Multiple Sclerosis

Patients with relapsing-remitting multiple sclerosis (MS) treated with autologous hematopoietic stem cell transplantation (AHSCT) were 74% more likely than were those taking fingolimod to be relapse free 1 year after treatment, a new study suggests.

The multicenter observational study showed that AHSCT was associated with a better overall annual relapse rate and significantly greater disability improvement versus fingolimod. Stem cell transplantation also offered a slight advantage compared with natalizumab but showed no benefit over ocrelizumab.

“Based on these results, we can conclude that in this observational study AHSCT is substantially superior to fingolimod and marginally superior to natalizumab in reducing the risk of posttreatment relapses,” study investigator Tomas Kalincik, MD, PhD, said at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Research gap

Prior studies have suggested that AHSCT is associated with better disability outcomes than other immunotherapies in patients with active secondary progressive MS. Findings from another study on long-term efficacy in relapse prevention are also promising.

“The information that we are still lacking is the head-to-head comparison of the effectiveness of AHSCT in relapsing-remitting disease to concrete, highly effective therapies, which is the aim of this current study,” said Dr. Kalincik, professor of neurology at the University of Melbourne and head of the Multiple Sclerosis and Neuroimmunology Service at the Royal Melbourne Hospital, Australia.

The study included 167 patients with relapsing-remitting MS from six centers in Ottawa, Uppsala, Sheffield, Bergen, Sydney, and Melbourne, combined with 1,675 patients from MSBase. Patients were included if they were treated with AHSCT or fingolimod (n = 769), natalizumab (n = 730) or ocrelizumab (n = 343).

Researchers used propensity matching to ensure the AHSCT and disease-modifying therapy (DMT) groups had similar relapse rates and disability scores at baseline. At 1 year, patients who underwent AHSCT were 74% more likely than were those on fingolimod to be relapse free (hazard ratio [HR], 0.26; P < .0001).

The AHSCT group had a lower overall annualized relapse rate (0.09 vs. 0.19, respectively; P < .0001) and a higher cumulative probability of remaining relapse free at 2 years (90% vs. 68%, respectively) and 5 years (85% vs. 54%, respectively). AHSCT was associated with significantly better confirmed disability improvement at 6 months compared with fingolimod (HR, 2.70; P < .0001).

The researchers found better outcomes with AHSCT compared with natalizumab, but the results weren’t as promising. The annual relapse rate with AHSCT was statistically significant (P = .03) but the clinical benefit was marginal, Dr. Kalincik said. However, the confirmed disability improvement was significantly better with AHSCT (HR, 2.68; P < .0001).

There was no significant difference in outcomes with AHSCT compared to ocrelizumab.

Adverse events were common with stem cell transplantation, a sticking point for at least one conference attendee who raised safety concerns. Among those treated with AHSCT, 23% had febrile neutropenia, 11% had serum sickness, and 36% experienced complications after discharge, mostly infection. There was one AHSCT treatment-related death.

“We’re showing that AHSCT is a highly potent therapy that definitely is competitive vis a vis the most potent standard conventional disease modifying therapies,” said Dr. Kalincik, who noted the high rate of adverse events. Still, treatment-related mortality from AHSCT has improved since the therapy was first used in MS patients, he added.

“I’m hoping the data provides some evidence to convince you that this treatment still has a place in our armamentarium,” Dr. Kalincik said.
 

Questions remain

Eva Kubala Havrdová, MD, PhD, professor of neurology in the Multiple Sclerosis Center at Charles University in Prague, Czech Republic, said the results add to a growing body of data on the efficacy of AHSCT in patients with highly active relapsing-remitting MS, but questions remain.

“It is important to understand that AHSCT provides advantage in terms of effectiveness compared with most of the DMTs,” Dr. Kubala Havrdová said. “However, it is a therapy associated with high risk of adverse events and this needs to be considered when one decides whether other, less invasive options have been exploited.”

Study funding was not reported. Dr. Kalincik disclosed ties with BioCSL, Biogen, BMS, Celgene, Eisai, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, Teva, and WebMD Global. Dr. Kubala Havrdová reported no relevant financial relationships.

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

Patients with relapsing-remitting multiple sclerosis (MS) treated with autologous hematopoietic stem cell transplantation (AHSCT) were 74% more likely than were those taking fingolimod to be relapse free 1 year after treatment, a new study suggests.

The multicenter observational study showed that AHSCT was associated with a better overall annual relapse rate and significantly greater disability improvement versus fingolimod. Stem cell transplantation also offered a slight advantage compared with natalizumab but showed no benefit over ocrelizumab.

“Based on these results, we can conclude that in this observational study AHSCT is substantially superior to fingolimod and marginally superior to natalizumab in reducing the risk of posttreatment relapses,” study investigator Tomas Kalincik, MD, PhD, said at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Research gap

Prior studies have suggested that AHSCT is associated with better disability outcomes than other immunotherapies in patients with active secondary progressive MS. Findings from another study on long-term efficacy in relapse prevention are also promising.

“The information that we are still lacking is the head-to-head comparison of the effectiveness of AHSCT in relapsing-remitting disease to concrete, highly effective therapies, which is the aim of this current study,” said Dr. Kalincik, professor of neurology at the University of Melbourne and head of the Multiple Sclerosis and Neuroimmunology Service at the Royal Melbourne Hospital, Australia.

The study included 167 patients with relapsing-remitting MS from six centers in Ottawa, Uppsala, Sheffield, Bergen, Sydney, and Melbourne, combined with 1,675 patients from MSBase. Patients were included if they were treated with AHSCT or fingolimod (n = 769), natalizumab (n = 730) or ocrelizumab (n = 343).

Researchers used propensity matching to ensure the AHSCT and disease-modifying therapy (DMT) groups had similar relapse rates and disability scores at baseline. At 1 year, patients who underwent AHSCT were 74% more likely than were those on fingolimod to be relapse free (hazard ratio [HR], 0.26; P < .0001).

The AHSCT group had a lower overall annualized relapse rate (0.09 vs. 0.19, respectively; P < .0001) and a higher cumulative probability of remaining relapse free at 2 years (90% vs. 68%, respectively) and 5 years (85% vs. 54%, respectively). AHSCT was associated with significantly better confirmed disability improvement at 6 months compared with fingolimod (HR, 2.70; P < .0001).

The researchers found better outcomes with AHSCT compared with natalizumab, but the results weren’t as promising. The annual relapse rate with AHSCT was statistically significant (P = .03) but the clinical benefit was marginal, Dr. Kalincik said. However, the confirmed disability improvement was significantly better with AHSCT (HR, 2.68; P < .0001).

There was no significant difference in outcomes with AHSCT compared to ocrelizumab.

Adverse events were common with stem cell transplantation, a sticking point for at least one conference attendee who raised safety concerns. Among those treated with AHSCT, 23% had febrile neutropenia, 11% had serum sickness, and 36% experienced complications after discharge, mostly infection. There was one AHSCT treatment-related death.

“We’re showing that AHSCT is a highly potent therapy that definitely is competitive vis a vis the most potent standard conventional disease modifying therapies,” said Dr. Kalincik, who noted the high rate of adverse events. Still, treatment-related mortality from AHSCT has improved since the therapy was first used in MS patients, he added.

“I’m hoping the data provides some evidence to convince you that this treatment still has a place in our armamentarium,” Dr. Kalincik said.
 

Questions remain

Eva Kubala Havrdová, MD, PhD, professor of neurology in the Multiple Sclerosis Center at Charles University in Prague, Czech Republic, said the results add to a growing body of data on the efficacy of AHSCT in patients with highly active relapsing-remitting MS, but questions remain.

“It is important to understand that AHSCT provides advantage in terms of effectiveness compared with most of the DMTs,” Dr. Kubala Havrdová said. “However, it is a therapy associated with high risk of adverse events and this needs to be considered when one decides whether other, less invasive options have been exploited.”

Study funding was not reported. Dr. Kalincik disclosed ties with BioCSL, Biogen, BMS, Celgene, Eisai, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, Teva, and WebMD Global. Dr. Kubala Havrdová reported no relevant financial relationships.

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

Patients with relapsing-remitting multiple sclerosis (MS) treated with autologous hematopoietic stem cell transplantation (AHSCT) were 74% more likely than were those taking fingolimod to be relapse free 1 year after treatment, a new study suggests.

The multicenter observational study showed that AHSCT was associated with a better overall annual relapse rate and significantly greater disability improvement versus fingolimod. Stem cell transplantation also offered a slight advantage compared with natalizumab but showed no benefit over ocrelizumab.

“Based on these results, we can conclude that in this observational study AHSCT is substantially superior to fingolimod and marginally superior to natalizumab in reducing the risk of posttreatment relapses,” study investigator Tomas Kalincik, MD, PhD, said at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Research gap

Prior studies have suggested that AHSCT is associated with better disability outcomes than other immunotherapies in patients with active secondary progressive MS. Findings from another study on long-term efficacy in relapse prevention are also promising.

“The information that we are still lacking is the head-to-head comparison of the effectiveness of AHSCT in relapsing-remitting disease to concrete, highly effective therapies, which is the aim of this current study,” said Dr. Kalincik, professor of neurology at the University of Melbourne and head of the Multiple Sclerosis and Neuroimmunology Service at the Royal Melbourne Hospital, Australia.

The study included 167 patients with relapsing-remitting MS from six centers in Ottawa, Uppsala, Sheffield, Bergen, Sydney, and Melbourne, combined with 1,675 patients from MSBase. Patients were included if they were treated with AHSCT or fingolimod (n = 769), natalizumab (n = 730) or ocrelizumab (n = 343).

Researchers used propensity matching to ensure the AHSCT and disease-modifying therapy (DMT) groups had similar relapse rates and disability scores at baseline. At 1 year, patients who underwent AHSCT were 74% more likely than were those on fingolimod to be relapse free (hazard ratio [HR], 0.26; P < .0001).

The AHSCT group had a lower overall annualized relapse rate (0.09 vs. 0.19, respectively; P < .0001) and a higher cumulative probability of remaining relapse free at 2 years (90% vs. 68%, respectively) and 5 years (85% vs. 54%, respectively). AHSCT was associated with significantly better confirmed disability improvement at 6 months compared with fingolimod (HR, 2.70; P < .0001).

The researchers found better outcomes with AHSCT compared with natalizumab, but the results weren’t as promising. The annual relapse rate with AHSCT was statistically significant (P = .03) but the clinical benefit was marginal, Dr. Kalincik said. However, the confirmed disability improvement was significantly better with AHSCT (HR, 2.68; P < .0001).

There was no significant difference in outcomes with AHSCT compared to ocrelizumab.

Adverse events were common with stem cell transplantation, a sticking point for at least one conference attendee who raised safety concerns. Among those treated with AHSCT, 23% had febrile neutropenia, 11% had serum sickness, and 36% experienced complications after discharge, mostly infection. There was one AHSCT treatment-related death.

“We’re showing that AHSCT is a highly potent therapy that definitely is competitive vis a vis the most potent standard conventional disease modifying therapies,” said Dr. Kalincik, who noted the high rate of adverse events. Still, treatment-related mortality from AHSCT has improved since the therapy was first used in MS patients, he added.

“I’m hoping the data provides some evidence to convince you that this treatment still has a place in our armamentarium,” Dr. Kalincik said.
 

Questions remain

Eva Kubala Havrdová, MD, PhD, professor of neurology in the Multiple Sclerosis Center at Charles University in Prague, Czech Republic, said the results add to a growing body of data on the efficacy of AHSCT in patients with highly active relapsing-remitting MS, but questions remain.

“It is important to understand that AHSCT provides advantage in terms of effectiveness compared with most of the DMTs,” Dr. Kubala Havrdová said. “However, it is a therapy associated with high risk of adverse events and this needs to be considered when one decides whether other, less invasive options have been exploited.”

Study funding was not reported. Dr. Kalincik disclosed ties with BioCSL, Biogen, BMS, Celgene, Eisai, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, Teva, and WebMD Global. Dr. Kubala Havrdová reported no relevant financial relationships.

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

Cardiorespiratory fitness protects against declines in gait quality in patients with multiple sclerosis (MS), new research shows. Investigators found that over time, lower cardiorespiratory fitness predicts increased variability in stride time and could represent a biomarker for subtle neuromuscular decline in patients with MS.

Cardiorespiratory fitness “may exert neuroprotective effects on the central nervous system,” study investigator Syamala Buragadda, neurophysical therapist and PhD candidate, Memorial University, St. John’s, Nfld..

She reported her research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Gait changes

Gait is a complicated process involving coordination of multiple systems, but steps are almost always consistent and symmetric, said Ms. Buragadda. Patients with MS can experience subtle declines in gait quality even without relapses. Considering the neuroprotective properties of exercise, having higher fitness levels could prevent brain atrophy and protect against subtle gait changes.

Calculating stride time variability is a sensitive method to map changes in gait quality.

Ms. Buragadda, with co-investigator Michelle Ploughman, PhD, also with Memorial University, evaluated stride time variability over time in people with MS and explored whether cardiorespiratory fitness predicts stride time variability.

They recruited 49 adults with relapsing-remitting MS (63% women) and mild disability (Expanded Disability Status Scale [EDSS] score < 4; median, 2.0) from MS clinics in Canada. None required walking aids, and none had experienced relapses in the prior 3 months.

Gait quality was assessed on an instrumented walkway, and variability was measured as the coefficient of variation of stride time. Cardiorespiratory fitness was measured as maximal oxygen uptake (VO₂max) during a graded exercise test using recumbent stepper. Tests were conducted 2 years apart.

There were no significant changes in EDSS scores over the study period. However, stride time variability increased from 7.3% at baseline to 8.3% at 2 years.

Cardiorespiratory fitness at baseline significantly correlated with stride time variability 2 years later (P = .016) and was a significant predictor of stride time variability at 2 years, accounting for 10% of its variance, Ms. Buragadda reported.

Stride time variability, measured on an instrumented walkway, could be a biomarker for subtle changes to walking and balance, she said.

Limitations of the study include a convenience sample that may not represent the diversity of MS. Also, assessments were made at only two time points, and more time points would likely yield better predictive power. In addition, the lack of MRI images limits correlating structural changes with clinical observations of gait changes.
 

A buffer against disability?

In a comment, Valerie Block, physical therapist and adjunct instructor, department of physical therapy and rehabilitation science, University of California, San Francisco, and UCSF Weill Institute for Neuroscience, said the findings in this study are not surprising and align with what she has observed, subjectively, in her work.

“In the general population, cardiovascular fitness has a wide array of benefits. Depending on what means the person uses to maintain or improve cardiovascular fitness (that is, running, walking, swimming, etc.), this would have the potential for neuroplastic effects on gait – even in MS and other neurological disorders,” Ms. Block said.

Also offering perspective, Brain Sandroff, PhD, senior research scientist, Kessler Foundation, West Orange, N.J., said the study provides “more evidence on the multisystemic benefits of exercise training and having better physical fitness in persons with MS. The evidence seems to be converging more and more on this, as research groups across countries and continents are reporting on similar themes,” said Dr. Sandroff.

He noted that the findings from this study coincide with some other data that showed that premorbid physical activity is associated with reduced mobility decline over time in persons with MS.

“Collectively, the data suggest that perhaps engaging in exercise training early in the disease (or having better cardiorespiratory fitness at diagnosis) provides a buffer against disability progression over time,” Dr. Sandroff said.

He said it would be interesting to see whether “physical fitness/premorbid physical activity provides such a buffer in those who already demonstrate mobility problems.”

The study had no specific funding. Ms. Buragadda, Dr. Ploughman, Ms. Block, and Dr. Sandroff have disclosed no relevant financial relationships.

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

Cardiorespiratory fitness protects against declines in gait quality in patients with multiple sclerosis (MS), new research shows. Investigators found that over time, lower cardiorespiratory fitness predicts increased variability in stride time and could represent a biomarker for subtle neuromuscular decline in patients with MS.

Cardiorespiratory fitness “may exert neuroprotective effects on the central nervous system,” study investigator Syamala Buragadda, neurophysical therapist and PhD candidate, Memorial University, St. John’s, Nfld..

She reported her research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Gait changes

Gait is a complicated process involving coordination of multiple systems, but steps are almost always consistent and symmetric, said Ms. Buragadda. Patients with MS can experience subtle declines in gait quality even without relapses. Considering the neuroprotective properties of exercise, having higher fitness levels could prevent brain atrophy and protect against subtle gait changes.

Calculating stride time variability is a sensitive method to map changes in gait quality.

Ms. Buragadda, with co-investigator Michelle Ploughman, PhD, also with Memorial University, evaluated stride time variability over time in people with MS and explored whether cardiorespiratory fitness predicts stride time variability.

They recruited 49 adults with relapsing-remitting MS (63% women) and mild disability (Expanded Disability Status Scale [EDSS] score < 4; median, 2.0) from MS clinics in Canada. None required walking aids, and none had experienced relapses in the prior 3 months.

Gait quality was assessed on an instrumented walkway, and variability was measured as the coefficient of variation of stride time. Cardiorespiratory fitness was measured as maximal oxygen uptake (VO₂max) during a graded exercise test using recumbent stepper. Tests were conducted 2 years apart.

There were no significant changes in EDSS scores over the study period. However, stride time variability increased from 7.3% at baseline to 8.3% at 2 years.

Cardiorespiratory fitness at baseline significantly correlated with stride time variability 2 years later (P = .016) and was a significant predictor of stride time variability at 2 years, accounting for 10% of its variance, Ms. Buragadda reported.

Stride time variability, measured on an instrumented walkway, could be a biomarker for subtle changes to walking and balance, she said.

Limitations of the study include a convenience sample that may not represent the diversity of MS. Also, assessments were made at only two time points, and more time points would likely yield better predictive power. In addition, the lack of MRI images limits correlating structural changes with clinical observations of gait changes.
 

A buffer against disability?

In a comment, Valerie Block, physical therapist and adjunct instructor, department of physical therapy and rehabilitation science, University of California, San Francisco, and UCSF Weill Institute for Neuroscience, said the findings in this study are not surprising and align with what she has observed, subjectively, in her work.

“In the general population, cardiovascular fitness has a wide array of benefits. Depending on what means the person uses to maintain or improve cardiovascular fitness (that is, running, walking, swimming, etc.), this would have the potential for neuroplastic effects on gait – even in MS and other neurological disorders,” Ms. Block said.

Also offering perspective, Brain Sandroff, PhD, senior research scientist, Kessler Foundation, West Orange, N.J., said the study provides “more evidence on the multisystemic benefits of exercise training and having better physical fitness in persons with MS. The evidence seems to be converging more and more on this, as research groups across countries and continents are reporting on similar themes,” said Dr. Sandroff.

He noted that the findings from this study coincide with some other data that showed that premorbid physical activity is associated with reduced mobility decline over time in persons with MS.

“Collectively, the data suggest that perhaps engaging in exercise training early in the disease (or having better cardiorespiratory fitness at diagnosis) provides a buffer against disability progression over time,” Dr. Sandroff said.

He said it would be interesting to see whether “physical fitness/premorbid physical activity provides such a buffer in those who already demonstrate mobility problems.”

The study had no specific funding. Ms. Buragadda, Dr. Ploughman, Ms. Block, and Dr. Sandroff have disclosed no relevant financial relationships.

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

Cardiorespiratory fitness protects against declines in gait quality in patients with multiple sclerosis (MS), new research shows. Investigators found that over time, lower cardiorespiratory fitness predicts increased variability in stride time and could represent a biomarker for subtle neuromuscular decline in patients with MS.

Cardiorespiratory fitness “may exert neuroprotective effects on the central nervous system,” study investigator Syamala Buragadda, neurophysical therapist and PhD candidate, Memorial University, St. John’s, Nfld..

She reported her research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Gait changes

Gait is a complicated process involving coordination of multiple systems, but steps are almost always consistent and symmetric, said Ms. Buragadda. Patients with MS can experience subtle declines in gait quality even without relapses. Considering the neuroprotective properties of exercise, having higher fitness levels could prevent brain atrophy and protect against subtle gait changes.

Calculating stride time variability is a sensitive method to map changes in gait quality.

Ms. Buragadda, with co-investigator Michelle Ploughman, PhD, also with Memorial University, evaluated stride time variability over time in people with MS and explored whether cardiorespiratory fitness predicts stride time variability.

They recruited 49 adults with relapsing-remitting MS (63% women) and mild disability (Expanded Disability Status Scale [EDSS] score < 4; median, 2.0) from MS clinics in Canada. None required walking aids, and none had experienced relapses in the prior 3 months.

Gait quality was assessed on an instrumented walkway, and variability was measured as the coefficient of variation of stride time. Cardiorespiratory fitness was measured as maximal oxygen uptake (VO₂max) during a graded exercise test using recumbent stepper. Tests were conducted 2 years apart.

There were no significant changes in EDSS scores over the study period. However, stride time variability increased from 7.3% at baseline to 8.3% at 2 years.

Cardiorespiratory fitness at baseline significantly correlated with stride time variability 2 years later (P = .016) and was a significant predictor of stride time variability at 2 years, accounting for 10% of its variance, Ms. Buragadda reported.

Stride time variability, measured on an instrumented walkway, could be a biomarker for subtle changes to walking and balance, she said.

Limitations of the study include a convenience sample that may not represent the diversity of MS. Also, assessments were made at only two time points, and more time points would likely yield better predictive power. In addition, the lack of MRI images limits correlating structural changes with clinical observations of gait changes.
 

A buffer against disability?

In a comment, Valerie Block, physical therapist and adjunct instructor, department of physical therapy and rehabilitation science, University of California, San Francisco, and UCSF Weill Institute for Neuroscience, said the findings in this study are not surprising and align with what she has observed, subjectively, in her work.

“In the general population, cardiovascular fitness has a wide array of benefits. Depending on what means the person uses to maintain or improve cardiovascular fitness (that is, running, walking, swimming, etc.), this would have the potential for neuroplastic effects on gait – even in MS and other neurological disorders,” Ms. Block said.

Also offering perspective, Brain Sandroff, PhD, senior research scientist, Kessler Foundation, West Orange, N.J., said the study provides “more evidence on the multisystemic benefits of exercise training and having better physical fitness in persons with MS. The evidence seems to be converging more and more on this, as research groups across countries and continents are reporting on similar themes,” said Dr. Sandroff.

He noted that the findings from this study coincide with some other data that showed that premorbid physical activity is associated with reduced mobility decline over time in persons with MS.

“Collectively, the data suggest that perhaps engaging in exercise training early in the disease (or having better cardiorespiratory fitness at diagnosis) provides a buffer against disability progression over time,” Dr. Sandroff said.

He said it would be interesting to see whether “physical fitness/premorbid physical activity provides such a buffer in those who already demonstrate mobility problems.”

The study had no specific funding. Ms. Buragadda, Dr. Ploughman, Ms. Block, and Dr. Sandroff have disclosed no relevant financial relationships.

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

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

High-efficacy therapies for multiple sclerosis (MS) have improved disease outcomes for many patients, but physicians are uncertain when to use them. Despite better long-term disease outcomes, there are concerns over long-term safety, and some physicians and patients remain wary of these medications.

High-efficacy therapies were the subject of a session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Key topics included patient selection, timing of escalation to high-efficacy therapies, and initial use of high-efficacy therapies. The session produced a compelling message, according to moderator Patricia Coyle, MD. “I think [the speakers provided] accumulating data that this is a smart thing to do: Use high-efficacy therapies early to get the maximum bang for the buck,” Dr. Coyle said in an interview. She is professor of neurology and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University.
 

Consider baseline characteristics

In the first talk, Xavier Montalban, MD, PhD, noted that a statement from the ECTRIMS/EAN (European Academy of Neurology) guideline update in 2021 said that a high-efficacy disease-modifying therapy (DMT) should be considered early in the disease course. A key question is whether any baseline characteristics can be used to select patients, and studies have shown worse prognosis with older age, male sex, low levels of vitamin D, and smoking status, among various other factors.

He presented subgroup analyses from trials of fingolimod and ozanimod, which showed that the drugs did not work as well in patients with poor prognostic factors such as an Expanded Disability Status Scale (EDSS) score of 4 or above and age over 40 years. Lower doses also tend to have less efficacy in males. “If you have [a patient with] bad baseline prognostic factors, you need high-efficacy medication at the right dose, because a lower dose will not work well. It is the same phenomenon for age,” Dr. Montalban said in his talk. On the other hand, he showed the results of a study of ofatumumab and ocrelizumab, both of which showed high efficacy even in patients with poor prognostic factors.

Among patients with secondary progressive MS, clinical or MRI evidence of inflammatory activity is the only poor prognostic factor that appears to be a good predictor of treatment response.

Dr. Montalban also addressed the timing of intervention with DMTs. A study from his group prospectively followed 1,015 patients treated with DMTs. “Interestingly, what we observed is that patients who were treated with DMTs just after the first attack did better than those who were treated after the second attack, and you have to take into consideration that we treat those patients after the first attack, those who had the worst prognostic factors, so treatment was very effective in that sense,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona.
 

Switching DMTs

In the second presentation, Dalia Rotstein, MD, discussed how to incorporate prognostic factors when switching a patient to high-efficacy therapies as a result of new disease activity while on another therapy.

Patients with favorable prognostic factors at baseline may be started out on immunomodulatory therapy. “Essentially, we want to match the intensity of the therapy to the intensity of the disease of the patient in front of us,” Dr. Rotstein said in her talk. Nevertheless, the course of MS is unpredictable, and the first year or two of immunomodulatory therapy can give physicians clues about the longer-term course of the disease. “We need to observe closely for disease activity in the first year, but even up to 2 years on therapy to determine a need for early escalation,” said Dr. Rotstein, assistant professor of medicine at University of Toronto.

For switching to high-efficacy therapies, any relapse, disability progression, or an EDSS change of 1 point or more could be a consideration. MRI indicators are more controversial, but one to three new T2 lesions also could prompt a switch.

Serum neural filament light chain (sNFL) is a useful biomarker for monitoring disease activity as it correlates well with new disease activity within the next year. It can be monitored every 3-4 months and adjusted for clinical factors and monitored for changing levels. A concerning finding can be followed up with an MRI or in-person visit.

When switching to a high-efficacy therapy, it’s important to administer any vaccines well in advance to ensure a good immune response.

When it comes to a washout period, physicians need to consider both the risk of immunosuppression and breakthrough disease activity. “But in general, we’ve observed that we can minimize the duration of the washout when stopping initial immunomodulator therapy to reduce the risk of breakthrough disease activity. We need to pay particular attention to the risk of rebound activity with longer washouts after stopping sphingosine-1 phosphate (S1P) receptor modulators because the rebound activity can be devastating,” said Dr. Rotstein.

A study of timing of relapses after fingolimod washout, carried out by Dr. Rotstein’s group, found a stark signal. “We observed that when the washout after fingolimod discontinuation was 30 days or more, there is a very high risk of early relapse,” she said.
 

The case for induction therapy

In the third talk, Gavin Giovannoni, MBBCh, PhD, discussed “flipping the pyramid” – that is, starting patients off immediately with high-efficacy therapies rather than waiting until they progress on other therapies. He likened such a decision to a gambler, because MS patients on less-effective therapy can suffer irreversible, long-term physical consequences, as well as social consequences such as unemployment due to cognitive effects.

“We always tend to put up a graph about the risks and benefits of a specific treatment, and we forget about the risks of untreated or undertreated MS. Keep that in mind when making decisions about high-efficacy therapies,” said Dr. Giovannoni, professor of neurology at Queen Mary University of London.

About 80% of patients on tier 1, or low-efficacy therapies, will have breakthrough activity on MRI within 4 years. Moving up a tier gets to about a 60% rate of breakthrough activity. High-efficacy therapies attain an efficacy of about 80% at 6 months. “If you have MS, you’ve got to realize that if you had to roll the dice, which tier would you want to be in? By putting all of them [on high-efficacy therapies], you’re going to get the majority responding and a few of them will break through,” said Dr. Giovannoni.

He presented some real-world evidence to back up the argument: A study comparing outcomes in Sweden and Denmark, which have similar demographics. In Denmark, 7.6% of patients with MS received high-efficacy therapies initially, while in Sweden the proportion was 34.5%. Patients with MS treated in Sweden had a 29% lower probability of progressing to disability (P = .004) and there were 22% fewer discontinuations of DMTs (P < .001). Since that study, the proportion of patients receiving high-efficacy therapies to begin with is closer to 70%. “This is compelling evidence that you want to be on a [high-efficacy therapy] early. If I had MS, I would want to live in Sweden,” said Dr. Giovannoni.

Historical treatments focused on reducing relapses, and more recently on eliminating evidence of inflammatory disease. He said that physicians are prioritizing brain volume loss to improve long-term outcomes in MS, and some are studying long-term disability. “We know that brain volume loss in MS is a prognostic sign both at baseline and at follow-up. It predicts poor outcome, poor cognition and employment, poor quality of life, et cetera,” said Dr. Giovannoni.

He cited data from studies of alemtuzumab that showed a significant reduction in brain volume loss. “The rate is about 0.2% per annum, which is kind of getting into the normal range for age-matched controls. Those people who were started off on interferons in the study lost a lot of brain volume in those first 2 years, and that’s irreversible,” said Dr. Giovannoni.

He pointed out that studies of hematopoietic stem cell therapy showed similar brain-volume outcomes. “So flipping the pyramid with the two most highly effective therapies almost normalizes brain volume loss in people with MS,” said Dr. Giovannoni.

There is also evidence in other autoimmune diseases that early use of high-efficacy therapies improves outcomes. More aggressive therapy in rheumatoid arthritis has reduced joint replacements by 90%.

“I think you really, really need to give your patients the opportunity of flipping the pyramid. You shouldn’t decide that for them,” said Dr. Giovannoni.

Dr. Coyle has consulted for nearly all pharmaceutical companies developing drugs in the MS space. Dr. Montalban has financial relationships with Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva, Roche, Celgene, Actelion, Mylan, BMS, and Sandoz. Dr. Rotstein has financial ties with Roche Canada, Alexion, Biogen, EMD Serono, Novartis, Roche, and Sanofi Aventis. Dr. Giovannoni has financial ties with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co., Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva.

Chronic pruritus occurs in 1 out of 3 patients with multiple sclerosis (MS) and may be associated with more advanced disease, according to investigators.

Itch is historically underrecognized as a symptom of MS, but physicians should know that it is common and may negatively impact quality of life, reported lead author Giuseppe Ingrasci, MD, a dermatology research fellow at the University of Miami, Miller School of Medicine, and colleagues.

A common problem that may indicate more severe disease

At the Multiple Sclerosis Center of Excellence in Miami, 27 out of 79 outpatients with MS (35%) reported pruritus, with an average severity of 5.42 out of 10. Among those with itch, the extremities were affected in about half of the patients, while the face, scalp, and trunk were affected in about one-third of the patients. Many described paroxysmal itch that was aggravated by heat, and about half experienced itch on a weekly basis.

Further investigation showed that itch was associated with more severe MS. Compared with patients not experiencing itch, those with itch were significantly more likely to report fatigue (77% vs. 44%), anxiety or depression (48% vs. 16%), and cognitive impairment (62% vs. 26%).

MRI findings backed up these clinical results. Compared with patients not experiencing itch, patients with itch had significantly more T2 hyperintensities in the posterior cervical cord (74.1% vs. 46.0%) and anterior pons/ventromedial medulla (62% vs. 26%). These hyperintensities in the medulla were also associated with an 11-fold increased rate of itch on the face or scalp (odds ratio, 11.3; 95% confidence interval, 1.6-78.6, P = 0.025).

“Health care providers should be aware of episodes of localized, neuropathic itch in MS patients, as they appear to be more prevalent than previously thought and may impair these patients’ quality of life,” the investigators concluded.
 

Challenges with symptom characterization, management

“This is an important study for both patients and clinicians,” said Justin Abbatemarco, MD, of Cleveland Clinic’s Mellen Center for Multiple Sclerosis, in a written comment. “As the authors mention, many of our patients experience transient symptoms, including many different types of sensory disturbance (that is, pins & needles, burning, electrical shocks, and itching). These symptoms can be really distressing for patients and their caregivers.”

While Dr. Abbatemarco has encountered severe itching in “several patients” with MS, he maintained that it is “relatively uncommon” and noted that MS symptomatology is an inherently cloudy subject.

Cool the itch?

Noting how heat appears to aggravate itch in patients with MS, Dr. Yosipovitch suggested that one of those unique – and simple – treatment approaches may be cooling itchy areas. Alternatively, clinicians may consider oral agents, like gabapentin to dampen neural transmission, or compounded formulations applied to the skin to reduce neural sensitivity, such as topical ketamine. Finally, Dr. Yosipovitch speculated that newer antibody agents for MS could potentially reduce itch.

All these treatment suggestions are purely hypothetical, he said, and require further investigation before they can be recommended with confidence.

The investigators disclosed relationships with Galderma, Pfizer, Novartis, and others. Dr. Abbatemarco disclosed no conflicts of interest.

Correction, 9/19/22: An earlier version of this article misidentified the photo of Dr. Justin Abbatemarco.

Chronic pruritus occurs in 1 out of 3 patients with multiple sclerosis (MS) and may be associated with more advanced disease, according to investigators.

Itch is historically underrecognized as a symptom of MS, but physicians should know that it is common and may negatively impact quality of life, reported lead author Giuseppe Ingrasci, MD, a dermatology research fellow at the University of Miami, Miller School of Medicine, and colleagues.

A common problem that may indicate more severe disease

At the Multiple Sclerosis Center of Excellence in Miami, 27 out of 79 outpatients with MS (35%) reported pruritus, with an average severity of 5.42 out of 10. Among those with itch, the extremities were affected in about half of the patients, while the face, scalp, and trunk were affected in about one-third of the patients. Many described paroxysmal itch that was aggravated by heat, and about half experienced itch on a weekly basis.

Further investigation showed that itch was associated with more severe MS. Compared with patients not experiencing itch, those with itch were significantly more likely to report fatigue (77% vs. 44%), anxiety or depression (48% vs. 16%), and cognitive impairment (62% vs. 26%).

MRI findings backed up these clinical results. Compared with patients not experiencing itch, patients with itch had significantly more T2 hyperintensities in the posterior cervical cord (74.1% vs. 46.0%) and anterior pons/ventromedial medulla (62% vs. 26%). These hyperintensities in the medulla were also associated with an 11-fold increased rate of itch on the face or scalp (odds ratio, 11.3; 95% confidence interval, 1.6-78.6, P = 0.025).

“Health care providers should be aware of episodes of localized, neuropathic itch in MS patients, as they appear to be more prevalent than previously thought and may impair these patients’ quality of life,” the investigators concluded.
 

Challenges with symptom characterization, management

“This is an important study for both patients and clinicians,” said Justin Abbatemarco, MD, of Cleveland Clinic’s Mellen Center for Multiple Sclerosis, in a written comment. “As the authors mention, many of our patients experience transient symptoms, including many different types of sensory disturbance (that is, pins & needles, burning, electrical shocks, and itching). These symptoms can be really distressing for patients and their caregivers.”

While Dr. Abbatemarco has encountered severe itching in “several patients” with MS, he maintained that it is “relatively uncommon” and noted that MS symptomatology is an inherently cloudy subject.

Cool the itch?

Noting how heat appears to aggravate itch in patients with MS, Dr. Yosipovitch suggested that one of those unique – and simple – treatment approaches may be cooling itchy areas. Alternatively, clinicians may consider oral agents, like gabapentin to dampen neural transmission, or compounded formulations applied to the skin to reduce neural sensitivity, such as topical ketamine. Finally, Dr. Yosipovitch speculated that newer antibody agents for MS could potentially reduce itch.

All these treatment suggestions are purely hypothetical, he said, and require further investigation before they can be recommended with confidence.

The investigators disclosed relationships with Galderma, Pfizer, Novartis, and others. Dr. Abbatemarco disclosed no conflicts of interest.

Correction, 9/19/22: An earlier version of this article misidentified the photo of Dr. Justin Abbatemarco.

Chronic pruritus occurs in 1 out of 3 patients with multiple sclerosis (MS) and may be associated with more advanced disease, according to investigators.

Itch is historically underrecognized as a symptom of MS, but physicians should know that it is common and may negatively impact quality of life, reported lead author Giuseppe Ingrasci, MD, a dermatology research fellow at the University of Miami, Miller School of Medicine, and colleagues.

A common problem that may indicate more severe disease

At the Multiple Sclerosis Center of Excellence in Miami, 27 out of 79 outpatients with MS (35%) reported pruritus, with an average severity of 5.42 out of 10. Among those with itch, the extremities were affected in about half of the patients, while the face, scalp, and trunk were affected in about one-third of the patients. Many described paroxysmal itch that was aggravated by heat, and about half experienced itch on a weekly basis.

Further investigation showed that itch was associated with more severe MS. Compared with patients not experiencing itch, those with itch were significantly more likely to report fatigue (77% vs. 44%), anxiety or depression (48% vs. 16%), and cognitive impairment (62% vs. 26%).

MRI findings backed up these clinical results. Compared with patients not experiencing itch, patients with itch had significantly more T2 hyperintensities in the posterior cervical cord (74.1% vs. 46.0%) and anterior pons/ventromedial medulla (62% vs. 26%). These hyperintensities in the medulla were also associated with an 11-fold increased rate of itch on the face or scalp (odds ratio, 11.3; 95% confidence interval, 1.6-78.6, P = 0.025).

“Health care providers should be aware of episodes of localized, neuropathic itch in MS patients, as they appear to be more prevalent than previously thought and may impair these patients’ quality of life,” the investigators concluded.
 

Challenges with symptom characterization, management

“This is an important study for both patients and clinicians,” said Justin Abbatemarco, MD, of Cleveland Clinic’s Mellen Center for Multiple Sclerosis, in a written comment. “As the authors mention, many of our patients experience transient symptoms, including many different types of sensory disturbance (that is, pins & needles, burning, electrical shocks, and itching). These symptoms can be really distressing for patients and their caregivers.”

While Dr. Abbatemarco has encountered severe itching in “several patients” with MS, he maintained that it is “relatively uncommon” and noted that MS symptomatology is an inherently cloudy subject.

Cool the itch?

Noting how heat appears to aggravate itch in patients with MS, Dr. Yosipovitch suggested that one of those unique – and simple – treatment approaches may be cooling itchy areas. Alternatively, clinicians may consider oral agents, like gabapentin to dampen neural transmission, or compounded formulations applied to the skin to reduce neural sensitivity, such as topical ketamine. Finally, Dr. Yosipovitch speculated that newer antibody agents for MS could potentially reduce itch.

All these treatment suggestions are purely hypothetical, he said, and require further investigation before they can be recommended with confidence.

The investigators disclosed relationships with Galderma, Pfizer, Novartis, and others. Dr. Abbatemarco disclosed no conflicts of interest.

Correction, 9/19/22: An earlier version of this article misidentified the photo of Dr. Justin Abbatemarco.

The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction, energy failure, and neuronal and glial death.

While most new and investigational therapies aim to address immune dysfunction, a new idea—

one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?

Mitochondria, oxidative stress, and MS

Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction. 

Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability. 

Current therapeutic landscape

While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation  and decrease inflammation. Current therapies  may be able to control this macroscopic inflammatory activity. 

However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway. Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level. 

Metformin, the mitochondria, and neurodegeneration

Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier, scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?

Oligodendrocytes and remyelination

Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.

So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg,      clemastine fumarate), showed a modest yet promising effect on biomarkers in small clinical trials. 

A discussion on molecule failures

What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect. 

Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts. 

Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so? 

Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin. 

Metformin and the 3 “Rs”

One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States). 

Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.

If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
 

Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.

The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction, energy failure, and neuronal and glial death.

While most new and investigational therapies aim to address immune dysfunction, a new idea—

one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?

Mitochondria, oxidative stress, and MS

Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction. 

Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability. 

Current therapeutic landscape

While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation  and decrease inflammation. Current therapies  may be able to control this macroscopic inflammatory activity. 

However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway. Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level. 

Metformin, the mitochondria, and neurodegeneration

Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier, scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?

Oligodendrocytes and remyelination

Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.

So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg,      clemastine fumarate), showed a modest yet promising effect on biomarkers in small clinical trials. 

A discussion on molecule failures

What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect. 

Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts. 

Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so? 

Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin. 

Metformin and the 3 “Rs”

One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States). 

Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.

If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
 

Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.

The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction, energy failure, and neuronal and glial death.

While most new and investigational therapies aim to address immune dysfunction, a new idea—

one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?

Mitochondria, oxidative stress, and MS

Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction. 

Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability. 

Current therapeutic landscape

While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation  and decrease inflammation. Current therapies  may be able to control this macroscopic inflammatory activity. 

However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway. Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level. 

Metformin, the mitochondria, and neurodegeneration

Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier, scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?

Oligodendrocytes and remyelination

Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.

So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg,      clemastine fumarate), showed a modest yet promising effect on biomarkers in small clinical trials. 

A discussion on molecule failures

What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect. 

Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts. 

Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so? 

Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin. 

Metformin and the 3 “Rs”

One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States). 

Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.

If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
 

Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.

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.

Dr Robert Shin, from Georgetown University Hospital, highlights key presentations in disease-modifying therapy for multiple sclerosis (MS) presented at the 2022 annual meeting of the Consortium of Multiple Sclerosis Centers. 

First, Dr Shin discusses BTK inhibitors as an emerging treatment for multiple forms of MS, including progressive MS. 

Next, he shares preliminary results from the DISCOMS trial, which studied the safety of discontinuing vs continuing disease-modifying therapy in older MS patients. Although discontinuation was associated with more disease, Dr Shin suggests that a rigorous review of the data reveals no significant difference between the two groups. He comments that more data are needed. 

Dr Shin closes his commentary by highlighting a presentation focused on COVID and MS patients, specifically covering immune response to the COVID-19 vaccine in people being treated for MS.  

--

Professor, Department of Neurology, MedStar Georgetown University Hospital; Director, Georgetown MS and Neuroimmunology Center, Washington, DC 

Robert Shin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Novartis; Roche; Sanofi Genzyme 

Serve(d) as a speaker or a member of a speakers bureau for: Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Novartis; Roche; Sanofi Genzyme 

Dr Robert Shin, from Georgetown University Hospital, highlights key presentations in disease-modifying therapy for multiple sclerosis (MS) presented at the 2022 annual meeting of the Consortium of Multiple Sclerosis Centers. 

First, Dr Shin discusses BTK inhibitors as an emerging treatment for multiple forms of MS, including progressive MS. 

Next, he shares preliminary results from the DISCOMS trial, which studied the safety of discontinuing vs continuing disease-modifying therapy in older MS patients. Although discontinuation was associated with more disease, Dr Shin suggests that a rigorous review of the data reveals no significant difference between the two groups. He comments that more data are needed. 

Dr Shin closes his commentary by highlighting a presentation focused on COVID and MS patients, specifically covering immune response to the COVID-19 vaccine in people being treated for MS.  

--

Professor, Department of Neurology, MedStar Georgetown University Hospital; Director, Georgetown MS and Neuroimmunology Center, Washington, DC 

Robert Shin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Novartis; Roche; Sanofi Genzyme 

Serve(d) as a speaker or a member of a speakers bureau for: Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Novartis; Roche; Sanofi Genzyme 

Dr Robert Shin, from Georgetown University Hospital, highlights key presentations in disease-modifying therapy for multiple sclerosis (MS) presented at the 2022 annual meeting of the Consortium of Multiple Sclerosis Centers. 

First, Dr Shin discusses BTK inhibitors as an emerging treatment for multiple forms of MS, including progressive MS. 

Next, he shares preliminary results from the DISCOMS trial, which studied the safety of discontinuing vs continuing disease-modifying therapy in older MS patients. Although discontinuation was associated with more disease, Dr Shin suggests that a rigorous review of the data reveals no significant difference between the two groups. He comments that more data are needed. 

Dr Shin closes his commentary by highlighting a presentation focused on COVID and MS patients, specifically covering immune response to the COVID-19 vaccine in people being treated for MS.  

--

Professor, Department of Neurology, MedStar Georgetown University Hospital; Director, Georgetown MS and Neuroimmunology Center, Washington, DC 

Robert Shin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Novartis; Roche; Sanofi Genzyme 

Serve(d) as a speaker or a member of a speakers bureau for: Alexion; Biogen; Bristol Myers Squibb; EMD Serono; Genentech; Horizon; Novartis; Roche; Sanofi Genzyme 

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.