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MS-tailored weight loss program achieves meaningful results
MILAN – results of a new trial show.
Seventy patients with MS and a high body mass index (BMI) were randomized to receive a multifaceted weight loss program or treatment as usual, resulting in almost two-thirds of the intervention group patients losing at least 5% of their body weight.
“Our weight loss intervention achieved clinically significant weight loss and improved mental quality of life,” said study presenter Sharon G. Lynch, MD, professor in the department of neurology at the University of Kansas Medical Center, Kansas City.
The results also showed weight loss “was associated with improved mobility, reduced fatigability, and improved physical quality of life.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Obesity linked to MS progression
Dr. Lynch noted that almost 40% of people with MS have comorbid obesity, and that obesity “is associated with developing MS in some studies, and also disease progression.” Moreover, MS and obesity share common chronic symptoms, particularly mobility problems, depression, fatigue, and reduced quality of life.
Despite this, no randomized controlled trials have been specifically designed to help people with MS lose weight, he noted.
The team therefore examined the efficacy of a behavioral weight loss program designed for patients with the disease, as well as the impact of weight loss on mobility and other chronic symptoms.
The participants were required to be English speaking, with access to a telephone and/or computer, and to have a confirmed diagnosis of MS. They also had to be aged 18-70 years, have a BMI of 29-50 kg/m2, and have a Patient-Determined Disease Steps (PDDS) score of less than 4.
The patients were randomly assigned to receive either a weight loss intervention or brief health education and treatment as usual. They were assessed at 6 months to measure their weight loss, mobility, and self-reported quality of life and perceived fatigability.
Dr. Lynch said the intervention was “fairly time intensive,” with an hour-long telehealth group weight loss session every week for 24 weeks, as well as monthly individual sessions for 6 months.
The participants were provided with a Fitbit activity tracker, a set of Bluetooth-enabled weighing scales, and access to the Lose It! weight loss app.
Caloric restriction was encouraged, with a focus on increasing intake of fruits and vegetables, alongside a target of 150 minutes per week of moderate to vigorous physical activity, in line with Centers for Disease Control and Prevention and American Heart Association recommendations.
Significant loss in body weight
Seventy individuals with MS took part in the trial, of whom 83% were female and 88% were White, 9% African American, and 3% Hispanic or Latino. The mean age was 46.7 years, and the mean number of years in education was 11.8.
The vast majority (96%) of the participants had relapsing remitting MS, at a mean disease duration of 10.9 years, and 82% had a score of 0 or 1 on the PDDS.
Dr. Lynch showed that participants in the intervention group lost, over the course of the study, 8.6% of their total body weight, compared with a loss of 0.7% among controls (P < .001).
Moreover, 65% of the intervention group lost at least 5% of their body weight, whereas 41% lost at least 10% of their body weight, which again was significantly higher than that seen in the control group (P < .001).
There was also a significant increase in moderate to vigorous physical activity in the intervention group as measured by accelerometry (P < .05), although Dr. Lynch pointed out this “did not necessarily correlate with their weight loss.”
Dr. Lynch showed there were significant differences across a range of anthropometric measures from baseline to follow-up between the intervention and control groups.
The adjusted difference in weight loss between the intervention and control participants was 7.8 kg, whereas the difference in reduction of BMI was 2.7 (P = .001 for both).
There was also a significant difference in the reduction in waist-to-hip ratio between the groups, at 0.033 in favor of the intervention, as well as a difference in the reduction in fat tissue, at 3.1% (P = .001 for both).
Further analyses showed weight loss was associated with significant improvements on the 6-minute walk test, at an r value of 0.48 (P = .015), and in the 25-foot walk test (r = 0.42; P = .015). Weight loss was also linked to reductions in perceived fatigability (r = 0.48; P = .005).
Dr. Lynch also reported that a 5% reduction in body weight was associated with a “clinically meaningful” improvement of 50 meters on the 6-minute walk test.
Finally, it was found the intervention was associated with a significant improvement in mental quality of life (P = .01), whereas weight loss specifically was linked to improved physical quality of life (P = .02).
“We believe that future studies should examine weight loss in people with MS who have more advanced disability,” Dr. Lynch said, and “we should examine the effects of weight loss on the underlying disease processes.”
She added they also “need to follow the patient for longer and see if they can maintain their weight loss.”
Emphasizing the social side of interventions
Session cochair Brian M. Sandroff, PhD, director of the Exercise Neurorehabilitation Research Laboratory at the Kessler Foundation, East Hanover, N.J., commented that the results are “really exciting.”
He said that the improvements across the range of measures assessed in the study were not surprising, “considering the intervention was multicomponent, and so had the potential to affect a number of different physical and cognitive domains.”
One factor in managing MS that came up again and again during the discussion at the end of the session was the social aspect of interventions, with Dr. Lynch saying the group sessions in particular were appreciated by participants in her trial.
Dr. Sandroff, who was not involved in the study, said that it has been questioned whether the social side should be controlled for when assessing interventions, or “maybe it’s something we should promote within our studies.”
He explained that being social “overcomes a lot of isolation-related issues among people with MS who have comorbidities,” which can result in “reduced quality of life and differences in symptomatic manifestations.”
“Providing that group setting might have lots of outcomes besides just a biological loss of mass” because of the intervention itself, Dr. Sandroff said.
The study was supported by grants from the National MS Society. Dr. Lynch declares relationships with Biogen, Genzyme, Teva, Sanofi, Novartis, Celgene, Roche, Immunic, National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Anokion, TG Therapeutics, and Actelion. Other authors also declared relationships. Dr. Sandroff declared no relevant relationships.
A version of this article first appeared on Medscape.com.
MILAN – results of a new trial show.
Seventy patients with MS and a high body mass index (BMI) were randomized to receive a multifaceted weight loss program or treatment as usual, resulting in almost two-thirds of the intervention group patients losing at least 5% of their body weight.
“Our weight loss intervention achieved clinically significant weight loss and improved mental quality of life,” said study presenter Sharon G. Lynch, MD, professor in the department of neurology at the University of Kansas Medical Center, Kansas City.
The results also showed weight loss “was associated with improved mobility, reduced fatigability, and improved physical quality of life.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Obesity linked to MS progression
Dr. Lynch noted that almost 40% of people with MS have comorbid obesity, and that obesity “is associated with developing MS in some studies, and also disease progression.” Moreover, MS and obesity share common chronic symptoms, particularly mobility problems, depression, fatigue, and reduced quality of life.
Despite this, no randomized controlled trials have been specifically designed to help people with MS lose weight, he noted.
The team therefore examined the efficacy of a behavioral weight loss program designed for patients with the disease, as well as the impact of weight loss on mobility and other chronic symptoms.
The participants were required to be English speaking, with access to a telephone and/or computer, and to have a confirmed diagnosis of MS. They also had to be aged 18-70 years, have a BMI of 29-50 kg/m2, and have a Patient-Determined Disease Steps (PDDS) score of less than 4.
The patients were randomly assigned to receive either a weight loss intervention or brief health education and treatment as usual. They were assessed at 6 months to measure their weight loss, mobility, and self-reported quality of life and perceived fatigability.
Dr. Lynch said the intervention was “fairly time intensive,” with an hour-long telehealth group weight loss session every week for 24 weeks, as well as monthly individual sessions for 6 months.
The participants were provided with a Fitbit activity tracker, a set of Bluetooth-enabled weighing scales, and access to the Lose It! weight loss app.
Caloric restriction was encouraged, with a focus on increasing intake of fruits and vegetables, alongside a target of 150 minutes per week of moderate to vigorous physical activity, in line with Centers for Disease Control and Prevention and American Heart Association recommendations.
Significant loss in body weight
Seventy individuals with MS took part in the trial, of whom 83% were female and 88% were White, 9% African American, and 3% Hispanic or Latino. The mean age was 46.7 years, and the mean number of years in education was 11.8.
The vast majority (96%) of the participants had relapsing remitting MS, at a mean disease duration of 10.9 years, and 82% had a score of 0 or 1 on the PDDS.
Dr. Lynch showed that participants in the intervention group lost, over the course of the study, 8.6% of their total body weight, compared with a loss of 0.7% among controls (P < .001).
Moreover, 65% of the intervention group lost at least 5% of their body weight, whereas 41% lost at least 10% of their body weight, which again was significantly higher than that seen in the control group (P < .001).
There was also a significant increase in moderate to vigorous physical activity in the intervention group as measured by accelerometry (P < .05), although Dr. Lynch pointed out this “did not necessarily correlate with their weight loss.”
Dr. Lynch showed there were significant differences across a range of anthropometric measures from baseline to follow-up between the intervention and control groups.
The adjusted difference in weight loss between the intervention and control participants was 7.8 kg, whereas the difference in reduction of BMI was 2.7 (P = .001 for both).
There was also a significant difference in the reduction in waist-to-hip ratio between the groups, at 0.033 in favor of the intervention, as well as a difference in the reduction in fat tissue, at 3.1% (P = .001 for both).
Further analyses showed weight loss was associated with significant improvements on the 6-minute walk test, at an r value of 0.48 (P = .015), and in the 25-foot walk test (r = 0.42; P = .015). Weight loss was also linked to reductions in perceived fatigability (r = 0.48; P = .005).
Dr. Lynch also reported that a 5% reduction in body weight was associated with a “clinically meaningful” improvement of 50 meters on the 6-minute walk test.
Finally, it was found the intervention was associated with a significant improvement in mental quality of life (P = .01), whereas weight loss specifically was linked to improved physical quality of life (P = .02).
“We believe that future studies should examine weight loss in people with MS who have more advanced disability,” Dr. Lynch said, and “we should examine the effects of weight loss on the underlying disease processes.”
She added they also “need to follow the patient for longer and see if they can maintain their weight loss.”
Emphasizing the social side of interventions
Session cochair Brian M. Sandroff, PhD, director of the Exercise Neurorehabilitation Research Laboratory at the Kessler Foundation, East Hanover, N.J., commented that the results are “really exciting.”
He said that the improvements across the range of measures assessed in the study were not surprising, “considering the intervention was multicomponent, and so had the potential to affect a number of different physical and cognitive domains.”
One factor in managing MS that came up again and again during the discussion at the end of the session was the social aspect of interventions, with Dr. Lynch saying the group sessions in particular were appreciated by participants in her trial.
Dr. Sandroff, who was not involved in the study, said that it has been questioned whether the social side should be controlled for when assessing interventions, or “maybe it’s something we should promote within our studies.”
He explained that being social “overcomes a lot of isolation-related issues among people with MS who have comorbidities,” which can result in “reduced quality of life and differences in symptomatic manifestations.”
“Providing that group setting might have lots of outcomes besides just a biological loss of mass” because of the intervention itself, Dr. Sandroff said.
The study was supported by grants from the National MS Society. Dr. Lynch declares relationships with Biogen, Genzyme, Teva, Sanofi, Novartis, Celgene, Roche, Immunic, National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Anokion, TG Therapeutics, and Actelion. Other authors also declared relationships. Dr. Sandroff declared no relevant relationships.
A version of this article first appeared on Medscape.com.
MILAN – results of a new trial show.
Seventy patients with MS and a high body mass index (BMI) were randomized to receive a multifaceted weight loss program or treatment as usual, resulting in almost two-thirds of the intervention group patients losing at least 5% of their body weight.
“Our weight loss intervention achieved clinically significant weight loss and improved mental quality of life,” said study presenter Sharon G. Lynch, MD, professor in the department of neurology at the University of Kansas Medical Center, Kansas City.
The results also showed weight loss “was associated with improved mobility, reduced fatigability, and improved physical quality of life.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Obesity linked to MS progression
Dr. Lynch noted that almost 40% of people with MS have comorbid obesity, and that obesity “is associated with developing MS in some studies, and also disease progression.” Moreover, MS and obesity share common chronic symptoms, particularly mobility problems, depression, fatigue, and reduced quality of life.
Despite this, no randomized controlled trials have been specifically designed to help people with MS lose weight, he noted.
The team therefore examined the efficacy of a behavioral weight loss program designed for patients with the disease, as well as the impact of weight loss on mobility and other chronic symptoms.
The participants were required to be English speaking, with access to a telephone and/or computer, and to have a confirmed diagnosis of MS. They also had to be aged 18-70 years, have a BMI of 29-50 kg/m2, and have a Patient-Determined Disease Steps (PDDS) score of less than 4.
The patients were randomly assigned to receive either a weight loss intervention or brief health education and treatment as usual. They were assessed at 6 months to measure their weight loss, mobility, and self-reported quality of life and perceived fatigability.
Dr. Lynch said the intervention was “fairly time intensive,” with an hour-long telehealth group weight loss session every week for 24 weeks, as well as monthly individual sessions for 6 months.
The participants were provided with a Fitbit activity tracker, a set of Bluetooth-enabled weighing scales, and access to the Lose It! weight loss app.
Caloric restriction was encouraged, with a focus on increasing intake of fruits and vegetables, alongside a target of 150 minutes per week of moderate to vigorous physical activity, in line with Centers for Disease Control and Prevention and American Heart Association recommendations.
Significant loss in body weight
Seventy individuals with MS took part in the trial, of whom 83% were female and 88% were White, 9% African American, and 3% Hispanic or Latino. The mean age was 46.7 years, and the mean number of years in education was 11.8.
The vast majority (96%) of the participants had relapsing remitting MS, at a mean disease duration of 10.9 years, and 82% had a score of 0 or 1 on the PDDS.
Dr. Lynch showed that participants in the intervention group lost, over the course of the study, 8.6% of their total body weight, compared with a loss of 0.7% among controls (P < .001).
Moreover, 65% of the intervention group lost at least 5% of their body weight, whereas 41% lost at least 10% of their body weight, which again was significantly higher than that seen in the control group (P < .001).
There was also a significant increase in moderate to vigorous physical activity in the intervention group as measured by accelerometry (P < .05), although Dr. Lynch pointed out this “did not necessarily correlate with their weight loss.”
Dr. Lynch showed there were significant differences across a range of anthropometric measures from baseline to follow-up between the intervention and control groups.
The adjusted difference in weight loss between the intervention and control participants was 7.8 kg, whereas the difference in reduction of BMI was 2.7 (P = .001 for both).
There was also a significant difference in the reduction in waist-to-hip ratio between the groups, at 0.033 in favor of the intervention, as well as a difference in the reduction in fat tissue, at 3.1% (P = .001 for both).
Further analyses showed weight loss was associated with significant improvements on the 6-minute walk test, at an r value of 0.48 (P = .015), and in the 25-foot walk test (r = 0.42; P = .015). Weight loss was also linked to reductions in perceived fatigability (r = 0.48; P = .005).
Dr. Lynch also reported that a 5% reduction in body weight was associated with a “clinically meaningful” improvement of 50 meters on the 6-minute walk test.
Finally, it was found the intervention was associated with a significant improvement in mental quality of life (P = .01), whereas weight loss specifically was linked to improved physical quality of life (P = .02).
“We believe that future studies should examine weight loss in people with MS who have more advanced disability,” Dr. Lynch said, and “we should examine the effects of weight loss on the underlying disease processes.”
She added they also “need to follow the patient for longer and see if they can maintain their weight loss.”
Emphasizing the social side of interventions
Session cochair Brian M. Sandroff, PhD, director of the Exercise Neurorehabilitation Research Laboratory at the Kessler Foundation, East Hanover, N.J., commented that the results are “really exciting.”
He said that the improvements across the range of measures assessed in the study were not surprising, “considering the intervention was multicomponent, and so had the potential to affect a number of different physical and cognitive domains.”
One factor in managing MS that came up again and again during the discussion at the end of the session was the social aspect of interventions, with Dr. Lynch saying the group sessions in particular were appreciated by participants in her trial.
Dr. Sandroff, who was not involved in the study, said that it has been questioned whether the social side should be controlled for when assessing interventions, or “maybe it’s something we should promote within our studies.”
He explained that being social “overcomes a lot of isolation-related issues among people with MS who have comorbidities,” which can result in “reduced quality of life and differences in symptomatic manifestations.”
“Providing that group setting might have lots of outcomes besides just a biological loss of mass” because of the intervention itself, Dr. Sandroff said.
The study was supported by grants from the National MS Society. Dr. Lynch declares relationships with Biogen, Genzyme, Teva, Sanofi, Novartis, Celgene, Roche, Immunic, National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Anokion, TG Therapeutics, and Actelion. Other authors also declared relationships. Dr. Sandroff declared no relevant relationships.
A version of this article first appeared on Medscape.com.
AT ECTRIMS 2023
‘We’re halfway home’: UCSF’s Dr. Stephen Hauser sketches MS future
MILAN – University of California, San Francisco, neurology professor Stephen Hauser, MD, told colleagues in a highlighted lecture at the 9th Joint ECTRIMS-ACTRIMS meeting.
Going forward, the MS field should emphasize identifying early biomarkers of MS, Dr. Hauser said.
He noted that many experts had anticipated “that, if we could intervene early in the relapsing phase of the disease, we would stabilize neurodegeneration and patient disability. But one of the big surprises was that that was not the case. Instead, the observed course was that by silencing relapses and focal inflammation, a clinically silent, slow, insidious progression continues during the relapsing phase of disease in patients who are not having ongoing relapses.”
Even as focal activity detected via MRI is silenced, “progression continues” he said. “This remains the great unsolved challenge.”
Dr. Hauser asked colleagues to consider a three-stage model of MS that begins with benign autoimmunity followed by pathogenic autoimmunity with subclinical tissue damage. The third stage is clinical autoimmunity.
How can you determine who’s at risk? Genetics can only fill in part of the picture because they can’t pinpoint exactly who’s likely to develop the disease. “In other autoimmune diseases, serologic autoantibodies have been by far the most effective biomarkers,” he said. “There is real-world support – not only in mice – for the concept that autoimmunity begins as a highly focused immune response that then spreads over time.”
In systemic lupus erythematosus, the cascade toward disease begins about 9 years before clinical presentation, he said. It’s 7 months in type 1 diabetes, and 20 years in rheumatoid arthritis. “These have been enormously powerful in designing both observational and therapeutic studies to try to interrupt autoimmunity at the earliest possible stage.”
What can be done if a MS biomarker is developed and shows that a person is at risk? Dr. Hauser highlighted how the anti-CD3 antibody teplizumab has been developed – and Food and Drug Administration approved – to greatly reduce the risk of type 1 diabetes in high-risk patients. Per a 2021 study, a single-14-day course of the drug was linked to lowering the risk of disease over a median 923 days by more than 50% (hazard ratio, 0.457; P < 0.01). Half of those who received the drug were free of diabetes versus just 22% of those treated by placebo.
“We’ve not yet had those serologic biomarkers in MS. But I’d like to show you that maybe we are getting close to having them,” Dr. Hauser said. He pointed to new research into a U.S. Department of Defense serum repository that’s turned up “a pretty rock-solid prediagnostic biomarker specific to MS.”
Moving on to therapy, Dr. Hauser said it’s clear that “the earlier that we treat, the more likely we are to have a large response. Highly effective therapies delivered as first-line therapies have better long-term outcomes for disability then does a graded approach that doesn’t begin with high-efficacy therapy.”
What constitutes a cure?
What else needs to be done going forward? Dr. Hauser called for the MS field to develop a definition of cure. “We should take the lead from cancer therapeutics, where they define what a cure means.” In B-cell leukemia, for example, patients are considered cured “if they remain completely disease-free in terms of clinical symptoms and biomarkers of clonal proliferation for 4 years. They have less than a 1% lifetime risk of relapse. They’re essentially cured. Our equivalent could also be developed for MS.”
He highlighted the IMPACT MS phase 4 trial, a small single-center study of ocrelizumab, which just finished enrollment and will examine the effect of the drug on treatment-naive patients at the moment of their first-ever attack. The primary endpoint is oligoclonal bands in 3 years. “I think more of these studies will probably follow,” Dr. Hauser said.
Is intervention possible at the presymptomatic stage? Targets could be members of families with multiple affected relatives who test positive for the predictive antibody signature and who have a high genetic score, he said. “We could do perhaps an Epstein-Barr virus intervention trial in this population. Then, if we have the courage and are more confident in our biomarkers, perhaps even a therapeutic trial, as has been done in these other diseases.”
As for next-generation therapies, “we’ll need to neutralize multiple cell types, especially in later disease,” he said. Bruton tyrosine kinase inhibitors “seem to be a class of drugs that was designed for the MS patient because they not only hit B cells, but also the plasmablasts that CD20s don’t hit and are the main component of the humoral pathology in chronic MS lesions.”
Dr. Hauser discloses scientific board (Accure, Alector, Annexon), board of directors (Neurona), consulting (BD, Moderna, NGM Bio), and travel reimbursement/writing support (Roche and Novartis).
MILAN – University of California, San Francisco, neurology professor Stephen Hauser, MD, told colleagues in a highlighted lecture at the 9th Joint ECTRIMS-ACTRIMS meeting.
Going forward, the MS field should emphasize identifying early biomarkers of MS, Dr. Hauser said.
He noted that many experts had anticipated “that, if we could intervene early in the relapsing phase of the disease, we would stabilize neurodegeneration and patient disability. But one of the big surprises was that that was not the case. Instead, the observed course was that by silencing relapses and focal inflammation, a clinically silent, slow, insidious progression continues during the relapsing phase of disease in patients who are not having ongoing relapses.”
Even as focal activity detected via MRI is silenced, “progression continues” he said. “This remains the great unsolved challenge.”
Dr. Hauser asked colleagues to consider a three-stage model of MS that begins with benign autoimmunity followed by pathogenic autoimmunity with subclinical tissue damage. The third stage is clinical autoimmunity.
How can you determine who’s at risk? Genetics can only fill in part of the picture because they can’t pinpoint exactly who’s likely to develop the disease. “In other autoimmune diseases, serologic autoantibodies have been by far the most effective biomarkers,” he said. “There is real-world support – not only in mice – for the concept that autoimmunity begins as a highly focused immune response that then spreads over time.”
In systemic lupus erythematosus, the cascade toward disease begins about 9 years before clinical presentation, he said. It’s 7 months in type 1 diabetes, and 20 years in rheumatoid arthritis. “These have been enormously powerful in designing both observational and therapeutic studies to try to interrupt autoimmunity at the earliest possible stage.”
What can be done if a MS biomarker is developed and shows that a person is at risk? Dr. Hauser highlighted how the anti-CD3 antibody teplizumab has been developed – and Food and Drug Administration approved – to greatly reduce the risk of type 1 diabetes in high-risk patients. Per a 2021 study, a single-14-day course of the drug was linked to lowering the risk of disease over a median 923 days by more than 50% (hazard ratio, 0.457; P < 0.01). Half of those who received the drug were free of diabetes versus just 22% of those treated by placebo.
“We’ve not yet had those serologic biomarkers in MS. But I’d like to show you that maybe we are getting close to having them,” Dr. Hauser said. He pointed to new research into a U.S. Department of Defense serum repository that’s turned up “a pretty rock-solid prediagnostic biomarker specific to MS.”
Moving on to therapy, Dr. Hauser said it’s clear that “the earlier that we treat, the more likely we are to have a large response. Highly effective therapies delivered as first-line therapies have better long-term outcomes for disability then does a graded approach that doesn’t begin with high-efficacy therapy.”
What constitutes a cure?
What else needs to be done going forward? Dr. Hauser called for the MS field to develop a definition of cure. “We should take the lead from cancer therapeutics, where they define what a cure means.” In B-cell leukemia, for example, patients are considered cured “if they remain completely disease-free in terms of clinical symptoms and biomarkers of clonal proliferation for 4 years. They have less than a 1% lifetime risk of relapse. They’re essentially cured. Our equivalent could also be developed for MS.”
He highlighted the IMPACT MS phase 4 trial, a small single-center study of ocrelizumab, which just finished enrollment and will examine the effect of the drug on treatment-naive patients at the moment of their first-ever attack. The primary endpoint is oligoclonal bands in 3 years. “I think more of these studies will probably follow,” Dr. Hauser said.
Is intervention possible at the presymptomatic stage? Targets could be members of families with multiple affected relatives who test positive for the predictive antibody signature and who have a high genetic score, he said. “We could do perhaps an Epstein-Barr virus intervention trial in this population. Then, if we have the courage and are more confident in our biomarkers, perhaps even a therapeutic trial, as has been done in these other diseases.”
As for next-generation therapies, “we’ll need to neutralize multiple cell types, especially in later disease,” he said. Bruton tyrosine kinase inhibitors “seem to be a class of drugs that was designed for the MS patient because they not only hit B cells, but also the plasmablasts that CD20s don’t hit and are the main component of the humoral pathology in chronic MS lesions.”
Dr. Hauser discloses scientific board (Accure, Alector, Annexon), board of directors (Neurona), consulting (BD, Moderna, NGM Bio), and travel reimbursement/writing support (Roche and Novartis).
MILAN – University of California, San Francisco, neurology professor Stephen Hauser, MD, told colleagues in a highlighted lecture at the 9th Joint ECTRIMS-ACTRIMS meeting.
Going forward, the MS field should emphasize identifying early biomarkers of MS, Dr. Hauser said.
He noted that many experts had anticipated “that, if we could intervene early in the relapsing phase of the disease, we would stabilize neurodegeneration and patient disability. But one of the big surprises was that that was not the case. Instead, the observed course was that by silencing relapses and focal inflammation, a clinically silent, slow, insidious progression continues during the relapsing phase of disease in patients who are not having ongoing relapses.”
Even as focal activity detected via MRI is silenced, “progression continues” he said. “This remains the great unsolved challenge.”
Dr. Hauser asked colleagues to consider a three-stage model of MS that begins with benign autoimmunity followed by pathogenic autoimmunity with subclinical tissue damage. The third stage is clinical autoimmunity.
How can you determine who’s at risk? Genetics can only fill in part of the picture because they can’t pinpoint exactly who’s likely to develop the disease. “In other autoimmune diseases, serologic autoantibodies have been by far the most effective biomarkers,” he said. “There is real-world support – not only in mice – for the concept that autoimmunity begins as a highly focused immune response that then spreads over time.”
In systemic lupus erythematosus, the cascade toward disease begins about 9 years before clinical presentation, he said. It’s 7 months in type 1 diabetes, and 20 years in rheumatoid arthritis. “These have been enormously powerful in designing both observational and therapeutic studies to try to interrupt autoimmunity at the earliest possible stage.”
What can be done if a MS biomarker is developed and shows that a person is at risk? Dr. Hauser highlighted how the anti-CD3 antibody teplizumab has been developed – and Food and Drug Administration approved – to greatly reduce the risk of type 1 diabetes in high-risk patients. Per a 2021 study, a single-14-day course of the drug was linked to lowering the risk of disease over a median 923 days by more than 50% (hazard ratio, 0.457; P < 0.01). Half of those who received the drug were free of diabetes versus just 22% of those treated by placebo.
“We’ve not yet had those serologic biomarkers in MS. But I’d like to show you that maybe we are getting close to having them,” Dr. Hauser said. He pointed to new research into a U.S. Department of Defense serum repository that’s turned up “a pretty rock-solid prediagnostic biomarker specific to MS.”
Moving on to therapy, Dr. Hauser said it’s clear that “the earlier that we treat, the more likely we are to have a large response. Highly effective therapies delivered as first-line therapies have better long-term outcomes for disability then does a graded approach that doesn’t begin with high-efficacy therapy.”
What constitutes a cure?
What else needs to be done going forward? Dr. Hauser called for the MS field to develop a definition of cure. “We should take the lead from cancer therapeutics, where they define what a cure means.” In B-cell leukemia, for example, patients are considered cured “if they remain completely disease-free in terms of clinical symptoms and biomarkers of clonal proliferation for 4 years. They have less than a 1% lifetime risk of relapse. They’re essentially cured. Our equivalent could also be developed for MS.”
He highlighted the IMPACT MS phase 4 trial, a small single-center study of ocrelizumab, which just finished enrollment and will examine the effect of the drug on treatment-naive patients at the moment of their first-ever attack. The primary endpoint is oligoclonal bands in 3 years. “I think more of these studies will probably follow,” Dr. Hauser said.
Is intervention possible at the presymptomatic stage? Targets could be members of families with multiple affected relatives who test positive for the predictive antibody signature and who have a high genetic score, he said. “We could do perhaps an Epstein-Barr virus intervention trial in this population. Then, if we have the courage and are more confident in our biomarkers, perhaps even a therapeutic trial, as has been done in these other diseases.”
As for next-generation therapies, “we’ll need to neutralize multiple cell types, especially in later disease,” he said. Bruton tyrosine kinase inhibitors “seem to be a class of drugs that was designed for the MS patient because they not only hit B cells, but also the plasmablasts that CD20s don’t hit and are the main component of the humoral pathology in chronic MS lesions.”
Dr. Hauser discloses scientific board (Accure, Alector, Annexon), board of directors (Neurona), consulting (BD, Moderna, NGM Bio), and travel reimbursement/writing support (Roche and Novartis).
AT ECTRIMS 2023
Next up in MS trials: More insight into progressive disease
MILAN – , neurologist Jeremy Chataway, MD, PhD, of University College London and Queen Square Multiple Sclerosis Center told colleagues at the 9th Joint ECTRIMS-ACTRIMS meeting.
“They’re all very different, and I think that’s exciting,” he said. “It’s a rich trial environment.”
The problem: At a median of almost 3 years in treatment for primary progressive MS, “we know that about a third of patients will progress despite on being on anti-inflammatory treatment. The same is true for secondary progressive MS. That is the hard core of what we have to think about. We want to improve the efficacy gap between control and active.”
First, Dr. Chataway highlighted the MS-STAT2 trial of simvastatin (Zocor), an inexpensive statin used to lower cholesterol. He is one of the leaders of the 3-year, multicenter, double-blind, randomized, placebo-controlled study, which is testing whether 80-mg daily doses of simvastatin will slow MS progression.
As Dr. Chataway noted, an earlier study – MS-STAT1 – found less brain atrophy in patients who took a high dose of the drug, which was “well tolerated and safe.”
Vascular morbidity drives disability and mortality in MS. “This is low-hanging fruit because we have the tools to do something about it,” he said. “There’s an opportunity here to add into our treatment paradigms across people with MS by actively treating their vascular comorbidity. It will have an effect.”
Recruitment for a trial of this approach is complete, and study results are expected in 2024 and 2025, Dr. Chataway said.
Another new study is exploring the possible effects of the antioxidant lipoic acid, also known as alpha-lipoic acid. As Dr. Chataway noted, a 2017 single-center, randomized, double-blind pilot study of daily oral 1,200 mg lipoic acid versus placebo linked the intervention to a dramatic lowering of brain atrophy – by about 50%.
The new LAPMS study, sponsored by the Veterans Administration, will explore whether lipoic acid affects walking ability, clinical outcome, and brain atrophy, Dr. Chataway said. Results from phase 2 are expected in a year or two, he said.
Dr. Chataway also highlighted one of his own trials, the OCTOPUS study, a multiarm, multistage study that will examine multiple drugs to treat progressive MS. It’s starting with metformin and will look at lipoic acid too, he said.
He also noted the phase 2 CALLIPER trial, which has completed enrollment and expects to provide top-line data in 2025. The multicenter, randomized, double-blind, placebo-controlled will test vidofludimus calcium in patients with progressive MS.
Finally, Dr. Chataway highlighted the randomized, double-blind, placebo-controlled, add-on phase 2 NACPMS trial of n-acetyl cysteine and the phase 1 randomized, double-blind, placebo-controlled trial of SAR443820, a central nervous system penetrant oral RIPK1 inhibitor.
Dr. Chataway discloses grants (UK Multiple Sclerosis Society, National Multiple Sclerosis Society, Efficacy and Mechanism Evaluation Board, Health Technology Assessment, Multiple Sclerosis Trials Collaboration, and Rosetrees Trust), advisory board service (Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis, and Roche), other support (National Institute of Health Research Support, University College London Hospitals Biomedical Research Centers funding scheme), and serving as an trial investigator (Canadian MS Society, Ionis, Novartis, and Roche).
MILAN – , neurologist Jeremy Chataway, MD, PhD, of University College London and Queen Square Multiple Sclerosis Center told colleagues at the 9th Joint ECTRIMS-ACTRIMS meeting.
“They’re all very different, and I think that’s exciting,” he said. “It’s a rich trial environment.”
The problem: At a median of almost 3 years in treatment for primary progressive MS, “we know that about a third of patients will progress despite on being on anti-inflammatory treatment. The same is true for secondary progressive MS. That is the hard core of what we have to think about. We want to improve the efficacy gap between control and active.”
First, Dr. Chataway highlighted the MS-STAT2 trial of simvastatin (Zocor), an inexpensive statin used to lower cholesterol. He is one of the leaders of the 3-year, multicenter, double-blind, randomized, placebo-controlled study, which is testing whether 80-mg daily doses of simvastatin will slow MS progression.
As Dr. Chataway noted, an earlier study – MS-STAT1 – found less brain atrophy in patients who took a high dose of the drug, which was “well tolerated and safe.”
Vascular morbidity drives disability and mortality in MS. “This is low-hanging fruit because we have the tools to do something about it,” he said. “There’s an opportunity here to add into our treatment paradigms across people with MS by actively treating their vascular comorbidity. It will have an effect.”
Recruitment for a trial of this approach is complete, and study results are expected in 2024 and 2025, Dr. Chataway said.
Another new study is exploring the possible effects of the antioxidant lipoic acid, also known as alpha-lipoic acid. As Dr. Chataway noted, a 2017 single-center, randomized, double-blind pilot study of daily oral 1,200 mg lipoic acid versus placebo linked the intervention to a dramatic lowering of brain atrophy – by about 50%.
The new LAPMS study, sponsored by the Veterans Administration, will explore whether lipoic acid affects walking ability, clinical outcome, and brain atrophy, Dr. Chataway said. Results from phase 2 are expected in a year or two, he said.
Dr. Chataway also highlighted one of his own trials, the OCTOPUS study, a multiarm, multistage study that will examine multiple drugs to treat progressive MS. It’s starting with metformin and will look at lipoic acid too, he said.
He also noted the phase 2 CALLIPER trial, which has completed enrollment and expects to provide top-line data in 2025. The multicenter, randomized, double-blind, placebo-controlled will test vidofludimus calcium in patients with progressive MS.
Finally, Dr. Chataway highlighted the randomized, double-blind, placebo-controlled, add-on phase 2 NACPMS trial of n-acetyl cysteine and the phase 1 randomized, double-blind, placebo-controlled trial of SAR443820, a central nervous system penetrant oral RIPK1 inhibitor.
Dr. Chataway discloses grants (UK Multiple Sclerosis Society, National Multiple Sclerosis Society, Efficacy and Mechanism Evaluation Board, Health Technology Assessment, Multiple Sclerosis Trials Collaboration, and Rosetrees Trust), advisory board service (Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis, and Roche), other support (National Institute of Health Research Support, University College London Hospitals Biomedical Research Centers funding scheme), and serving as an trial investigator (Canadian MS Society, Ionis, Novartis, and Roche).
MILAN – , neurologist Jeremy Chataway, MD, PhD, of University College London and Queen Square Multiple Sclerosis Center told colleagues at the 9th Joint ECTRIMS-ACTRIMS meeting.
“They’re all very different, and I think that’s exciting,” he said. “It’s a rich trial environment.”
The problem: At a median of almost 3 years in treatment for primary progressive MS, “we know that about a third of patients will progress despite on being on anti-inflammatory treatment. The same is true for secondary progressive MS. That is the hard core of what we have to think about. We want to improve the efficacy gap between control and active.”
First, Dr. Chataway highlighted the MS-STAT2 trial of simvastatin (Zocor), an inexpensive statin used to lower cholesterol. He is one of the leaders of the 3-year, multicenter, double-blind, randomized, placebo-controlled study, which is testing whether 80-mg daily doses of simvastatin will slow MS progression.
As Dr. Chataway noted, an earlier study – MS-STAT1 – found less brain atrophy in patients who took a high dose of the drug, which was “well tolerated and safe.”
Vascular morbidity drives disability and mortality in MS. “This is low-hanging fruit because we have the tools to do something about it,” he said. “There’s an opportunity here to add into our treatment paradigms across people with MS by actively treating their vascular comorbidity. It will have an effect.”
Recruitment for a trial of this approach is complete, and study results are expected in 2024 and 2025, Dr. Chataway said.
Another new study is exploring the possible effects of the antioxidant lipoic acid, also known as alpha-lipoic acid. As Dr. Chataway noted, a 2017 single-center, randomized, double-blind pilot study of daily oral 1,200 mg lipoic acid versus placebo linked the intervention to a dramatic lowering of brain atrophy – by about 50%.
The new LAPMS study, sponsored by the Veterans Administration, will explore whether lipoic acid affects walking ability, clinical outcome, and brain atrophy, Dr. Chataway said. Results from phase 2 are expected in a year or two, he said.
Dr. Chataway also highlighted one of his own trials, the OCTOPUS study, a multiarm, multistage study that will examine multiple drugs to treat progressive MS. It’s starting with metformin and will look at lipoic acid too, he said.
He also noted the phase 2 CALLIPER trial, which has completed enrollment and expects to provide top-line data in 2025. The multicenter, randomized, double-blind, placebo-controlled will test vidofludimus calcium in patients with progressive MS.
Finally, Dr. Chataway highlighted the randomized, double-blind, placebo-controlled, add-on phase 2 NACPMS trial of n-acetyl cysteine and the phase 1 randomized, double-blind, placebo-controlled trial of SAR443820, a central nervous system penetrant oral RIPK1 inhibitor.
Dr. Chataway discloses grants (UK Multiple Sclerosis Society, National Multiple Sclerosis Society, Efficacy and Mechanism Evaluation Board, Health Technology Assessment, Multiple Sclerosis Trials Collaboration, and Rosetrees Trust), advisory board service (Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis, and Roche), other support (National Institute of Health Research Support, University College London Hospitals Biomedical Research Centers funding scheme), and serving as an trial investigator (Canadian MS Society, Ionis, Novartis, and Roche).
AT ECTRIMS 2023
AI tool reveals MS drug interactions, offers safer options
MILAN – , German researchers reported.
The team fed the medication plans of almost 630 patients into a deep neural network, which identified drug-drug interactions in more than 80% of cases, in particular when switching from one medication to another, alongside potential food interactions.
The tool was able to identify specific interactions that could be avoided if a drug was replaced with one with a similar pharmacologic profile, but a lower risk of adverse effects.
“Potential drug-drug interactions are a major safety concern in patients with MS,” said study presenter Michael Hecker, PhD, department of neurology, Rostock (Germany) University Medical Center.
Such deep learning–based methods are “useful” in screening for potential interactions both between drugs and with foods, they concluded.
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS Meeting.
Unknown interactions
During his presentation, Dr. Hecker noted that most patients with MS take two or more drugs “to treat their disease and to mitigate their symptoms and comorbidities.” He pointed out, however, that patients who take multiple medications are at an increased risk for side effects, as one drug may affect the pharmacokinetic or pharmacodynamic properties of another.
“For instance, it may change its metabolism,” Dr. Hecker said, and therefore affect its mechanism of action and the response to the drug, with medications potentially having synergistic, antagonistic, or additive effects.
He explained that the online DrugBank database “provides a huge collection” of known drug-drug interactions for compounds that have a track record. “However, for other drugs, and especially those that are tested only in clinical trials, there’s no information about drug-drug and drug-food interactions,” Dr. Hecker said.
“Moreover, it is quite time-consuming to search a database for individual drug-drug interactions,” he added.
34 million parameters
Consequently, there is increasing interest in the use of deep neural networks to study drug-drug interactions, Dr. Hecker said. DeepDDI is the “state-of-the-art deep learning framework” for predicting interactions. It takes drug-drug or drug-food pairs and compares their structures to determine their similarity. This information is fed into a deep neural network with almost 34 million trainable parameters.
The framework then provides a prediction of any interactions in the same terms as the DrugBank, suggesting, for example, that Drug A may decrease the antihypertensive activities of Drug B.
For the current study, the researchers trained the deep neural network on the most recent release of the DrugBank database, finding it was able to replicate the drug-drug interactions in the database at an accuracy of 92.2% in the validation set and 92.1% in the testing set. They then put the medication plans of 627 patients with MS into the deep neural network.
The patients had a mean age of 48.6 years, 70.3% were women, and the median disease duration was 10 years. They were taking an average of 5.3 medications, and 62% were using disease-modifying therapies (DMT).
The team compared the structures of the drugs they were taking with those of 367 drugs used for the treatment of MS, as well as with structural data for 1,673 food compounds from the FooDB database.
Swapping drugs could reduce interactions
The overall prevalence of potential drug-drug interactions among the patients included in the study was 81.2%.
The researchers then determined the proportion of patients who would be at risk of additional drug-drug interaction if they switched from one DMT to another, or to a Bruton tyrosine kinase inhibitor, given all their other medications.
They found, for example, that more than 40% of patients who switched to the immunomodulator fingolimod (Gilenya) would be at increased risk for bradycardia.
Just under 40% of patients who changed their DMT to the purine analogue cladribine (Mavenclad) would have an increased risk, or worsening, of bleeding, as would approximately 25% of those who switched to the anthracenedione antineoplastic agent mitoxantrone (Novantrone).
Dr. Hecker also showed the deep neural network could make suggestions as to how critical drug-drug interactions could be avoided by replacing interacting drugs with alternatives that have similar pharmacological effects.
For example, carbamazepine (Tegretol, Equetro) could be replaced with topiramate (several brand names) to avoid hepatotoxicity in patients also taking acetaminophen, while liothyronine (Cytomel, Triostat) could replace levothyroxine in patients also taking teriflunomide (Aubagio).
Finally, Dr. Hecker reported there was a subset of 6,860 potential drug-food interactions with the patients’ medications, resulting in reduced or increased concentrations of the drugs, particularly with fish or mushroom consumption.
He conceded, however, there were several limitations to their study, including that it included only small-molecule drugs, and that they did not ask patients about their diet or if they had observed any undesired drug effects.
Furthermore, “only a small number” of the potential drug-drug or drug-food interactions they identified would be “clinically relevant.”
Dr. Hecker also pointed out that each drug has one record, but it is used for different indications, with different dosages, and has different side effects, depending how it is used. “The model does not distinguish this,” he said, and so some of the interactions it highlights could be related to other doses than the one used in MS, for example.
Promise for the future
Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, commented that, as with all AI tools, “it’s only as good as what we’re putting into it.”
Dr. Bhargava, who cochaired the session, said that “there’s limitations on the information in the databases” that are being fed into the deep neural network.
He also highlighted that, “at this point, it didn’t seem like it was coming up with much clinically useful information,” but noted that, “we may get to that point.”
“Right now, there’s promise,” Dr. Bhargava said, but “it’s still not quite there.”
No funding was declared. Dr. Hecker declares relationships with Bayer HealthCare, Biogen, Merck Healthcare, Novartis, and Teva. Several other coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – , German researchers reported.
The team fed the medication plans of almost 630 patients into a deep neural network, which identified drug-drug interactions in more than 80% of cases, in particular when switching from one medication to another, alongside potential food interactions.
The tool was able to identify specific interactions that could be avoided if a drug was replaced with one with a similar pharmacologic profile, but a lower risk of adverse effects.
“Potential drug-drug interactions are a major safety concern in patients with MS,” said study presenter Michael Hecker, PhD, department of neurology, Rostock (Germany) University Medical Center.
Such deep learning–based methods are “useful” in screening for potential interactions both between drugs and with foods, they concluded.
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS Meeting.
Unknown interactions
During his presentation, Dr. Hecker noted that most patients with MS take two or more drugs “to treat their disease and to mitigate their symptoms and comorbidities.” He pointed out, however, that patients who take multiple medications are at an increased risk for side effects, as one drug may affect the pharmacokinetic or pharmacodynamic properties of another.
“For instance, it may change its metabolism,” Dr. Hecker said, and therefore affect its mechanism of action and the response to the drug, with medications potentially having synergistic, antagonistic, or additive effects.
He explained that the online DrugBank database “provides a huge collection” of known drug-drug interactions for compounds that have a track record. “However, for other drugs, and especially those that are tested only in clinical trials, there’s no information about drug-drug and drug-food interactions,” Dr. Hecker said.
“Moreover, it is quite time-consuming to search a database for individual drug-drug interactions,” he added.
34 million parameters
Consequently, there is increasing interest in the use of deep neural networks to study drug-drug interactions, Dr. Hecker said. DeepDDI is the “state-of-the-art deep learning framework” for predicting interactions. It takes drug-drug or drug-food pairs and compares their structures to determine their similarity. This information is fed into a deep neural network with almost 34 million trainable parameters.
The framework then provides a prediction of any interactions in the same terms as the DrugBank, suggesting, for example, that Drug A may decrease the antihypertensive activities of Drug B.
For the current study, the researchers trained the deep neural network on the most recent release of the DrugBank database, finding it was able to replicate the drug-drug interactions in the database at an accuracy of 92.2% in the validation set and 92.1% in the testing set. They then put the medication plans of 627 patients with MS into the deep neural network.
The patients had a mean age of 48.6 years, 70.3% were women, and the median disease duration was 10 years. They were taking an average of 5.3 medications, and 62% were using disease-modifying therapies (DMT).
The team compared the structures of the drugs they were taking with those of 367 drugs used for the treatment of MS, as well as with structural data for 1,673 food compounds from the FooDB database.
Swapping drugs could reduce interactions
The overall prevalence of potential drug-drug interactions among the patients included in the study was 81.2%.
The researchers then determined the proportion of patients who would be at risk of additional drug-drug interaction if they switched from one DMT to another, or to a Bruton tyrosine kinase inhibitor, given all their other medications.
They found, for example, that more than 40% of patients who switched to the immunomodulator fingolimod (Gilenya) would be at increased risk for bradycardia.
Just under 40% of patients who changed their DMT to the purine analogue cladribine (Mavenclad) would have an increased risk, or worsening, of bleeding, as would approximately 25% of those who switched to the anthracenedione antineoplastic agent mitoxantrone (Novantrone).
Dr. Hecker also showed the deep neural network could make suggestions as to how critical drug-drug interactions could be avoided by replacing interacting drugs with alternatives that have similar pharmacological effects.
For example, carbamazepine (Tegretol, Equetro) could be replaced with topiramate (several brand names) to avoid hepatotoxicity in patients also taking acetaminophen, while liothyronine (Cytomel, Triostat) could replace levothyroxine in patients also taking teriflunomide (Aubagio).
Finally, Dr. Hecker reported there was a subset of 6,860 potential drug-food interactions with the patients’ medications, resulting in reduced or increased concentrations of the drugs, particularly with fish or mushroom consumption.
He conceded, however, there were several limitations to their study, including that it included only small-molecule drugs, and that they did not ask patients about their diet or if they had observed any undesired drug effects.
Furthermore, “only a small number” of the potential drug-drug or drug-food interactions they identified would be “clinically relevant.”
Dr. Hecker also pointed out that each drug has one record, but it is used for different indications, with different dosages, and has different side effects, depending how it is used. “The model does not distinguish this,” he said, and so some of the interactions it highlights could be related to other doses than the one used in MS, for example.
Promise for the future
Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, commented that, as with all AI tools, “it’s only as good as what we’re putting into it.”
Dr. Bhargava, who cochaired the session, said that “there’s limitations on the information in the databases” that are being fed into the deep neural network.
He also highlighted that, “at this point, it didn’t seem like it was coming up with much clinically useful information,” but noted that, “we may get to that point.”
“Right now, there’s promise,” Dr. Bhargava said, but “it’s still not quite there.”
No funding was declared. Dr. Hecker declares relationships with Bayer HealthCare, Biogen, Merck Healthcare, Novartis, and Teva. Several other coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – , German researchers reported.
The team fed the medication plans of almost 630 patients into a deep neural network, which identified drug-drug interactions in more than 80% of cases, in particular when switching from one medication to another, alongside potential food interactions.
The tool was able to identify specific interactions that could be avoided if a drug was replaced with one with a similar pharmacologic profile, but a lower risk of adverse effects.
“Potential drug-drug interactions are a major safety concern in patients with MS,” said study presenter Michael Hecker, PhD, department of neurology, Rostock (Germany) University Medical Center.
Such deep learning–based methods are “useful” in screening for potential interactions both between drugs and with foods, they concluded.
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS Meeting.
Unknown interactions
During his presentation, Dr. Hecker noted that most patients with MS take two or more drugs “to treat their disease and to mitigate their symptoms and comorbidities.” He pointed out, however, that patients who take multiple medications are at an increased risk for side effects, as one drug may affect the pharmacokinetic or pharmacodynamic properties of another.
“For instance, it may change its metabolism,” Dr. Hecker said, and therefore affect its mechanism of action and the response to the drug, with medications potentially having synergistic, antagonistic, or additive effects.
He explained that the online DrugBank database “provides a huge collection” of known drug-drug interactions for compounds that have a track record. “However, for other drugs, and especially those that are tested only in clinical trials, there’s no information about drug-drug and drug-food interactions,” Dr. Hecker said.
“Moreover, it is quite time-consuming to search a database for individual drug-drug interactions,” he added.
34 million parameters
Consequently, there is increasing interest in the use of deep neural networks to study drug-drug interactions, Dr. Hecker said. DeepDDI is the “state-of-the-art deep learning framework” for predicting interactions. It takes drug-drug or drug-food pairs and compares their structures to determine their similarity. This information is fed into a deep neural network with almost 34 million trainable parameters.
The framework then provides a prediction of any interactions in the same terms as the DrugBank, suggesting, for example, that Drug A may decrease the antihypertensive activities of Drug B.
For the current study, the researchers trained the deep neural network on the most recent release of the DrugBank database, finding it was able to replicate the drug-drug interactions in the database at an accuracy of 92.2% in the validation set and 92.1% in the testing set. They then put the medication plans of 627 patients with MS into the deep neural network.
The patients had a mean age of 48.6 years, 70.3% were women, and the median disease duration was 10 years. They were taking an average of 5.3 medications, and 62% were using disease-modifying therapies (DMT).
The team compared the structures of the drugs they were taking with those of 367 drugs used for the treatment of MS, as well as with structural data for 1,673 food compounds from the FooDB database.
Swapping drugs could reduce interactions
The overall prevalence of potential drug-drug interactions among the patients included in the study was 81.2%.
The researchers then determined the proportion of patients who would be at risk of additional drug-drug interaction if they switched from one DMT to another, or to a Bruton tyrosine kinase inhibitor, given all their other medications.
They found, for example, that more than 40% of patients who switched to the immunomodulator fingolimod (Gilenya) would be at increased risk for bradycardia.
Just under 40% of patients who changed their DMT to the purine analogue cladribine (Mavenclad) would have an increased risk, or worsening, of bleeding, as would approximately 25% of those who switched to the anthracenedione antineoplastic agent mitoxantrone (Novantrone).
Dr. Hecker also showed the deep neural network could make suggestions as to how critical drug-drug interactions could be avoided by replacing interacting drugs with alternatives that have similar pharmacological effects.
For example, carbamazepine (Tegretol, Equetro) could be replaced with topiramate (several brand names) to avoid hepatotoxicity in patients also taking acetaminophen, while liothyronine (Cytomel, Triostat) could replace levothyroxine in patients also taking teriflunomide (Aubagio).
Finally, Dr. Hecker reported there was a subset of 6,860 potential drug-food interactions with the patients’ medications, resulting in reduced or increased concentrations of the drugs, particularly with fish or mushroom consumption.
He conceded, however, there were several limitations to their study, including that it included only small-molecule drugs, and that they did not ask patients about their diet or if they had observed any undesired drug effects.
Furthermore, “only a small number” of the potential drug-drug or drug-food interactions they identified would be “clinically relevant.”
Dr. Hecker also pointed out that each drug has one record, but it is used for different indications, with different dosages, and has different side effects, depending how it is used. “The model does not distinguish this,” he said, and so some of the interactions it highlights could be related to other doses than the one used in MS, for example.
Promise for the future
Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, commented that, as with all AI tools, “it’s only as good as what we’re putting into it.”
Dr. Bhargava, who cochaired the session, said that “there’s limitations on the information in the databases” that are being fed into the deep neural network.
He also highlighted that, “at this point, it didn’t seem like it was coming up with much clinically useful information,” but noted that, “we may get to that point.”
“Right now, there’s promise,” Dr. Bhargava said, but “it’s still not quite there.”
No funding was declared. Dr. Hecker declares relationships with Bayer HealthCare, Biogen, Merck Healthcare, Novartis, and Teva. Several other coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2023
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
Diversity in Multiple Sclerosis Care: How the Field of Underrepresented Minorities Has Evolved, and Where We Still See Areas for Improvement
The persistent notion that multiple sclerosis (MS) is predominantly a White patient’s disease has been challenged by scientific data and our clinical experience in the field. Recent research has shown a higher risk of MS in non-White populations than originally thought. This may be surprising, but new data are influencing the way we now approach MS in under-represented minorities, bringing this topic to the forefront of scientific interest.
The early conviction that “there is no MS in minorities” led to underdiagnosis and misdiagnosis of MS in those patients, which in turn deepened these patients’ distrust of physicians and reluctance to seek further medical care, very often delivered by non-minority providers. Inequities in social determinants of health, low health literacy, and lack of private insurance, along with structural racism in healthcare, has further hindered active engagement with an already marginalized patient population in their MS care. This lack of engagement and lack of minorities in scientific research has proved to be unfavorable for MS research as well, creating large and persistent knowledge gaps in understanding MS course, severity, and response to treatment specific to this group. A 2014 PubMed search found 52,000 publications on MS in English, but in only 136 of those were minority patients with MS (Black or Hispanic/Latino) the primary research focus. In 2019, the same search indicated that the subsequent 5 years produced only 30 more articles focusing solely on minority patients.
Research participation of underrepresented minorities is another area where we, as a field, continue to fail these patients. A review of participant enrollment in MS clinical trials that took place between 1993 and 2006 showed a significant decrease in the percentage of enrolled Black patients (from 7% to about 4%). This trend did not improve by the DEFINE treatment trial (2012), in which only 2% of enrolled patients were Black. Of the 1246 participants in the 2019 SUNBEAM MS study, only 2 were Black. Low numbers of minority patients in trials prevent us from drawing any reasonable conclusion as to the efficacy of disease-modifying agents in those patients and make the goal of personalized medicine for this group impossible.
The results of the research conducted on these groups are compelling and should be prompting further work. Not only do Black patients have a higher risk of MS, but there is also now convincing evidence that MS in minorities is more severe overall, causing early progression of disability and necessitating assistive gait devices such as a cane or wheelchair. Minority patients tend to have more extensive involvement of spinal cord and infra-tentorial brain structures during the disease, which could explain the increased likelihood of more severe disease and earlier disability. Minority patients were admitted to nursing homes at a younger age, with greater physical and cognitive impairment than nonminority patients. A study looking at MS mortality between 1999 and 2015 found that Black males with MS had the highest mortality rate before age 45, and Black females before age 53. MS mortality increased with age but peaked at age 55 to 64 for Black patients and 65 to 74 for White patients. Underrepresented minorities are also less likely to use community resources, case management, medical equipment, and home nursing services. When looking at other measures of disease impact on these patients, studies evaluating magnetic resonance imaging (MRI) data showed higher lesion volume in Black patients with MS, as well as a higher degree of brain demyelination and atrophy when compared with White patients.
Treatment strategies currently used for underrepresented minority patients, as well as estimations of medication efficacy, treatment responses, and adverse-event profiles are largely driven by data from clinical trials with only minimal representation of those patients. How can we propose a patient-tailored and individualized treatment plan without these crucial data? Given that, to this day, not a single trial has focused solely on underrepresented minorities, we are left with either post hoc exploratory subgroup analyses of existing trials or pragmatic, observational, and very often retrospective studies using chart analysis. Notwithstanding the methodological flaws of either approach, prior studies did suggest worse response to platform therapies in Black patients, but equal response to high-efficacy therapies when compared with White patients.
Definitive biological underpinnings of disparities in disease severity have not been identified. In recent years, the field of health outcomes research has suggested we move away from considering racial categories as biologically distinct and instead focus on long-overlooked sociodemographic and modifiable lifestyle
factors. The role of diet, exercise, body mass index, smoking, and vascular comorbidities as risk factors associated with worse MS outcomes has been previously shown; however, these factors have not been rigorously assessed in underrepresented populations with MS. Recent studies focused on uncovering what drives the differences in MS severity in underrepresented populations disagree on the role biological differences, socioeconomic disparities, and structural racism in both healthcare settings and society play in answering this question. While it is plausible that a combination of these factors might explain our observations, more research on larger, underserved patient populations and better-defined measures of socioeconomic differences are needed to answer this complex question.
The path of recognizing and correcting our mistakes is not simple but must be done, and our underrepresented minority patients depend on our swift action. There are many places where we as a field of experts can and must do better—in communities, healthcare systems, and society in general.
Increasing community health literacy around MS, rebuilding trust, and addressing structural racism on every level is important. Outreach and educational programs that include in-person meetings and leverage social media platforms can help empower patients and their families—and hopefully increase trust in healthcare providers. Devising targeted interventions focusing on modifiable factors of a healthy lifestyle such as diet and exercise can increase community engagement and strengthen the support system for our patients. Increasing diversity in our own field of physicians, nurses, and other healthcare providers can also aid in strengthening mutual relationships.
Improving access to comprehensive MS care for underrepresented minorities who very often also lack robust insurance coverage is paramount. Recipients of comprehensive care are more likely to participate in research, as these patients receive more well-rounded care and have a lower risk of mismanaged comorbidities. Their involvement in the treatment plan is higher, which also improves compliance with treatment. Patients in comprehensive care centers are more likely to receive newer treatment agents with better efficacy without hindrance of monitoring barriers, and they are likely to benefit from treatment strategies using newly approved agents soon after US Food and Drug Administration approval.
Increasing research participation and, ideally, conducting a clinical trial devoted solely to studying MS in underrepresented minorities is something for which we should actively strive. Identifying the main factors prohibiting enrollment and retention of a high number of minority participants in trials is critical to success. Multiple deterrents in day-to-day life, very often directly connected to economic hardship and racism, pose a very real threat to equitable trial participation. To even consider a successful trial for underrepresented minorities, we must do better in devising strategies and accommodations to help overcome those barriers.
The underserved minorities with MS deserve and need our attention and focus. These patients have largely been neglected and forgotten, but now are emerging at the forefront of our attention—where they belong.
The persistent notion that multiple sclerosis (MS) is predominantly a White patient’s disease has been challenged by scientific data and our clinical experience in the field. Recent research has shown a higher risk of MS in non-White populations than originally thought. This may be surprising, but new data are influencing the way we now approach MS in under-represented minorities, bringing this topic to the forefront of scientific interest.
The early conviction that “there is no MS in minorities” led to underdiagnosis and misdiagnosis of MS in those patients, which in turn deepened these patients’ distrust of physicians and reluctance to seek further medical care, very often delivered by non-minority providers. Inequities in social determinants of health, low health literacy, and lack of private insurance, along with structural racism in healthcare, has further hindered active engagement with an already marginalized patient population in their MS care. This lack of engagement and lack of minorities in scientific research has proved to be unfavorable for MS research as well, creating large and persistent knowledge gaps in understanding MS course, severity, and response to treatment specific to this group. A 2014 PubMed search found 52,000 publications on MS in English, but in only 136 of those were minority patients with MS (Black or Hispanic/Latino) the primary research focus. In 2019, the same search indicated that the subsequent 5 years produced only 30 more articles focusing solely on minority patients.
Research participation of underrepresented minorities is another area where we, as a field, continue to fail these patients. A review of participant enrollment in MS clinical trials that took place between 1993 and 2006 showed a significant decrease in the percentage of enrolled Black patients (from 7% to about 4%). This trend did not improve by the DEFINE treatment trial (2012), in which only 2% of enrolled patients were Black. Of the 1246 participants in the 2019 SUNBEAM MS study, only 2 were Black. Low numbers of minority patients in trials prevent us from drawing any reasonable conclusion as to the efficacy of disease-modifying agents in those patients and make the goal of personalized medicine for this group impossible.
The results of the research conducted on these groups are compelling and should be prompting further work. Not only do Black patients have a higher risk of MS, but there is also now convincing evidence that MS in minorities is more severe overall, causing early progression of disability and necessitating assistive gait devices such as a cane or wheelchair. Minority patients tend to have more extensive involvement of spinal cord and infra-tentorial brain structures during the disease, which could explain the increased likelihood of more severe disease and earlier disability. Minority patients were admitted to nursing homes at a younger age, with greater physical and cognitive impairment than nonminority patients. A study looking at MS mortality between 1999 and 2015 found that Black males with MS had the highest mortality rate before age 45, and Black females before age 53. MS mortality increased with age but peaked at age 55 to 64 for Black patients and 65 to 74 for White patients. Underrepresented minorities are also less likely to use community resources, case management, medical equipment, and home nursing services. When looking at other measures of disease impact on these patients, studies evaluating magnetic resonance imaging (MRI) data showed higher lesion volume in Black patients with MS, as well as a higher degree of brain demyelination and atrophy when compared with White patients.
Treatment strategies currently used for underrepresented minority patients, as well as estimations of medication efficacy, treatment responses, and adverse-event profiles are largely driven by data from clinical trials with only minimal representation of those patients. How can we propose a patient-tailored and individualized treatment plan without these crucial data? Given that, to this day, not a single trial has focused solely on underrepresented minorities, we are left with either post hoc exploratory subgroup analyses of existing trials or pragmatic, observational, and very often retrospective studies using chart analysis. Notwithstanding the methodological flaws of either approach, prior studies did suggest worse response to platform therapies in Black patients, but equal response to high-efficacy therapies when compared with White patients.
Definitive biological underpinnings of disparities in disease severity have not been identified. In recent years, the field of health outcomes research has suggested we move away from considering racial categories as biologically distinct and instead focus on long-overlooked sociodemographic and modifiable lifestyle
factors. The role of diet, exercise, body mass index, smoking, and vascular comorbidities as risk factors associated with worse MS outcomes has been previously shown; however, these factors have not been rigorously assessed in underrepresented populations with MS. Recent studies focused on uncovering what drives the differences in MS severity in underrepresented populations disagree on the role biological differences, socioeconomic disparities, and structural racism in both healthcare settings and society play in answering this question. While it is plausible that a combination of these factors might explain our observations, more research on larger, underserved patient populations and better-defined measures of socioeconomic differences are needed to answer this complex question.
The path of recognizing and correcting our mistakes is not simple but must be done, and our underrepresented minority patients depend on our swift action. There are many places where we as a field of experts can and must do better—in communities, healthcare systems, and society in general.
Increasing community health literacy around MS, rebuilding trust, and addressing structural racism on every level is important. Outreach and educational programs that include in-person meetings and leverage social media platforms can help empower patients and their families—and hopefully increase trust in healthcare providers. Devising targeted interventions focusing on modifiable factors of a healthy lifestyle such as diet and exercise can increase community engagement and strengthen the support system for our patients. Increasing diversity in our own field of physicians, nurses, and other healthcare providers can also aid in strengthening mutual relationships.
Improving access to comprehensive MS care for underrepresented minorities who very often also lack robust insurance coverage is paramount. Recipients of comprehensive care are more likely to participate in research, as these patients receive more well-rounded care and have a lower risk of mismanaged comorbidities. Their involvement in the treatment plan is higher, which also improves compliance with treatment. Patients in comprehensive care centers are more likely to receive newer treatment agents with better efficacy without hindrance of monitoring barriers, and they are likely to benefit from treatment strategies using newly approved agents soon after US Food and Drug Administration approval.
Increasing research participation and, ideally, conducting a clinical trial devoted solely to studying MS in underrepresented minorities is something for which we should actively strive. Identifying the main factors prohibiting enrollment and retention of a high number of minority participants in trials is critical to success. Multiple deterrents in day-to-day life, very often directly connected to economic hardship and racism, pose a very real threat to equitable trial participation. To even consider a successful trial for underrepresented minorities, we must do better in devising strategies and accommodations to help overcome those barriers.
The underserved minorities with MS deserve and need our attention and focus. These patients have largely been neglected and forgotten, but now are emerging at the forefront of our attention—where they belong.
The persistent notion that multiple sclerosis (MS) is predominantly a White patient’s disease has been challenged by scientific data and our clinical experience in the field. Recent research has shown a higher risk of MS in non-White populations than originally thought. This may be surprising, but new data are influencing the way we now approach MS in under-represented minorities, bringing this topic to the forefront of scientific interest.
The early conviction that “there is no MS in minorities” led to underdiagnosis and misdiagnosis of MS in those patients, which in turn deepened these patients’ distrust of physicians and reluctance to seek further medical care, very often delivered by non-minority providers. Inequities in social determinants of health, low health literacy, and lack of private insurance, along with structural racism in healthcare, has further hindered active engagement with an already marginalized patient population in their MS care. This lack of engagement and lack of minorities in scientific research has proved to be unfavorable for MS research as well, creating large and persistent knowledge gaps in understanding MS course, severity, and response to treatment specific to this group. A 2014 PubMed search found 52,000 publications on MS in English, but in only 136 of those were minority patients with MS (Black or Hispanic/Latino) the primary research focus. In 2019, the same search indicated that the subsequent 5 years produced only 30 more articles focusing solely on minority patients.
Research participation of underrepresented minorities is another area where we, as a field, continue to fail these patients. A review of participant enrollment in MS clinical trials that took place between 1993 and 2006 showed a significant decrease in the percentage of enrolled Black patients (from 7% to about 4%). This trend did not improve by the DEFINE treatment trial (2012), in which only 2% of enrolled patients were Black. Of the 1246 participants in the 2019 SUNBEAM MS study, only 2 were Black. Low numbers of minority patients in trials prevent us from drawing any reasonable conclusion as to the efficacy of disease-modifying agents in those patients and make the goal of personalized medicine for this group impossible.
The results of the research conducted on these groups are compelling and should be prompting further work. Not only do Black patients have a higher risk of MS, but there is also now convincing evidence that MS in minorities is more severe overall, causing early progression of disability and necessitating assistive gait devices such as a cane or wheelchair. Minority patients tend to have more extensive involvement of spinal cord and infra-tentorial brain structures during the disease, which could explain the increased likelihood of more severe disease and earlier disability. Minority patients were admitted to nursing homes at a younger age, with greater physical and cognitive impairment than nonminority patients. A study looking at MS mortality between 1999 and 2015 found that Black males with MS had the highest mortality rate before age 45, and Black females before age 53. MS mortality increased with age but peaked at age 55 to 64 for Black patients and 65 to 74 for White patients. Underrepresented minorities are also less likely to use community resources, case management, medical equipment, and home nursing services. When looking at other measures of disease impact on these patients, studies evaluating magnetic resonance imaging (MRI) data showed higher lesion volume in Black patients with MS, as well as a higher degree of brain demyelination and atrophy when compared with White patients.
Treatment strategies currently used for underrepresented minority patients, as well as estimations of medication efficacy, treatment responses, and adverse-event profiles are largely driven by data from clinical trials with only minimal representation of those patients. How can we propose a patient-tailored and individualized treatment plan without these crucial data? Given that, to this day, not a single trial has focused solely on underrepresented minorities, we are left with either post hoc exploratory subgroup analyses of existing trials or pragmatic, observational, and very often retrospective studies using chart analysis. Notwithstanding the methodological flaws of either approach, prior studies did suggest worse response to platform therapies in Black patients, but equal response to high-efficacy therapies when compared with White patients.
Definitive biological underpinnings of disparities in disease severity have not been identified. In recent years, the field of health outcomes research has suggested we move away from considering racial categories as biologically distinct and instead focus on long-overlooked sociodemographic and modifiable lifestyle
factors. The role of diet, exercise, body mass index, smoking, and vascular comorbidities as risk factors associated with worse MS outcomes has been previously shown; however, these factors have not been rigorously assessed in underrepresented populations with MS. Recent studies focused on uncovering what drives the differences in MS severity in underrepresented populations disagree on the role biological differences, socioeconomic disparities, and structural racism in both healthcare settings and society play in answering this question. While it is plausible that a combination of these factors might explain our observations, more research on larger, underserved patient populations and better-defined measures of socioeconomic differences are needed to answer this complex question.
The path of recognizing and correcting our mistakes is not simple but must be done, and our underrepresented minority patients depend on our swift action. There are many places where we as a field of experts can and must do better—in communities, healthcare systems, and society in general.
Increasing community health literacy around MS, rebuilding trust, and addressing structural racism on every level is important. Outreach and educational programs that include in-person meetings and leverage social media platforms can help empower patients and their families—and hopefully increase trust in healthcare providers. Devising targeted interventions focusing on modifiable factors of a healthy lifestyle such as diet and exercise can increase community engagement and strengthen the support system for our patients. Increasing diversity in our own field of physicians, nurses, and other healthcare providers can also aid in strengthening mutual relationships.
Improving access to comprehensive MS care for underrepresented minorities who very often also lack robust insurance coverage is paramount. Recipients of comprehensive care are more likely to participate in research, as these patients receive more well-rounded care and have a lower risk of mismanaged comorbidities. Their involvement in the treatment plan is higher, which also improves compliance with treatment. Patients in comprehensive care centers are more likely to receive newer treatment agents with better efficacy without hindrance of monitoring barriers, and they are likely to benefit from treatment strategies using newly approved agents soon after US Food and Drug Administration approval.
Increasing research participation and, ideally, conducting a clinical trial devoted solely to studying MS in underrepresented minorities is something for which we should actively strive. Identifying the main factors prohibiting enrollment and retention of a high number of minority participants in trials is critical to success. Multiple deterrents in day-to-day life, very often directly connected to economic hardship and racism, pose a very real threat to equitable trial participation. To even consider a successful trial for underrepresented minorities, we must do better in devising strategies and accommodations to help overcome those barriers.
The underserved minorities with MS deserve and need our attention and focus. These patients have largely been neglected and forgotten, but now are emerging at the forefront of our attention—where they belong.
Multiple sclerosis has a misdiagnosis problem
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
DENVER – that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.
“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.
For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.
The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.
A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.
The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
The dangers of misdiagnosis
Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.
“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.
There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.
For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.
Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.
In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
Best hope for an accurate diagnosis
In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.
Dr. Coyle said that a comprehensive workup should include:
- A thorough neurologic history and exam.
- MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
- Adding spinal fluid evaluation, especially in any atypical cases.
- Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.
“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.
Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.
A version of this article originally appeared on Medscape.com.
AT CMSC 2023
No apparent drug interaction with ozanimod and antidepressants
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
AT CMSC 2023