ICYMI Multiple Sclerosis

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has received consulting fees from Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio and grant funding from Actelion, Alkermes, Bristol Myers Squibb, CorEvitas LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has received consulting fees from Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio and grant funding from Actelion, Alkermes, Bristol Myers Squibb, CorEvitas LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Patients with relapsing multiple sclerosis (MS) treated with intravenous ublituximab had fewer relapses and brain lesions compared with those treated with oral teriflunomide, although both therapies resulted in similar rates of worsening disability, according to results of the two identical phase 3 ULTIMATE I and II trials.

“In these two 96-week trials involving participants with MS, annualized relapse rates were lower with intravenous ublituximab than with oral teriflunomide. Ublituximab was associated with infusion-related reactions. Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing MS, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” noted lead author Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) University, and colleagues.

Two trials

The double-blind, double-dummy ULTIMATE I and II trials enrolled 549 and 545 participants respectively, with a median follow-up of 95 weeks. Subjects, aged between 18 and 55 years, were randomized to receive either oral placebo and intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72), or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary endpoint was the annualized relapse rate, defined as the number of confirmed MS relapses per participant-year, with a range of secondary end points including number of lesions on magnetic resonance imaging (MRI) by 96 weeks, and worsening of disability confirmed at 12 weeks.

Prevention and management of infusion-related reactions was with oral antihistamine and dexamethasone, administered 30 to 60 minutes before each intravenous dose of ublituximab or placebo, as well as reductions in infusion flow rates and discretionary acetaminophen.

Results for the primary endpoint in ULTIMATE I showed the adjusted annualized relapse rate over a period of 96 weeks was 0.08 in the ublituximab group and 0.19 in the teriflunomide group (rate ratio, 0.41; P < .001). Corresponding rates for ULTIMATE II were 0.09 and 0.18 (rate ratio, 0.51; P = .002).

The mean number of lesions in both ublituximab arms of the trials was 0.02 and 0.01 compared with 0.49 and 0.25 in the teriflunomide arms (rate ratios 0.03 and 0.04 respectively; P < .001 for both).
 

Similar disability worsening in both groups

A pooled analysis of the two trials showed worsening disability in 5.2% of the ublituximab group, and 5.9% of the teriflunomide group (hazard ratio, 0.84; P = 0.51). “In both trials, teriflunomide was associated with a numerically lower rate of worsening of disability than that reported in previous studies with this drug, but no conclusions can be drawn from these comparisons,” noted the authors.

Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group, consisting mainly of mild to moderate pyrexia, headache, chills, and influenza-like illness. “The reactions may have been related to cytokine release from immune cells (B and NK cells) on interaction of the Fc antibody domain with Fc gamma receptors on effector cells,” they suggested.

Although no opportunistic infections occurred, a higher frequency of infections, including serious infections, was observed with ublituximab (5.0%) than with teriflunomide (2.9%).

While the ULTIMATE trials showed no difference between ublituximab and teriflunomide in confirmed worsening of disability, only a small percentage of participants in either arm showed deterioration, Dr. Coyle remarked. “In a relatively short trial (96 weeks), in a relapsing population on active treatment, this result was not surprising … If the study was bigger, or longer it would increase the chances of seeing a progressive slow worsening component to affect the EDSS [Expanded Disability Status Scale],” she added.
 

Equivalent efficacy

Ultimately, “it appears likely” that ublituximab is “equivalent in efficacy” to the earlier anti-CD20 agents ocrelizumab and ofatumumab, Dr. Coyle said. While all three agents target B-cells, “ublituximab targets a novel CD20 binding site, and is bioengineered to have a particularly potent antibody dependent cell cytotoxicity lysis mechanism,” she added. “It has been touted to ultimately allow a short infusion of 1 hour.”

Although the serious infection rate is slightly higher with ublituximab (5.0% vs. 2.5% for ofatumumab, and 1.3% for ocrelizumab), “it is still low,” and infusion-related reactions are also higher with ublituximab, she added (47.7% vs. 20.2% and 34.3%, respectively). She suggested factors that might influence which treatment is chosen for a given patient might include cost, convenience, whether it is more or less likely to cause low IgG, interference with vaccination, or influence on cancer or COVID risk.

The trials were supported by TG Therapeutics.

Dr. Coyle has received consulting fees from Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Novartis, Sanofi Genzyme, and Viela Bio and grant funding from Actelion, Alkermes, Bristol Myers Squibb, CorEvitas LLD, Genentech/Roche, Sanofi Genzyme, MedDay, NINDS, and Novartis.

Cognitive impairment is a good predictor of physical disability progression in patients with multiple sclerosis (MS), new research suggests. In an analysis of more than 1,600 patients with secondary-progressive MS (SPMS), the likelihood of needing a wheelchair was almost doubled in those who had the worst scores on cognitive testing measures, compared with their counterparts who had the best scores.

“These findings should change our world view of MS,” study investigator Gavin Giovannoni, PhD, professor of neurology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, told attendees at the Congress of the European Academy of Neurology.

Expand data

Cognitive impairment occurs very early in the course of MS and is part of the disease, although to a greater or lesser degree depending on the patient, Dr. Giovannoni noted. Such impairment has a significant impact on quality of life for patients dealing with this disease, he added.

EXPAND was a phase 3 study of siponimod. Results showed the now-approved oral selective sphingosine 1–phosphate receptor modulator significantly reduced the risk for disability progression in patients with SPMS.

Using the EXPAND clinical trial database, the current researchers assessed 1,628 participants for an association between cognitive processing speed, as measured with the Symbol Digit Modality Test (SDMT), and physical disability progression, as measured with the Expanded Disability Status Scale (EDSS). A score of 7 or more on the EDSS indicates wheelchair dependence.

Dr. Giovannoni noted that cognitive processing speed is considered an indirect measure of thalamic network efficiency and functional brain reserve.

Investigators looked at both the core study, in which all patients continued on treatment or placebo for up to 37 months, and the core plus extension part, in which patients received treatment for up to 5 years.

They separated SDMT scores into quartiles: from worst (n = 435) to two intermediate quartiles (n = 808) to the best quartile (n = 385).
 

Wheelchair dependence

In addition, the researchers examined the predictive value by baseline SDMT, adjusting for treatment, age, gender, baseline EDSS score, baseline SCMT quartile, and treatment-by-baseline SCMT quartile interaction. On-study SDMT change (month 0-24) was also assessed after adjusting for treatment, age, gender, baseline EDS, baseline SCMT, and on-study change in SCMT quartile.

In the core study, those in the worst SDMT quartile at baseline were numerically more likely to reach deterioration to EDSS 7 or greater (wheelchair dependent), compared with patients in the best SDMT quartile (hazard ratio, 1.31; 95% confidence interval, .72-2.38; P = .371).

The short-term predictive value of baseline SDMT for reaching sustained EDSS of at least 7 was more obvious in the placebo arm than in the treatment arm.

Dr. Giovannoni said this is likely due to the treatment effect of siponimod preventing relatively more events in the worse quartile, and so reducing the risk for wheelchair dependency.

In the core plus extension part, there was an almost twofold increased risk for wheelchair dependence in the worse versus best SDMT groups (HR, 1.81; 95% CI, 1.17-2.78; P = .007).

Both baseline SDMT (HR, 1.81; P = .007) and on-study change in SDMT (HR, 1.73; P = .046) predicted wheelchair dependence in the long-term.
 

‘More important than a walking stick’

Measuring cognitive change over time “may be a more important predictor than a walking stick in terms of quality of life and outcomes, and it affects clinical decisionmaking,” said Dr. Giovannoni.

The findings are not novel, as post hoc analyses of other studies showed similar results. However, this new analysis adds more evidence to the importance of cognition in MS, Dr. Giovannoni noted.

“I have patients with EDSS of 0 or 1 who are profoundly disabled because of cognition. You shouldn’t just assume someone is not disabled because they don’t have physical disability,” he said.

However, Dr. Giovannoni noted that the study found an association and does not necessarily indicate a cause.
 

‘Valuable’ insights

Antonia Lefter, MD, of NeuroHope, Monza Oncologic Hospital, Bucharest, Romania, cochaired the session highlighting the research. Commenting on the study, she called this analysis from the “renowned” EXPAND study “valuable.”

In addition, it “underscores” the importance of assessing cognitive processing speed, as it may predict long-term disability progression in patients with SPMS, Dr. Lefter said.

The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Giovannoni, a steering committee member of the EXPAND trial, reported receiving consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, and Reva. He has also received compensation for research from Biogen, Roche, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. Dr. Lefter has reported no relevant financial relationships.

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

Cognitive impairment is a good predictor of physical disability progression in patients with multiple sclerosis (MS), new research suggests. In an analysis of more than 1,600 patients with secondary-progressive MS (SPMS), the likelihood of needing a wheelchair was almost doubled in those who had the worst scores on cognitive testing measures, compared with their counterparts who had the best scores.

“These findings should change our world view of MS,” study investigator Gavin Giovannoni, PhD, professor of neurology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, told attendees at the Congress of the European Academy of Neurology.

Expand data

Cognitive impairment occurs very early in the course of MS and is part of the disease, although to a greater or lesser degree depending on the patient, Dr. Giovannoni noted. Such impairment has a significant impact on quality of life for patients dealing with this disease, he added.

EXPAND was a phase 3 study of siponimod. Results showed the now-approved oral selective sphingosine 1–phosphate receptor modulator significantly reduced the risk for disability progression in patients with SPMS.

Using the EXPAND clinical trial database, the current researchers assessed 1,628 participants for an association between cognitive processing speed, as measured with the Symbol Digit Modality Test (SDMT), and physical disability progression, as measured with the Expanded Disability Status Scale (EDSS). A score of 7 or more on the EDSS indicates wheelchair dependence.

Dr. Giovannoni noted that cognitive processing speed is considered an indirect measure of thalamic network efficiency and functional brain reserve.

Investigators looked at both the core study, in which all patients continued on treatment or placebo for up to 37 months, and the core plus extension part, in which patients received treatment for up to 5 years.

They separated SDMT scores into quartiles: from worst (n = 435) to two intermediate quartiles (n = 808) to the best quartile (n = 385).
 

Wheelchair dependence

In addition, the researchers examined the predictive value by baseline SDMT, adjusting for treatment, age, gender, baseline EDSS score, baseline SCMT quartile, and treatment-by-baseline SCMT quartile interaction. On-study SDMT change (month 0-24) was also assessed after adjusting for treatment, age, gender, baseline EDS, baseline SCMT, and on-study change in SCMT quartile.

In the core study, those in the worst SDMT quartile at baseline were numerically more likely to reach deterioration to EDSS 7 or greater (wheelchair dependent), compared with patients in the best SDMT quartile (hazard ratio, 1.31; 95% confidence interval, .72-2.38; P = .371).

The short-term predictive value of baseline SDMT for reaching sustained EDSS of at least 7 was more obvious in the placebo arm than in the treatment arm.

Dr. Giovannoni said this is likely due to the treatment effect of siponimod preventing relatively more events in the worse quartile, and so reducing the risk for wheelchair dependency.

In the core plus extension part, there was an almost twofold increased risk for wheelchair dependence in the worse versus best SDMT groups (HR, 1.81; 95% CI, 1.17-2.78; P = .007).

Both baseline SDMT (HR, 1.81; P = .007) and on-study change in SDMT (HR, 1.73; P = .046) predicted wheelchair dependence in the long-term.
 

‘More important than a walking stick’

Measuring cognitive change over time “may be a more important predictor than a walking stick in terms of quality of life and outcomes, and it affects clinical decisionmaking,” said Dr. Giovannoni.

The findings are not novel, as post hoc analyses of other studies showed similar results. However, this new analysis adds more evidence to the importance of cognition in MS, Dr. Giovannoni noted.

“I have patients with EDSS of 0 or 1 who are profoundly disabled because of cognition. You shouldn’t just assume someone is not disabled because they don’t have physical disability,” he said.

However, Dr. Giovannoni noted that the study found an association and does not necessarily indicate a cause.
 

‘Valuable’ insights

Antonia Lefter, MD, of NeuroHope, Monza Oncologic Hospital, Bucharest, Romania, cochaired the session highlighting the research. Commenting on the study, she called this analysis from the “renowned” EXPAND study “valuable.”

In addition, it “underscores” the importance of assessing cognitive processing speed, as it may predict long-term disability progression in patients with SPMS, Dr. Lefter said.

The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Giovannoni, a steering committee member of the EXPAND trial, reported receiving consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, and Reva. He has also received compensation for research from Biogen, Roche, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. Dr. Lefter has reported no relevant financial relationships.

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

Cognitive impairment is a good predictor of physical disability progression in patients with multiple sclerosis (MS), new research suggests. In an analysis of more than 1,600 patients with secondary-progressive MS (SPMS), the likelihood of needing a wheelchair was almost doubled in those who had the worst scores on cognitive testing measures, compared with their counterparts who had the best scores.

“These findings should change our world view of MS,” study investigator Gavin Giovannoni, PhD, professor of neurology, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, told attendees at the Congress of the European Academy of Neurology.

Expand data

Cognitive impairment occurs very early in the course of MS and is part of the disease, although to a greater or lesser degree depending on the patient, Dr. Giovannoni noted. Such impairment has a significant impact on quality of life for patients dealing with this disease, he added.

EXPAND was a phase 3 study of siponimod. Results showed the now-approved oral selective sphingosine 1–phosphate receptor modulator significantly reduced the risk for disability progression in patients with SPMS.

Using the EXPAND clinical trial database, the current researchers assessed 1,628 participants for an association between cognitive processing speed, as measured with the Symbol Digit Modality Test (SDMT), and physical disability progression, as measured with the Expanded Disability Status Scale (EDSS). A score of 7 or more on the EDSS indicates wheelchair dependence.

Dr. Giovannoni noted that cognitive processing speed is considered an indirect measure of thalamic network efficiency and functional brain reserve.

Investigators looked at both the core study, in which all patients continued on treatment or placebo for up to 37 months, and the core plus extension part, in which patients received treatment for up to 5 years.

They separated SDMT scores into quartiles: from worst (n = 435) to two intermediate quartiles (n = 808) to the best quartile (n = 385).
 

Wheelchair dependence

In addition, the researchers examined the predictive value by baseline SDMT, adjusting for treatment, age, gender, baseline EDSS score, baseline SCMT quartile, and treatment-by-baseline SCMT quartile interaction. On-study SDMT change (month 0-24) was also assessed after adjusting for treatment, age, gender, baseline EDS, baseline SCMT, and on-study change in SCMT quartile.

In the core study, those in the worst SDMT quartile at baseline were numerically more likely to reach deterioration to EDSS 7 or greater (wheelchair dependent), compared with patients in the best SDMT quartile (hazard ratio, 1.31; 95% confidence interval, .72-2.38; P = .371).

The short-term predictive value of baseline SDMT for reaching sustained EDSS of at least 7 was more obvious in the placebo arm than in the treatment arm.

Dr. Giovannoni said this is likely due to the treatment effect of siponimod preventing relatively more events in the worse quartile, and so reducing the risk for wheelchair dependency.

In the core plus extension part, there was an almost twofold increased risk for wheelchair dependence in the worse versus best SDMT groups (HR, 1.81; 95% CI, 1.17-2.78; P = .007).

Both baseline SDMT (HR, 1.81; P = .007) and on-study change in SDMT (HR, 1.73; P = .046) predicted wheelchair dependence in the long-term.
 

‘More important than a walking stick’

Measuring cognitive change over time “may be a more important predictor than a walking stick in terms of quality of life and outcomes, and it affects clinical decisionmaking,” said Dr. Giovannoni.

The findings are not novel, as post hoc analyses of other studies showed similar results. However, this new analysis adds more evidence to the importance of cognition in MS, Dr. Giovannoni noted.

“I have patients with EDSS of 0 or 1 who are profoundly disabled because of cognition. You shouldn’t just assume someone is not disabled because they don’t have physical disability,” he said.

However, Dr. Giovannoni noted that the study found an association and does not necessarily indicate a cause.
 

‘Valuable’ insights

Antonia Lefter, MD, of NeuroHope, Monza Oncologic Hospital, Bucharest, Romania, cochaired the session highlighting the research. Commenting on the study, she called this analysis from the “renowned” EXPAND study “valuable.”

In addition, it “underscores” the importance of assessing cognitive processing speed, as it may predict long-term disability progression in patients with SPMS, Dr. Lefter said.

The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Giovannoni, a steering committee member of the EXPAND trial, reported receiving consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, and Reva. He has also received compensation for research from Biogen, Roche, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. Dr. Lefter has reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.

However, vaccine antibody response remains lower with anti-CD20 therapies.

One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.

Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).

Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
 

Vaccine response

The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.

The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).

The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.

Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.

“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.

“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.

Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.

“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.

He added that he reassures patients who need high-efficacy therapies that “they should use them.”

That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.

“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
 

Favorable findings

Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.

The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.

“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.

In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.

To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.

Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.

“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
 

Ponesimod results

In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.

The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.

Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.

Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.

A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.

None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.

“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.

“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.

In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.

“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
 

Concerns remain

In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.

“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.

“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.

Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”

Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.

“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.

Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.

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

NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.

However, vaccine antibody response remains lower with anti-CD20 therapies.

One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.

Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).

Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
 

Vaccine response

The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.

The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).

The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.

Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.

“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.

“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.

Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.

“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.

He added that he reassures patients who need high-efficacy therapies that “they should use them.”

That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.

“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
 

Favorable findings

Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.

The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.

“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.

In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.

To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.

Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.

“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
 

Ponesimod results

In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.

The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.

Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.

Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.

A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.

None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.

“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.

“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.

In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.

“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
 

Concerns remain

In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.

“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.

“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.

Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”

Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.

“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.

Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.

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

NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.

However, vaccine antibody response remains lower with anti-CD20 therapies.

One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.

Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).

Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
 

Vaccine response

The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.

The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).

The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.

Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.

“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.

“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.

Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.

“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.

He added that he reassures patients who need high-efficacy therapies that “they should use them.”

That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.

“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
 

Favorable findings

Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.

The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.

“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.

In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.

To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.

Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.

“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
 

Ponesimod results

In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.

The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.

Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.

Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.

A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.

None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.

“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.

“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.

In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.

“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
 

Concerns remain

In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.

“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.

“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.

Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”

Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.

“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.

Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.

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

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

NATIONAL HARBOR, MD – How often do patients with multiple sclerosis (MS) end up taking drugs that could dangerously interact with other medications they’re taking? A new German study provides a disturbing hint, a pharmacist who spoke at the annual meeting of the Consortium of Multiple Sclerosis Centers told colleagues: Out of 627 patients who took an average of 5.3 drugs each, about 1 in 25 faced a potentially severe interaction, and nearly two-thirds had at least one potentially risky interaction.

It’s crucial to “work on identifying those interactions,” said Jenelle H. Montgomery, PharmD, of Duke University Hospital, Durham, N.C., and to understand the risks. As she noted, interactions don’t just put patients at risk of adverse effects and hospitalization. They can also lead to secondary comorbidities and therapeutic failures.
 

Newer versus older drugs

Drug interactions in MS have become more common as disease-modifying therapies have evolved, she said. Some older drugs – such as glatiramer acetate, beta-interferons, and fumarates – have low interaction profiles. But newer drugs have more drug interactions caused in part by their side-effect profiles, oral routes of administration, and immunosuppressive instead of immunomodulatory effects, she said. Teriflunomide, for example, interacts with rosuvastatin and warfarin.

S1P modulators are especially complex on the interaction front, Dr. Montgomery said. Cardiology consults are recommended for patients taking siponimod, ozanimod, and ponesimod, and there are a number of potential interactions between these drugs and other medications.

In regard to other MS drugs, other medications can disrupt the metabolism of cladribine, she said, and the manufacturer recommends separating any other oral drug doses by 3 hours. Even MS-related drugs can interact: carbamazepine, used to treat MS-related neuropathic pain, interacts with drugs such as siponimod.
 

Who is most at risk?

How can medical professionals prevent harmful drug interactions in MS? One strategy could be to focus on patients who may be more susceptible. Dr. Montgomery highlighted the kinds of patients who were most at risk of polypharmacy, per the 2022 German study: older people, those with lower education levels, and those with more disability. And she pointed out that 77% of all drug interactions were between prescription drugs. Another 19% were between prescription drugs and over-the-counter medications, and 4% were between OTC drugs.

She also emphasized the importance of asking about everything that a patient is taking, including herbal supplements, as nearly 60% of people aged 20 and over take them, and about 75% of those over 60. A quarter of people over age 60 take at least four supplements.

Information about interactions with supplements isn’t always available, she said, but she did mention concerns about St. John’s wort interactions with siponimod and cladribine.

Dr. Montgomery also offered several tips: Periodically ask patients to bring in medication bottles or pillboxes; encourage annual checkups with primary physicians; and use drug resources such as Facts and Comparisons, Lexicomp, Clinical Pharmacology, Micromedex, and Natural Medicines.

Disclosures for Dr. Montgomery were not available.

NATIONAL HARBOR, MD – How often do patients with multiple sclerosis (MS) end up taking drugs that could dangerously interact with other medications they’re taking? A new German study provides a disturbing hint, a pharmacist who spoke at the annual meeting of the Consortium of Multiple Sclerosis Centers told colleagues: Out of 627 patients who took an average of 5.3 drugs each, about 1 in 25 faced a potentially severe interaction, and nearly two-thirds had at least one potentially risky interaction.

It’s crucial to “work on identifying those interactions,” said Jenelle H. Montgomery, PharmD, of Duke University Hospital, Durham, N.C., and to understand the risks. As she noted, interactions don’t just put patients at risk of adverse effects and hospitalization. They can also lead to secondary comorbidities and therapeutic failures.
 

Newer versus older drugs

Drug interactions in MS have become more common as disease-modifying therapies have evolved, she said. Some older drugs – such as glatiramer acetate, beta-interferons, and fumarates – have low interaction profiles. But newer drugs have more drug interactions caused in part by their side-effect profiles, oral routes of administration, and immunosuppressive instead of immunomodulatory effects, she said. Teriflunomide, for example, interacts with rosuvastatin and warfarin.

S1P modulators are especially complex on the interaction front, Dr. Montgomery said. Cardiology consults are recommended for patients taking siponimod, ozanimod, and ponesimod, and there are a number of potential interactions between these drugs and other medications.

In regard to other MS drugs, other medications can disrupt the metabolism of cladribine, she said, and the manufacturer recommends separating any other oral drug doses by 3 hours. Even MS-related drugs can interact: carbamazepine, used to treat MS-related neuropathic pain, interacts with drugs such as siponimod.
 

Who is most at risk?

How can medical professionals prevent harmful drug interactions in MS? One strategy could be to focus on patients who may be more susceptible. Dr. Montgomery highlighted the kinds of patients who were most at risk of polypharmacy, per the 2022 German study: older people, those with lower education levels, and those with more disability. And she pointed out that 77% of all drug interactions were between prescription drugs. Another 19% were between prescription drugs and over-the-counter medications, and 4% were between OTC drugs.

She also emphasized the importance of asking about everything that a patient is taking, including herbal supplements, as nearly 60% of people aged 20 and over take them, and about 75% of those over 60. A quarter of people over age 60 take at least four supplements.

Information about interactions with supplements isn’t always available, she said, but she did mention concerns about St. John’s wort interactions with siponimod and cladribine.

Dr. Montgomery also offered several tips: Periodically ask patients to bring in medication bottles or pillboxes; encourage annual checkups with primary physicians; and use drug resources such as Facts and Comparisons, Lexicomp, Clinical Pharmacology, Micromedex, and Natural Medicines.

Disclosures for Dr. Montgomery were not available.

NATIONAL HARBOR, MD – How often do patients with multiple sclerosis (MS) end up taking drugs that could dangerously interact with other medications they’re taking? A new German study provides a disturbing hint, a pharmacist who spoke at the annual meeting of the Consortium of Multiple Sclerosis Centers told colleagues: Out of 627 patients who took an average of 5.3 drugs each, about 1 in 25 faced a potentially severe interaction, and nearly two-thirds had at least one potentially risky interaction.

It’s crucial to “work on identifying those interactions,” said Jenelle H. Montgomery, PharmD, of Duke University Hospital, Durham, N.C., and to understand the risks. As she noted, interactions don’t just put patients at risk of adverse effects and hospitalization. They can also lead to secondary comorbidities and therapeutic failures.
 

Newer versus older drugs

Drug interactions in MS have become more common as disease-modifying therapies have evolved, she said. Some older drugs – such as glatiramer acetate, beta-interferons, and fumarates – have low interaction profiles. But newer drugs have more drug interactions caused in part by their side-effect profiles, oral routes of administration, and immunosuppressive instead of immunomodulatory effects, she said. Teriflunomide, for example, interacts with rosuvastatin and warfarin.

S1P modulators are especially complex on the interaction front, Dr. Montgomery said. Cardiology consults are recommended for patients taking siponimod, ozanimod, and ponesimod, and there are a number of potential interactions between these drugs and other medications.

In regard to other MS drugs, other medications can disrupt the metabolism of cladribine, she said, and the manufacturer recommends separating any other oral drug doses by 3 hours. Even MS-related drugs can interact: carbamazepine, used to treat MS-related neuropathic pain, interacts with drugs such as siponimod.
 

Who is most at risk?

How can medical professionals prevent harmful drug interactions in MS? One strategy could be to focus on patients who may be more susceptible. Dr. Montgomery highlighted the kinds of patients who were most at risk of polypharmacy, per the 2022 German study: older people, those with lower education levels, and those with more disability. And she pointed out that 77% of all drug interactions were between prescription drugs. Another 19% were between prescription drugs and over-the-counter medications, and 4% were between OTC drugs.

She also emphasized the importance of asking about everything that a patient is taking, including herbal supplements, as nearly 60% of people aged 20 and over take them, and about 75% of those over 60. A quarter of people over age 60 take at least four supplements.

Information about interactions with supplements isn’t always available, she said, but she did mention concerns about St. John’s wort interactions with siponimod and cladribine.

Dr. Montgomery also offered several tips: Periodically ask patients to bring in medication bottles or pillboxes; encourage annual checkups with primary physicians; and use drug resources such as Facts and Comparisons, Lexicomp, Clinical Pharmacology, Micromedex, and Natural Medicines.

Disclosures for Dr. Montgomery were not available.

NATIONAL HARBOR, MD. – Treatment guidelines are helpful in treating relapsing-remitting multiple sclerosis (RRMS), a neurologist told colleagues, but they’re only useful to an extent. Consider his 40-year-old female patient who’s averse to vaccines, often misses appointments, and seems to be unable to take blood pressure drugs as prescribed. In this case, the best strategy may not be the drug with the highest efficacy.

“There’s no pharmaceutical insert that’s going to tell you what to do with all of this information,” John R. Rinker II, MD, of the University of Alabama at Birmingham, said in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s important to not only know about the disease and the specifics of the pharmaceuticals, but also about the patient’s personal circumstances, their comorbidities, their social situation, and how it all ties together.”

Fortunately, he said, there are about two dozen medication options now available for RRMS. Noting that his scale is at best “a crude approximation of reality,” he said their efficacy runs the gamut from low (glatiramer acetate and beta-interferons) to high (cladribine, alemtuzumab). He places sphingosine-1 phosphate (SIP1) modulators in the mid-range in terms of efficacy and B cell-depleting agents and natalizumab toward the high side.
 

Why go low?

Why put someone on a low-efficacy drug? One reason is because they’re the safest options, he said, while the two highest-efficacy drugs – cladribine and alemtuzumab – are the least safe. But even the older, safer drugs can cause problems: Beta interferons can cause flu-like symptoms early on along with depression and miscarriage, and glatiramer acetate can spur injection site reactions and acute post injection syndrome “that can feel like a panic attack or even a heart attack.”

Dimethyl fumarate “is probably the easiest of the oral agents to initiate because there’s no extra doctor’s appointments. And there’s no concerns really about hair loss, liver failure, or birth defects,” he said. “But it’s one of the oral agents that has the most side effects associated with it.” Flushing is almost universal but “rarely a cause of discontinuation,” while gastrointestinal symptoms can lead to discontinuation.

Alemtuzumab, a high-efficacy drug that’s administered in two annual cycles, he said, is especially convenient but monthly labs are required for years to check for problems due to its dampening of the immune system. Patients on ocrelizumab must be closely monitored for the same reason.

There are other factors to consider. Lower-efficacy drugs tend to be better options in younger patients – “they’re more resilient, and they tend to recover a little bit better after their early relapses,” Dr. Rinker said.

The drugs are especially helpful in patients who recover well after their initial episodes and who have sensory instead of motor symptoms, he said.
 

The case for high efficacy

Higher-efficacy drugs are best for older patients and those with heavy disease burden.

What about the 40-year-old patient? She’s female (women get less sick from MS) and has low disease burden, suggesting that a lower-efficacy drug may be appropriate, he said. “On the other hand, she has an incomplete recovery, and she’s got spinal cord disease and motor symptoms, so the tendency is going to be more towards the higher-efficacy end of the [drug] spectrum.”

But which drug? S1P modulators aren’t a good option since they require redosing or titration if doses are missed: “It’s important that you don’t prescribe them to patients where you have concerns about compliance.”

Also, he said, “we don’t think we’re to the point that we’re willing to put her at risk of severe medical complications by putting her on medicines with a high monitoring burden like cladribine or alemtuzumab.”

The best option may be teriflunomide, a once-daily pill, he said. It’s forgiving if a patient misses a dose since the medication stays in the body for a long time.

“There’s no single right answer,” Dr. Rinker said. “But there are ways to eliminate a lot of the choices based upon what we know about the medications and what we know about the patient. Then we can tailor a specific range of medications for a specific patient.”

Dr. Rinker disclosed research support from GW Pharmaceuticals.

NATIONAL HARBOR, MD. – Treatment guidelines are helpful in treating relapsing-remitting multiple sclerosis (RRMS), a neurologist told colleagues, but they’re only useful to an extent. Consider his 40-year-old female patient who’s averse to vaccines, often misses appointments, and seems to be unable to take blood pressure drugs as prescribed. In this case, the best strategy may not be the drug with the highest efficacy.

“There’s no pharmaceutical insert that’s going to tell you what to do with all of this information,” John R. Rinker II, MD, of the University of Alabama at Birmingham, said in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s important to not only know about the disease and the specifics of the pharmaceuticals, but also about the patient’s personal circumstances, their comorbidities, their social situation, and how it all ties together.”

Fortunately, he said, there are about two dozen medication options now available for RRMS. Noting that his scale is at best “a crude approximation of reality,” he said their efficacy runs the gamut from low (glatiramer acetate and beta-interferons) to high (cladribine, alemtuzumab). He places sphingosine-1 phosphate (SIP1) modulators in the mid-range in terms of efficacy and B cell-depleting agents and natalizumab toward the high side.
 

Why go low?

Why put someone on a low-efficacy drug? One reason is because they’re the safest options, he said, while the two highest-efficacy drugs – cladribine and alemtuzumab – are the least safe. But even the older, safer drugs can cause problems: Beta interferons can cause flu-like symptoms early on along with depression and miscarriage, and glatiramer acetate can spur injection site reactions and acute post injection syndrome “that can feel like a panic attack or even a heart attack.”

Dimethyl fumarate “is probably the easiest of the oral agents to initiate because there’s no extra doctor’s appointments. And there’s no concerns really about hair loss, liver failure, or birth defects,” he said. “But it’s one of the oral agents that has the most side effects associated with it.” Flushing is almost universal but “rarely a cause of discontinuation,” while gastrointestinal symptoms can lead to discontinuation.

Alemtuzumab, a high-efficacy drug that’s administered in two annual cycles, he said, is especially convenient but monthly labs are required for years to check for problems due to its dampening of the immune system. Patients on ocrelizumab must be closely monitored for the same reason.

There are other factors to consider. Lower-efficacy drugs tend to be better options in younger patients – “they’re more resilient, and they tend to recover a little bit better after their early relapses,” Dr. Rinker said.

The drugs are especially helpful in patients who recover well after their initial episodes and who have sensory instead of motor symptoms, he said.
 

The case for high efficacy

Higher-efficacy drugs are best for older patients and those with heavy disease burden.

What about the 40-year-old patient? She’s female (women get less sick from MS) and has low disease burden, suggesting that a lower-efficacy drug may be appropriate, he said. “On the other hand, she has an incomplete recovery, and she’s got spinal cord disease and motor symptoms, so the tendency is going to be more towards the higher-efficacy end of the [drug] spectrum.”

But which drug? S1P modulators aren’t a good option since they require redosing or titration if doses are missed: “It’s important that you don’t prescribe them to patients where you have concerns about compliance.”

Also, he said, “we don’t think we’re to the point that we’re willing to put her at risk of severe medical complications by putting her on medicines with a high monitoring burden like cladribine or alemtuzumab.”

The best option may be teriflunomide, a once-daily pill, he said. It’s forgiving if a patient misses a dose since the medication stays in the body for a long time.

“There’s no single right answer,” Dr. Rinker said. “But there are ways to eliminate a lot of the choices based upon what we know about the medications and what we know about the patient. Then we can tailor a specific range of medications for a specific patient.”

Dr. Rinker disclosed research support from GW Pharmaceuticals.

NATIONAL HARBOR, MD. – Treatment guidelines are helpful in treating relapsing-remitting multiple sclerosis (RRMS), a neurologist told colleagues, but they’re only useful to an extent. Consider his 40-year-old female patient who’s averse to vaccines, often misses appointments, and seems to be unable to take blood pressure drugs as prescribed. In this case, the best strategy may not be the drug with the highest efficacy.

“There’s no pharmaceutical insert that’s going to tell you what to do with all of this information,” John R. Rinker II, MD, of the University of Alabama at Birmingham, said in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. “It’s important to not only know about the disease and the specifics of the pharmaceuticals, but also about the patient’s personal circumstances, their comorbidities, their social situation, and how it all ties together.”

Fortunately, he said, there are about two dozen medication options now available for RRMS. Noting that his scale is at best “a crude approximation of reality,” he said their efficacy runs the gamut from low (glatiramer acetate and beta-interferons) to high (cladribine, alemtuzumab). He places sphingosine-1 phosphate (SIP1) modulators in the mid-range in terms of efficacy and B cell-depleting agents and natalizumab toward the high side.
 

Why go low?

Why put someone on a low-efficacy drug? One reason is because they’re the safest options, he said, while the two highest-efficacy drugs – cladribine and alemtuzumab – are the least safe. But even the older, safer drugs can cause problems: Beta interferons can cause flu-like symptoms early on along with depression and miscarriage, and glatiramer acetate can spur injection site reactions and acute post injection syndrome “that can feel like a panic attack or even a heart attack.”

Dimethyl fumarate “is probably the easiest of the oral agents to initiate because there’s no extra doctor’s appointments. And there’s no concerns really about hair loss, liver failure, or birth defects,” he said. “But it’s one of the oral agents that has the most side effects associated with it.” Flushing is almost universal but “rarely a cause of discontinuation,” while gastrointestinal symptoms can lead to discontinuation.

Alemtuzumab, a high-efficacy drug that’s administered in two annual cycles, he said, is especially convenient but monthly labs are required for years to check for problems due to its dampening of the immune system. Patients on ocrelizumab must be closely monitored for the same reason.

There are other factors to consider. Lower-efficacy drugs tend to be better options in younger patients – “they’re more resilient, and they tend to recover a little bit better after their early relapses,” Dr. Rinker said.

The drugs are especially helpful in patients who recover well after their initial episodes and who have sensory instead of motor symptoms, he said.
 

The case for high efficacy

Higher-efficacy drugs are best for older patients and those with heavy disease burden.

What about the 40-year-old patient? She’s female (women get less sick from MS) and has low disease burden, suggesting that a lower-efficacy drug may be appropriate, he said. “On the other hand, she has an incomplete recovery, and she’s got spinal cord disease and motor symptoms, so the tendency is going to be more towards the higher-efficacy end of the [drug] spectrum.”

But which drug? S1P modulators aren’t a good option since they require redosing or titration if doses are missed: “It’s important that you don’t prescribe them to patients where you have concerns about compliance.”

Also, he said, “we don’t think we’re to the point that we’re willing to put her at risk of severe medical complications by putting her on medicines with a high monitoring burden like cladribine or alemtuzumab.”

The best option may be teriflunomide, a once-daily pill, he said. It’s forgiving if a patient misses a dose since the medication stays in the body for a long time.

“There’s no single right answer,” Dr. Rinker said. “But there are ways to eliminate a lot of the choices based upon what we know about the medications and what we know about the patient. Then we can tailor a specific range of medications for a specific patient.”

Dr. Rinker disclosed research support from GW Pharmaceuticals.

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

B-cell depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
 

No significant differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.

“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.

Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
 

A new era?

Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.

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

NATIONAL HARBOR, MD. – Positive data support autologous hematopoietic stem-cell transplantation in patients with multiple sclerosis (MS), a neurologist told colleagues, and it’s a “reasonable option for people that have largely failed other disease-modifying options.” But, he said, it remains unclear which patients should undergo the procedure.

An especially pressing question is “whether transplant is an alternative to our high-efficacy disease-modifying therapies” (DMTs) in some high-risk patients, Jeffrey A. Cohen, MD, director of experimental therapeutics at Cleveland Clinic’s Mellen Center, said in a presidential lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers.

A handful of ongoing randomized controlled trials will bring answers, he said.

Stem cell therapy exists because there are gaps in MS treatment, Dr. Cohen said. “We have now more than 20 medications. However, none of these therapies is completely effective in all patients. In particular, there are some patients with very active disease who continue to have relapses or new MRI lesion activity despite treatment with all of the available therapies.”

And in progressive MS, the efficacy of a couple of agents is modest and mainly for people with ongoing focal lesion activity, he said. “Finally, all of these currently available therapies are intended primarily to prevent the accumulation of damage, and none of them directly promotes repair. So despite our progress in the field, there still are a number of unmet needs.”
 

‘Rebooting’ the immune system

Several types of stem cell therapy exist, including remyelination and anti-inflammatory therapy, Dr. Cohen said. In his lecture, he focused on immunoablative or myeloablative therapy followed by autologous hematopoietic stem cell transplantation.

This “complicated, multistep procedure” involves first eliminating the immune system to get rid of pathogenic inflammatory cells. This “big component is actually the therapy for MS. It’s also the step that has the most potential complications,” he said.

According to Dr. Cohen, the next step has been described as “rebooting” the immune system.

Does this procedure help patients with MS? In relapsing MS, reports suggest there’s “almost complete abrogation of disease activity following transplant,” he said, “a benefit that’s lasted 5-10-15 years. In addition, there’s also a benefit on the accumulation of CNS damage as measured by whole brain atrophy.”

Recent data, he said, suggests that MS patients most likely to benefit are young, developed MS relatively recently, are still ambulatory, and have highly active MS despite treatment with first- and second-line agents.

However, there have only been two randomized controlled trials of stem cell transplantation versus DMT, and Dr. Cohen said both studies have limitations. The first one, from 2015, is very small, with just 21 subjects. The second study – from 2019 – is larger (n = 103), but some patients weren’t taking higher-efficacy DMTs.

Other research is more promising: Dr. Cohen highlighted a 2017 analysis that found patients with relapsing/remitting MS who underwent stem-cell transplantation were more likely to be symptom-free at 2 years (78%-83%) than those who took DMTs in clinical trials (13%-46%).
 

Clinical concerns

As for side effects of stem cell transplantation, Dr. Cohen said, “most patients have some adverse effects during the procedure itself. There may be an MS relapse or pseudorelapses in association with the mobilization and the conditioning regimens.”

A wide range of other adverse effects is possible before the immune system is reconstituted, he said, including reactivation of various virus infections, such as HPV, CMV or EPV (Epstein-Barr virus), secondary autoimmune phenomenon, and secondary malignancy. EPV infection is also common after transplant, and is “probably the most troublesome posttransplant complication from a management point of view,” he said.

“Thankfully, once the patient ... recovers from the transplant procedure, late adverse effects are relatively uncommon, the most common of which would be infertility,” he said. “There have been some reports of successful pregnancies following transplant, but it’s important to advise people who are considering transplant that most men and women have infertility after the procedure. So if they desire to have children afterward, they need to be counseled on necessary preparations to do that.”

What about progressive multifocal leukoencephalopathy (PML), which seems a possible risk because of the suppression of the immune system? Dr. Cohen is aware of one case linked to a stem-cell transplant, and it may not have been caused by the procedure.

Cost is another potential obstacle, he noted. The National Multiple Sclerosis Society estimates that autologous hematopoietic stem cell transplants cost $150,000 on average in the U.S., although the expense varies widely.
 

Unanswered questions

Moving forward, Dr. Cohen said it remains unclear how these procedures fare against the newest generations of DMTs in MS. Five phase 3 randomized controlled trials are now trying to clarify the matter, he said, by pitting stem-cell transplantation against various MS drugs – alemtuzumab, cladribine, natalizumab, ocrelizumab, and rituximab.

There are also unanswered questions about the best conditioning regimens in the transplants, he said, and lack of clarity about where to draw the line between eligible and ineligible patients with MS. “How many DMTs does the person have to fail? What’s the upper level of disability beyond which it is unlikely to be helpful and more likely to cause harm?”

He added: “A particular profile that we’re seeing increasingly at our center is someone with very active disease and onset who gets started on a high-efficacy therapy as their first therapy and effectively stops relapses and MRI lesion activity. But within a couple of years, we can tell that they’re already starting to accumulate disability. Is this someone for whom transplant might be useful, and by extension, is transplant appropriate as the first therapy in some patients? And beyond MS, is transplant a consideration for other autoimmune CNS disorders? There are lots of unanswered questions, which future studies will hopefully begin to address.”

Dr. Cohen reports consulting for Biogen, Bristol‐Myers Squibb, Convelo, EMD Serono, GlaxoSmithKline (now GSK), Janssen, Mylan, and PSI. He serves as an editor of Multiple Sclerosis Journal.

NATIONAL HARBOR, MD. – Positive data support autologous hematopoietic stem-cell transplantation in patients with multiple sclerosis (MS), a neurologist told colleagues, and it’s a “reasonable option for people that have largely failed other disease-modifying options.” But, he said, it remains unclear which patients should undergo the procedure.

An especially pressing question is “whether transplant is an alternative to our high-efficacy disease-modifying therapies” (DMTs) in some high-risk patients, Jeffrey A. Cohen, MD, director of experimental therapeutics at Cleveland Clinic’s Mellen Center, said in a presidential lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers.

A handful of ongoing randomized controlled trials will bring answers, he said.

Stem cell therapy exists because there are gaps in MS treatment, Dr. Cohen said. “We have now more than 20 medications. However, none of these therapies is completely effective in all patients. In particular, there are some patients with very active disease who continue to have relapses or new MRI lesion activity despite treatment with all of the available therapies.”

And in progressive MS, the efficacy of a couple of agents is modest and mainly for people with ongoing focal lesion activity, he said. “Finally, all of these currently available therapies are intended primarily to prevent the accumulation of damage, and none of them directly promotes repair. So despite our progress in the field, there still are a number of unmet needs.”
 

‘Rebooting’ the immune system

Several types of stem cell therapy exist, including remyelination and anti-inflammatory therapy, Dr. Cohen said. In his lecture, he focused on immunoablative or myeloablative therapy followed by autologous hematopoietic stem cell transplantation.

This “complicated, multistep procedure” involves first eliminating the immune system to get rid of pathogenic inflammatory cells. This “big component is actually the therapy for MS. It’s also the step that has the most potential complications,” he said.

According to Dr. Cohen, the next step has been described as “rebooting” the immune system.

Does this procedure help patients with MS? In relapsing MS, reports suggest there’s “almost complete abrogation of disease activity following transplant,” he said, “a benefit that’s lasted 5-10-15 years. In addition, there’s also a benefit on the accumulation of CNS damage as measured by whole brain atrophy.”

Recent data, he said, suggests that MS patients most likely to benefit are young, developed MS relatively recently, are still ambulatory, and have highly active MS despite treatment with first- and second-line agents.

However, there have only been two randomized controlled trials of stem cell transplantation versus DMT, and Dr. Cohen said both studies have limitations. The first one, from 2015, is very small, with just 21 subjects. The second study – from 2019 – is larger (n = 103), but some patients weren’t taking higher-efficacy DMTs.

Other research is more promising: Dr. Cohen highlighted a 2017 analysis that found patients with relapsing/remitting MS who underwent stem-cell transplantation were more likely to be symptom-free at 2 years (78%-83%) than those who took DMTs in clinical trials (13%-46%).
 

Clinical concerns

As for side effects of stem cell transplantation, Dr. Cohen said, “most patients have some adverse effects during the procedure itself. There may be an MS relapse or pseudorelapses in association with the mobilization and the conditioning regimens.”

A wide range of other adverse effects is possible before the immune system is reconstituted, he said, including reactivation of various virus infections, such as HPV, CMV or EPV (Epstein-Barr virus), secondary autoimmune phenomenon, and secondary malignancy. EPV infection is also common after transplant, and is “probably the most troublesome posttransplant complication from a management point of view,” he said.

“Thankfully, once the patient ... recovers from the transplant procedure, late adverse effects are relatively uncommon, the most common of which would be infertility,” he said. “There have been some reports of successful pregnancies following transplant, but it’s important to advise people who are considering transplant that most men and women have infertility after the procedure. So if they desire to have children afterward, they need to be counseled on necessary preparations to do that.”

What about progressive multifocal leukoencephalopathy (PML), which seems a possible risk because of the suppression of the immune system? Dr. Cohen is aware of one case linked to a stem-cell transplant, and it may not have been caused by the procedure.

Cost is another potential obstacle, he noted. The National Multiple Sclerosis Society estimates that autologous hematopoietic stem cell transplants cost $150,000 on average in the U.S., although the expense varies widely.
 

Unanswered questions

Moving forward, Dr. Cohen said it remains unclear how these procedures fare against the newest generations of DMTs in MS. Five phase 3 randomized controlled trials are now trying to clarify the matter, he said, by pitting stem-cell transplantation against various MS drugs – alemtuzumab, cladribine, natalizumab, ocrelizumab, and rituximab.

There are also unanswered questions about the best conditioning regimens in the transplants, he said, and lack of clarity about where to draw the line between eligible and ineligible patients with MS. “How many DMTs does the person have to fail? What’s the upper level of disability beyond which it is unlikely to be helpful and more likely to cause harm?”

He added: “A particular profile that we’re seeing increasingly at our center is someone with very active disease and onset who gets started on a high-efficacy therapy as their first therapy and effectively stops relapses and MRI lesion activity. But within a couple of years, we can tell that they’re already starting to accumulate disability. Is this someone for whom transplant might be useful, and by extension, is transplant appropriate as the first therapy in some patients? And beyond MS, is transplant a consideration for other autoimmune CNS disorders? There are lots of unanswered questions, which future studies will hopefully begin to address.”

Dr. Cohen reports consulting for Biogen, Bristol‐Myers Squibb, Convelo, EMD Serono, GlaxoSmithKline (now GSK), Janssen, Mylan, and PSI. He serves as an editor of Multiple Sclerosis Journal.

NATIONAL HARBOR, MD. – Positive data support autologous hematopoietic stem-cell transplantation in patients with multiple sclerosis (MS), a neurologist told colleagues, and it’s a “reasonable option for people that have largely failed other disease-modifying options.” But, he said, it remains unclear which patients should undergo the procedure.

An especially pressing question is “whether transplant is an alternative to our high-efficacy disease-modifying therapies” (DMTs) in some high-risk patients, Jeffrey A. Cohen, MD, director of experimental therapeutics at Cleveland Clinic’s Mellen Center, said in a presidential lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers.

A handful of ongoing randomized controlled trials will bring answers, he said.

Stem cell therapy exists because there are gaps in MS treatment, Dr. Cohen said. “We have now more than 20 medications. However, none of these therapies is completely effective in all patients. In particular, there are some patients with very active disease who continue to have relapses or new MRI lesion activity despite treatment with all of the available therapies.”

And in progressive MS, the efficacy of a couple of agents is modest and mainly for people with ongoing focal lesion activity, he said. “Finally, all of these currently available therapies are intended primarily to prevent the accumulation of damage, and none of them directly promotes repair. So despite our progress in the field, there still are a number of unmet needs.”
 

‘Rebooting’ the immune system

Several types of stem cell therapy exist, including remyelination and anti-inflammatory therapy, Dr. Cohen said. In his lecture, he focused on immunoablative or myeloablative therapy followed by autologous hematopoietic stem cell transplantation.

This “complicated, multistep procedure” involves first eliminating the immune system to get rid of pathogenic inflammatory cells. This “big component is actually the therapy for MS. It’s also the step that has the most potential complications,” he said.

According to Dr. Cohen, the next step has been described as “rebooting” the immune system.

Does this procedure help patients with MS? In relapsing MS, reports suggest there’s “almost complete abrogation of disease activity following transplant,” he said, “a benefit that’s lasted 5-10-15 years. In addition, there’s also a benefit on the accumulation of CNS damage as measured by whole brain atrophy.”

Recent data, he said, suggests that MS patients most likely to benefit are young, developed MS relatively recently, are still ambulatory, and have highly active MS despite treatment with first- and second-line agents.

However, there have only been two randomized controlled trials of stem cell transplantation versus DMT, and Dr. Cohen said both studies have limitations. The first one, from 2015, is very small, with just 21 subjects. The second study – from 2019 – is larger (n = 103), but some patients weren’t taking higher-efficacy DMTs.

Other research is more promising: Dr. Cohen highlighted a 2017 analysis that found patients with relapsing/remitting MS who underwent stem-cell transplantation were more likely to be symptom-free at 2 years (78%-83%) than those who took DMTs in clinical trials (13%-46%).
 

Clinical concerns

As for side effects of stem cell transplantation, Dr. Cohen said, “most patients have some adverse effects during the procedure itself. There may be an MS relapse or pseudorelapses in association with the mobilization and the conditioning regimens.”

A wide range of other adverse effects is possible before the immune system is reconstituted, he said, including reactivation of various virus infections, such as HPV, CMV or EPV (Epstein-Barr virus), secondary autoimmune phenomenon, and secondary malignancy. EPV infection is also common after transplant, and is “probably the most troublesome posttransplant complication from a management point of view,” he said.

“Thankfully, once the patient ... recovers from the transplant procedure, late adverse effects are relatively uncommon, the most common of which would be infertility,” he said. “There have been some reports of successful pregnancies following transplant, but it’s important to advise people who are considering transplant that most men and women have infertility after the procedure. So if they desire to have children afterward, they need to be counseled on necessary preparations to do that.”

What about progressive multifocal leukoencephalopathy (PML), which seems a possible risk because of the suppression of the immune system? Dr. Cohen is aware of one case linked to a stem-cell transplant, and it may not have been caused by the procedure.

Cost is another potential obstacle, he noted. The National Multiple Sclerosis Society estimates that autologous hematopoietic stem cell transplants cost $150,000 on average in the U.S., although the expense varies widely.
 

Unanswered questions

Moving forward, Dr. Cohen said it remains unclear how these procedures fare against the newest generations of DMTs in MS. Five phase 3 randomized controlled trials are now trying to clarify the matter, he said, by pitting stem-cell transplantation against various MS drugs – alemtuzumab, cladribine, natalizumab, ocrelizumab, and rituximab.

There are also unanswered questions about the best conditioning regimens in the transplants, he said, and lack of clarity about where to draw the line between eligible and ineligible patients with MS. “How many DMTs does the person have to fail? What’s the upper level of disability beyond which it is unlikely to be helpful and more likely to cause harm?”

He added: “A particular profile that we’re seeing increasingly at our center is someone with very active disease and onset who gets started on a high-efficacy therapy as their first therapy and effectively stops relapses and MRI lesion activity. But within a couple of years, we can tell that they’re already starting to accumulate disability. Is this someone for whom transplant might be useful, and by extension, is transplant appropriate as the first therapy in some patients? And beyond MS, is transplant a consideration for other autoimmune CNS disorders? There are lots of unanswered questions, which future studies will hopefully begin to address.”

Dr. Cohen reports consulting for Biogen, Bristol‐Myers Squibb, Convelo, EMD Serono, GlaxoSmithKline (now GSK), Janssen, Mylan, and PSI. He serves as an editor of Multiple Sclerosis Journal.

NATIONAL HARBOR, MD. – While patients with multiple sclerosis (MS) don’t seem to be more likely to be infected with COVID-19, a neurologist told colleagues, the jury is still out over whether they face a higher mortality risk, especially if they take certain disease-modifying therapies (DMTs)

In regard to MS overall, “the data is conflicting, but any increased risk of mortality appears to be slight. And it appears to be chiefly the consequences associated with comorbidities as seen in other populations,” Joseph R. Berger, MD, said at the John F. Kurtzke Memorial Lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers. “If you’re old, if you’re infirm, if you have obesity and cardiovascular disease and underlying pulmonary disease, you’re at risk of dying yourself. It’s not so much the MS,” said Dr. Berger, professor of neurology at the Hospital of the University of Pennsylvania and chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia.

Dr. Berger had his own COVID-19 story to tell: He couldn’t attend the conference in person because he was quarantining in Portugal since he tested positive. At press time, he was faring well but had reported 4 days of intense back pain.

In regard to MS and COVID-19, Dr. Berger said consistent research suggests that patients with MS aren’t at higher risk of COVID infection, although hospitalization may be more common. There may be a very small increase in risk of MS relapse in patients with COVID-19, he said, but pseudorelapses are far more common. As for mortality, he highlighted a 2021 pooled analysis of 18 studies with 5,634 patients that suggested they had a crude death rate of 1.97%, standardized lethality ratio of 1.24, and a 24% increased risk of death.

Dr. Berger is skeptical of these findings, however, in light of overall death rate numbers. Early on in the pandemic, the fatality rate in China was estimated at 2.3%.

He said he’s more convinced by a retrospective 2021 German COVID-19 study that compared 551 patients with MS to 156,973 other patients and found lower rates of ICU admission (17.1% in patients with MS vs. 22.7% in those without it), ventilation (9.8% vs. 14.5%), and in‐hospital mortality (11.1% vs. 19.3%).

Meanwhile, a 2021 systematic review found no increase in mortality among 4,310 patients with MS (3% death rate, 20.7% hospitalization), but the death risk was highest among those on no DMTs and those taking anti-CD20 monoclonal antibodies. The COViMS Registry has reported similar findings regarding the anti-CD20 drugs rituximab and ocrelizumab, Dr. Berger noted, and a pooled study of Italian and French data links the monoclonal antibodies to more severe COVID. A 2021 aggregated study also linked the antibodies to increased risk of hospitalization and ICU admission.

“Anti-CD20 monoclonal antibodies appear to increase the risk of hospitalization and perhaps the acquisition of the virus, ICU admission, maybe death,” he said, with rituximab appearing to pose the most risk, followed by ocrelizumab and ofatumumab. “And it appears that the platform [older] therapies may be associated with lesser mortality.”

As for nondrug factors, Dr. Berger said, studies have linked higher risk to age, male sex, and comorbidities.

COVID-19 vaccines are another area of concern, he said. “The recommendation is to administer vaccination prior to the initiation of the anti-CD20s, alemtuzumab, and cladribine, and wait a period of time. Three months is ideal, maybe a little longer, because it appears that the antibody response seems to be best as your CD19 count starts to return.”

Finally, Dr. Berger noted that “passive vaccination” is now available via Evusheld (tixagevimab and cilgavimab) as a preexposure treatment for people with moderate to severe immune compromise who may not mount an effective immune response to COVID-19 vaccination or those who are allergic.

Dr. Berger reported multiple disclosures.

NATIONAL HARBOR, MD. – While patients with multiple sclerosis (MS) don’t seem to be more likely to be infected with COVID-19, a neurologist told colleagues, the jury is still out over whether they face a higher mortality risk, especially if they take certain disease-modifying therapies (DMTs)

In regard to MS overall, “the data is conflicting, but any increased risk of mortality appears to be slight. And it appears to be chiefly the consequences associated with comorbidities as seen in other populations,” Joseph R. Berger, MD, said at the John F. Kurtzke Memorial Lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers. “If you’re old, if you’re infirm, if you have obesity and cardiovascular disease and underlying pulmonary disease, you’re at risk of dying yourself. It’s not so much the MS,” said Dr. Berger, professor of neurology at the Hospital of the University of Pennsylvania and chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia.

Dr. Berger had his own COVID-19 story to tell: He couldn’t attend the conference in person because he was quarantining in Portugal since he tested positive. At press time, he was faring well but had reported 4 days of intense back pain.

In regard to MS and COVID-19, Dr. Berger said consistent research suggests that patients with MS aren’t at higher risk of COVID infection, although hospitalization may be more common. There may be a very small increase in risk of MS relapse in patients with COVID-19, he said, but pseudorelapses are far more common. As for mortality, he highlighted a 2021 pooled analysis of 18 studies with 5,634 patients that suggested they had a crude death rate of 1.97%, standardized lethality ratio of 1.24, and a 24% increased risk of death.

Dr. Berger is skeptical of these findings, however, in light of overall death rate numbers. Early on in the pandemic, the fatality rate in China was estimated at 2.3%.

He said he’s more convinced by a retrospective 2021 German COVID-19 study that compared 551 patients with MS to 156,973 other patients and found lower rates of ICU admission (17.1% in patients with MS vs. 22.7% in those without it), ventilation (9.8% vs. 14.5%), and in‐hospital mortality (11.1% vs. 19.3%).

Meanwhile, a 2021 systematic review found no increase in mortality among 4,310 patients with MS (3% death rate, 20.7% hospitalization), but the death risk was highest among those on no DMTs and those taking anti-CD20 monoclonal antibodies. The COViMS Registry has reported similar findings regarding the anti-CD20 drugs rituximab and ocrelizumab, Dr. Berger noted, and a pooled study of Italian and French data links the monoclonal antibodies to more severe COVID. A 2021 aggregated study also linked the antibodies to increased risk of hospitalization and ICU admission.

“Anti-CD20 monoclonal antibodies appear to increase the risk of hospitalization and perhaps the acquisition of the virus, ICU admission, maybe death,” he said, with rituximab appearing to pose the most risk, followed by ocrelizumab and ofatumumab. “And it appears that the platform [older] therapies may be associated with lesser mortality.”

As for nondrug factors, Dr. Berger said, studies have linked higher risk to age, male sex, and comorbidities.

COVID-19 vaccines are another area of concern, he said. “The recommendation is to administer vaccination prior to the initiation of the anti-CD20s, alemtuzumab, and cladribine, and wait a period of time. Three months is ideal, maybe a little longer, because it appears that the antibody response seems to be best as your CD19 count starts to return.”

Finally, Dr. Berger noted that “passive vaccination” is now available via Evusheld (tixagevimab and cilgavimab) as a preexposure treatment for people with moderate to severe immune compromise who may not mount an effective immune response to COVID-19 vaccination or those who are allergic.

Dr. Berger reported multiple disclosures.

NATIONAL HARBOR, MD. – While patients with multiple sclerosis (MS) don’t seem to be more likely to be infected with COVID-19, a neurologist told colleagues, the jury is still out over whether they face a higher mortality risk, especially if they take certain disease-modifying therapies (DMTs)

In regard to MS overall, “the data is conflicting, but any increased risk of mortality appears to be slight. And it appears to be chiefly the consequences associated with comorbidities as seen in other populations,” Joseph R. Berger, MD, said at the John F. Kurtzke Memorial Lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers. “If you’re old, if you’re infirm, if you have obesity and cardiovascular disease and underlying pulmonary disease, you’re at risk of dying yourself. It’s not so much the MS,” said Dr. Berger, professor of neurology at the Hospital of the University of Pennsylvania and chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia.

Dr. Berger had his own COVID-19 story to tell: He couldn’t attend the conference in person because he was quarantining in Portugal since he tested positive. At press time, he was faring well but had reported 4 days of intense back pain.

In regard to MS and COVID-19, Dr. Berger said consistent research suggests that patients with MS aren’t at higher risk of COVID infection, although hospitalization may be more common. There may be a very small increase in risk of MS relapse in patients with COVID-19, he said, but pseudorelapses are far more common. As for mortality, he highlighted a 2021 pooled analysis of 18 studies with 5,634 patients that suggested they had a crude death rate of 1.97%, standardized lethality ratio of 1.24, and a 24% increased risk of death.

Dr. Berger is skeptical of these findings, however, in light of overall death rate numbers. Early on in the pandemic, the fatality rate in China was estimated at 2.3%.

He said he’s more convinced by a retrospective 2021 German COVID-19 study that compared 551 patients with MS to 156,973 other patients and found lower rates of ICU admission (17.1% in patients with MS vs. 22.7% in those without it), ventilation (9.8% vs. 14.5%), and in‐hospital mortality (11.1% vs. 19.3%).

Meanwhile, a 2021 systematic review found no increase in mortality among 4,310 patients with MS (3% death rate, 20.7% hospitalization), but the death risk was highest among those on no DMTs and those taking anti-CD20 monoclonal antibodies. The COViMS Registry has reported similar findings regarding the anti-CD20 drugs rituximab and ocrelizumab, Dr. Berger noted, and a pooled study of Italian and French data links the monoclonal antibodies to more severe COVID. A 2021 aggregated study also linked the antibodies to increased risk of hospitalization and ICU admission.

“Anti-CD20 monoclonal antibodies appear to increase the risk of hospitalization and perhaps the acquisition of the virus, ICU admission, maybe death,” he said, with rituximab appearing to pose the most risk, followed by ocrelizumab and ofatumumab. “And it appears that the platform [older] therapies may be associated with lesser mortality.”

As for nondrug factors, Dr. Berger said, studies have linked higher risk to age, male sex, and comorbidities.

COVID-19 vaccines are another area of concern, he said. “The recommendation is to administer vaccination prior to the initiation of the anti-CD20s, alemtuzumab, and cladribine, and wait a period of time. Three months is ideal, maybe a little longer, because it appears that the antibody response seems to be best as your CD19 count starts to return.”

Finally, Dr. Berger noted that “passive vaccination” is now available via Evusheld (tixagevimab and cilgavimab) as a preexposure treatment for people with moderate to severe immune compromise who may not mount an effective immune response to COVID-19 vaccination or those who are allergic.

Dr. Berger reported multiple disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.