures. Dr. Olek reports no disclosures. Dr. Knox discloses research funding from the Saskatchewan Ministry of Health to evaluate and monitor long-term outcomes in MS.
FROM ECTRIMS 2023