Multiple Sclerosis

Chances are your female patients of childbearing age with multiple sclerosis—particularly if they become pregnant—will ask about breastfeeding. What are they likely to ask, and how should you answer? Here’s a quick rundown.

What kind of impact will breastfeeding have on my child?

We know that MS is not a genetic disease per se-it is neither autosomal recessive nor dominant. But there is an increased risk among family members, particularly first-degree relatives. If a patient asks, you can tell them it appears that infants who are breastfed are less likely to develop pediatric-onset MS.

In 2017, Brenton and colleagues asked individuals who experienced pediatric-onset MS (n=36)  and those in a control group (n=72) to complete a questionnaire that covered breastfeeding history and other birth and demographic features. While most demographic and birth features were similar, 36% of those in the pediatric-onset MS group reported being breastfed, compared with 71% of controls. Individuals who were not breastfed were nearly 4.5 times more likely to be diagnosed with pediatric-onset MS.

How will breastfeeding impact my risk of MS relapse after giving birth?

The issue of breastfeeding and MS relapses is somewhat controversial. In 1988, Nelson and colleagues  found that among 191 women with MS who became pregnant, 10% relapsed during pregnancy, but relapse rate rose to 34% during the 9 months after birth. Moreover, nearly 4 in 10 of those who breastfed experienced exacerbations, versus 3 in 10 among those who did not.

However, more recent studies demonstrate no association with breastfeeding and relapse. Just this year, Gould and colleagues published a study showing that among 466 pregnancies, annualized relapse rates declined during pregnancy, and there was no increase seen in the postpartum period. Moreover, women who exclusively breastfed saw their risk of an early postpartum relapse lowered by 63%.

In late 2019, Krysko and colleagues  published a meta-analysis of 24 studies involving nearly 3,000 women with MS which showed that breastfeeds were 43% less likely to experience postpartum relapse compared with their non-breastfeeding counterparts. The link was stronger in studies where women breastfed exclusively.

The bottom line: There is a plurality of physicians who believe that breastfeeding has a protective effect – and most will tell you that you should recommend exclusive breastfeeding.

What medicines can I take that will not adversely affect me and my baby?

Once a woman knows that breastfeeding could help her offspring avoid developing MS, and minimize her chance of a postpartum relapse, she will likely ask what to do about medications. You answer will depends on what she’s taking.

• Drugs she can take with relative peace of mind. Most experts believe it is safe to take corticosteroids and breastfeed. In fact, women who relapse while breastfeeding will in all likelihood be given intravenous corticosteroids, such as methylprednisolone. These medications are present in the blood at very low levels, peak an hour after infusion, and quickly dissipate. So, it’s important to tell your patients to delay breastfeeding by 2 to 4 hours after they receive the steroid.

• Drugs that are potentially concerning and require close monitoring. For the so-called platform therapies—such as interferon beta/glatiramer acetate, natalizumab, and their generic equivalents—there are no large studies that clearly demonstrate safety. Still, they are generally thought to be safe. Be sure to heed FDA labeling: weigh breastfeeding benefit against the potential risk

• Drug to avoid entirely. Under no circumstances should breastfeeding women receive teriflunomide, cladribine, alemtuzumab, or mitoxantrone. The jury is still out on rituximab—which is not yet approved for MS in the United States—and ocrelizumab. For now, err on the safe side and switch to another therapy.

Chances are your female patients of childbearing age with multiple sclerosis—particularly if they become pregnant—will ask about breastfeeding. What are they likely to ask, and how should you answer? Here’s a quick rundown.

What kind of impact will breastfeeding have on my child?

We know that MS is not a genetic disease per se-it is neither autosomal recessive nor dominant. But there is an increased risk among family members, particularly first-degree relatives. If a patient asks, you can tell them it appears that infants who are breastfed are less likely to develop pediatric-onset MS.

In 2017, Brenton and colleagues asked individuals who experienced pediatric-onset MS (n=36)  and those in a control group (n=72) to complete a questionnaire that covered breastfeeding history and other birth and demographic features. While most demographic and birth features were similar, 36% of those in the pediatric-onset MS group reported being breastfed, compared with 71% of controls. Individuals who were not breastfed were nearly 4.5 times more likely to be diagnosed with pediatric-onset MS.

How will breastfeeding impact my risk of MS relapse after giving birth?

The issue of breastfeeding and MS relapses is somewhat controversial. In 1988, Nelson and colleagues  found that among 191 women with MS who became pregnant, 10% relapsed during pregnancy, but relapse rate rose to 34% during the 9 months after birth. Moreover, nearly 4 in 10 of those who breastfed experienced exacerbations, versus 3 in 10 among those who did not.

However, more recent studies demonstrate no association with breastfeeding and relapse. Just this year, Gould and colleagues published a study showing that among 466 pregnancies, annualized relapse rates declined during pregnancy, and there was no increase seen in the postpartum period. Moreover, women who exclusively breastfed saw their risk of an early postpartum relapse lowered by 63%.

In late 2019, Krysko and colleagues  published a meta-analysis of 24 studies involving nearly 3,000 women with MS which showed that breastfeeds were 43% less likely to experience postpartum relapse compared with their non-breastfeeding counterparts. The link was stronger in studies where women breastfed exclusively.

The bottom line: There is a plurality of physicians who believe that breastfeeding has a protective effect – and most will tell you that you should recommend exclusive breastfeeding.

What medicines can I take that will not adversely affect me and my baby?

Once a woman knows that breastfeeding could help her offspring avoid developing MS, and minimize her chance of a postpartum relapse, she will likely ask what to do about medications. You answer will depends on what she’s taking.

• Drugs she can take with relative peace of mind. Most experts believe it is safe to take corticosteroids and breastfeed. In fact, women who relapse while breastfeeding will in all likelihood be given intravenous corticosteroids, such as methylprednisolone. These medications are present in the blood at very low levels, peak an hour after infusion, and quickly dissipate. So, it’s important to tell your patients to delay breastfeeding by 2 to 4 hours after they receive the steroid.

• Drugs that are potentially concerning and require close monitoring. For the so-called platform therapies—such as interferon beta/glatiramer acetate, natalizumab, and their generic equivalents—there are no large studies that clearly demonstrate safety. Still, they are generally thought to be safe. Be sure to heed FDA labeling: weigh breastfeeding benefit against the potential risk

• Drug to avoid entirely. Under no circumstances should breastfeeding women receive teriflunomide, cladribine, alemtuzumab, or mitoxantrone. The jury is still out on rituximab—which is not yet approved for MS in the United States—and ocrelizumab. For now, err on the safe side and switch to another therapy.

Chances are your female patients of childbearing age with multiple sclerosis—particularly if they become pregnant—will ask about breastfeeding. What are they likely to ask, and how should you answer? Here’s a quick rundown.

What kind of impact will breastfeeding have on my child?

We know that MS is not a genetic disease per se-it is neither autosomal recessive nor dominant. But there is an increased risk among family members, particularly first-degree relatives. If a patient asks, you can tell them it appears that infants who are breastfed are less likely to develop pediatric-onset MS.

In 2017, Brenton and colleagues asked individuals who experienced pediatric-onset MS (n=36)  and those in a control group (n=72) to complete a questionnaire that covered breastfeeding history and other birth and demographic features. While most demographic and birth features were similar, 36% of those in the pediatric-onset MS group reported being breastfed, compared with 71% of controls. Individuals who were not breastfed were nearly 4.5 times more likely to be diagnosed with pediatric-onset MS.

How will breastfeeding impact my risk of MS relapse after giving birth?

The issue of breastfeeding and MS relapses is somewhat controversial. In 1988, Nelson and colleagues  found that among 191 women with MS who became pregnant, 10% relapsed during pregnancy, but relapse rate rose to 34% during the 9 months after birth. Moreover, nearly 4 in 10 of those who breastfed experienced exacerbations, versus 3 in 10 among those who did not.

However, more recent studies demonstrate no association with breastfeeding and relapse. Just this year, Gould and colleagues published a study showing that among 466 pregnancies, annualized relapse rates declined during pregnancy, and there was no increase seen in the postpartum period. Moreover, women who exclusively breastfed saw their risk of an early postpartum relapse lowered by 63%.

In late 2019, Krysko and colleagues  published a meta-analysis of 24 studies involving nearly 3,000 women with MS which showed that breastfeeds were 43% less likely to experience postpartum relapse compared with their non-breastfeeding counterparts. The link was stronger in studies where women breastfed exclusively.

The bottom line: There is a plurality of physicians who believe that breastfeeding has a protective effect – and most will tell you that you should recommend exclusive breastfeeding.

What medicines can I take that will not adversely affect me and my baby?

Once a woman knows that breastfeeding could help her offspring avoid developing MS, and minimize her chance of a postpartum relapse, she will likely ask what to do about medications. You answer will depends on what she’s taking.

• Drugs she can take with relative peace of mind. Most experts believe it is safe to take corticosteroids and breastfeed. In fact, women who relapse while breastfeeding will in all likelihood be given intravenous corticosteroids, such as methylprednisolone. These medications are present in the blood at very low levels, peak an hour after infusion, and quickly dissipate. So, it’s important to tell your patients to delay breastfeeding by 2 to 4 hours after they receive the steroid.

• Drugs that are potentially concerning and require close monitoring. For the so-called platform therapies—such as interferon beta/glatiramer acetate, natalizumab, and their generic equivalents—there are no large studies that clearly demonstrate safety. Still, they are generally thought to be safe. Be sure to heed FDA labeling: weigh breastfeeding benefit against the potential risk

• Drug to avoid entirely. Under no circumstances should breastfeeding women receive teriflunomide, cladribine, alemtuzumab, or mitoxantrone. The jury is still out on rituximab—which is not yet approved for MS in the United States—and ocrelizumab. For now, err on the safe side and switch to another therapy.

Among patients with pediatric-onset relapsing-remitting multiple sclerosis (MS), newer disease-modifying therapies (DMTs) reduce clinical and radiological disease activity more effectively than older injectable therapies. Nevertheless, all DMTs reduce children’s annualized relapse rate (ARR), according to results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Our study adds weight to the argument for an imminent shift in clinical practice toward the use of newer, more efficacious DMTs in the first instance,” said Omar Abdel-Mannan, MD, of Great Ormond Street Hospital in London. MRI activity continues among patients treated with DMTs, and the number of relapses is highest in the period following diagnosis. But because the effect of treatment on brain atrophy is greatest in the initial period of disease, “this time period may represent a critical therapeutic window for the use of highly effective therapies,” said Dr. Abdel-Mannan.
 

An examination of medical records

MS is much less prevalent among children than among adults. Compared with adults with MS, children with MS have a higher relapse rate and slower accumulation of disability. The individual response to DMTs is variable, said Dr. Abdel-Mannan. Furthermore, current standards of care for pediatric MS vary by center and are based on adult protocols.

Dr. Abdel-Mannan and colleagues conducted a retrospective study to evaluate the real-world effectiveness of the newer oral and infusion DMTs, compared with the older injectable DMTs, in children with relapsing-remitting MS. They examined data from seven tertiary pediatric neurology centers in the United Kingdom and identified patients under age 18 years with relapsing-remitting MS who were treated with DMTs between 2012 and 2018. The investigators reviewed clinical and paraclinical data retrospectively using electronic medical records. They compared patients’ ARR, new radiological activity, and Expanded Disability Status Scale score pretreatment and on treatment.

The researchers included 103 patients in their analysis. The population’s median age was 14 years. The ratio of girls to boys was approximately 3:1. Whites and other races/ethnicities accounted for approximately equal groups of patients. About one-third of patients presented with a clinically isolated syndrome (CIS) in the form of transverse myelitis or optic neuritis. Two-thirds presented with other CIS phenotypes. Almost all children had an abnormal MRI at onset.
 

Most patients initiated injectable DMTs

Of the 103 patients, 89 started treatment with an injectable (e.g., glatiramer or interferon) or an older DMT. Fourteen patients began treatment with a newer DMT (e.g., dimethyl fumarate, fingolimod, natalizumab, and alemtuzumab). Three of the 89 patients on an injectable DMT switched to another injectable DMT, and two of these patients later escalated to a newer DMT. Thirty-five of the 89 patients who initiated an injectable DMT were escalated immediately to a newer DMT. One of these patients later switched to another newer DMT. Two of the 14 patients who started on a newer DMT as their first drug switched to another newer DMT.

The investigators observed a reduction in ARR for all DMTs used during the study period. Nevertheless, a significant number of patients receiving injectable DMTs continued to relapse on treatment. Almost all patients receiving newer DMTs, however, had a reduction in relapses. When Dr. Abdel-Mannan and colleagues performed Kaplan–Meier survival analysis, they found that patients receiving newer DMTs had a longer time to first relapse and a longer time to switch treatment over 2 years, compared with patients receiving injectable DMTs. In addition, patients receiving newer DMTs had a longer time to develop new radiological activity, compared with patients receiving injectables. The analysis also indicated that the proportion of patients with new radiological activity was higher than the proportion who had clinical relapses and an Expanded Disability Status Scale score increase of more than 1 point over 2 years.

In all, 55 of the children receiving injectable DMTs and 18 of the patients receiving newer DMTs had side effects. The most commonly reported side effects were flulike symptoms and injection-site reactions. Five patients discontinued or switched their DMTs because of side effects. “Reassuringly, no pediatric-specific side effects were reported,” said Dr. Abdel-Mannan. The newer DMTs had similar short-term safety, tolerability, and side-effect profiles in these children as in adult patients.

The study was conducted on behalf of the UK Childhood Inflammatory Demyelination Network. Dr. Abdel-Mannan had no relevant disclosures.

[email protected]

SOURCE: Abdel-Mannan O et al. CNS-ICNA 2020, Abstract PL10.

Among patients with pediatric-onset relapsing-remitting multiple sclerosis (MS), newer disease-modifying therapies (DMTs) reduce clinical and radiological disease activity more effectively than older injectable therapies. Nevertheless, all DMTs reduce children’s annualized relapse rate (ARR), according to results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Our study adds weight to the argument for an imminent shift in clinical practice toward the use of newer, more efficacious DMTs in the first instance,” said Omar Abdel-Mannan, MD, of Great Ormond Street Hospital in London. MRI activity continues among patients treated with DMTs, and the number of relapses is highest in the period following diagnosis. But because the effect of treatment on brain atrophy is greatest in the initial period of disease, “this time period may represent a critical therapeutic window for the use of highly effective therapies,” said Dr. Abdel-Mannan.
 

An examination of medical records

MS is much less prevalent among children than among adults. Compared with adults with MS, children with MS have a higher relapse rate and slower accumulation of disability. The individual response to DMTs is variable, said Dr. Abdel-Mannan. Furthermore, current standards of care for pediatric MS vary by center and are based on adult protocols.

Dr. Abdel-Mannan and colleagues conducted a retrospective study to evaluate the real-world effectiveness of the newer oral and infusion DMTs, compared with the older injectable DMTs, in children with relapsing-remitting MS. They examined data from seven tertiary pediatric neurology centers in the United Kingdom and identified patients under age 18 years with relapsing-remitting MS who were treated with DMTs between 2012 and 2018. The investigators reviewed clinical and paraclinical data retrospectively using electronic medical records. They compared patients’ ARR, new radiological activity, and Expanded Disability Status Scale score pretreatment and on treatment.

The researchers included 103 patients in their analysis. The population’s median age was 14 years. The ratio of girls to boys was approximately 3:1. Whites and other races/ethnicities accounted for approximately equal groups of patients. About one-third of patients presented with a clinically isolated syndrome (CIS) in the form of transverse myelitis or optic neuritis. Two-thirds presented with other CIS phenotypes. Almost all children had an abnormal MRI at onset.
 

Most patients initiated injectable DMTs

Of the 103 patients, 89 started treatment with an injectable (e.g., glatiramer or interferon) or an older DMT. Fourteen patients began treatment with a newer DMT (e.g., dimethyl fumarate, fingolimod, natalizumab, and alemtuzumab). Three of the 89 patients on an injectable DMT switched to another injectable DMT, and two of these patients later escalated to a newer DMT. Thirty-five of the 89 patients who initiated an injectable DMT were escalated immediately to a newer DMT. One of these patients later switched to another newer DMT. Two of the 14 patients who started on a newer DMT as their first drug switched to another newer DMT.

The investigators observed a reduction in ARR for all DMTs used during the study period. Nevertheless, a significant number of patients receiving injectable DMTs continued to relapse on treatment. Almost all patients receiving newer DMTs, however, had a reduction in relapses. When Dr. Abdel-Mannan and colleagues performed Kaplan–Meier survival analysis, they found that patients receiving newer DMTs had a longer time to first relapse and a longer time to switch treatment over 2 years, compared with patients receiving injectable DMTs. In addition, patients receiving newer DMTs had a longer time to develop new radiological activity, compared with patients receiving injectables. The analysis also indicated that the proportion of patients with new radiological activity was higher than the proportion who had clinical relapses and an Expanded Disability Status Scale score increase of more than 1 point over 2 years.

In all, 55 of the children receiving injectable DMTs and 18 of the patients receiving newer DMTs had side effects. The most commonly reported side effects were flulike symptoms and injection-site reactions. Five patients discontinued or switched their DMTs because of side effects. “Reassuringly, no pediatric-specific side effects were reported,” said Dr. Abdel-Mannan. The newer DMTs had similar short-term safety, tolerability, and side-effect profiles in these children as in adult patients.

The study was conducted on behalf of the UK Childhood Inflammatory Demyelination Network. Dr. Abdel-Mannan had no relevant disclosures.

[email protected]

SOURCE: Abdel-Mannan O et al. CNS-ICNA 2020, Abstract PL10.

Among patients with pediatric-onset relapsing-remitting multiple sclerosis (MS), newer disease-modifying therapies (DMTs) reduce clinical and radiological disease activity more effectively than older injectable therapies. Nevertheless, all DMTs reduce children’s annualized relapse rate (ARR), according to results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Our study adds weight to the argument for an imminent shift in clinical practice toward the use of newer, more efficacious DMTs in the first instance,” said Omar Abdel-Mannan, MD, of Great Ormond Street Hospital in London. MRI activity continues among patients treated with DMTs, and the number of relapses is highest in the period following diagnosis. But because the effect of treatment on brain atrophy is greatest in the initial period of disease, “this time period may represent a critical therapeutic window for the use of highly effective therapies,” said Dr. Abdel-Mannan.
 

An examination of medical records

MS is much less prevalent among children than among adults. Compared with adults with MS, children with MS have a higher relapse rate and slower accumulation of disability. The individual response to DMTs is variable, said Dr. Abdel-Mannan. Furthermore, current standards of care for pediatric MS vary by center and are based on adult protocols.

Dr. Abdel-Mannan and colleagues conducted a retrospective study to evaluate the real-world effectiveness of the newer oral and infusion DMTs, compared with the older injectable DMTs, in children with relapsing-remitting MS. They examined data from seven tertiary pediatric neurology centers in the United Kingdom and identified patients under age 18 years with relapsing-remitting MS who were treated with DMTs between 2012 and 2018. The investigators reviewed clinical and paraclinical data retrospectively using electronic medical records. They compared patients’ ARR, new radiological activity, and Expanded Disability Status Scale score pretreatment and on treatment.

The researchers included 103 patients in their analysis. The population’s median age was 14 years. The ratio of girls to boys was approximately 3:1. Whites and other races/ethnicities accounted for approximately equal groups of patients. About one-third of patients presented with a clinically isolated syndrome (CIS) in the form of transverse myelitis or optic neuritis. Two-thirds presented with other CIS phenotypes. Almost all children had an abnormal MRI at onset.
 

Most patients initiated injectable DMTs

Of the 103 patients, 89 started treatment with an injectable (e.g., glatiramer or interferon) or an older DMT. Fourteen patients began treatment with a newer DMT (e.g., dimethyl fumarate, fingolimod, natalizumab, and alemtuzumab). Three of the 89 patients on an injectable DMT switched to another injectable DMT, and two of these patients later escalated to a newer DMT. Thirty-five of the 89 patients who initiated an injectable DMT were escalated immediately to a newer DMT. One of these patients later switched to another newer DMT. Two of the 14 patients who started on a newer DMT as their first drug switched to another newer DMT.

The investigators observed a reduction in ARR for all DMTs used during the study period. Nevertheless, a significant number of patients receiving injectable DMTs continued to relapse on treatment. Almost all patients receiving newer DMTs, however, had a reduction in relapses. When Dr. Abdel-Mannan and colleagues performed Kaplan–Meier survival analysis, they found that patients receiving newer DMTs had a longer time to first relapse and a longer time to switch treatment over 2 years, compared with patients receiving injectable DMTs. In addition, patients receiving newer DMTs had a longer time to develop new radiological activity, compared with patients receiving injectables. The analysis also indicated that the proportion of patients with new radiological activity was higher than the proportion who had clinical relapses and an Expanded Disability Status Scale score increase of more than 1 point over 2 years.

In all, 55 of the children receiving injectable DMTs and 18 of the patients receiving newer DMTs had side effects. The most commonly reported side effects were flulike symptoms and injection-site reactions. Five patients discontinued or switched their DMTs because of side effects. “Reassuringly, no pediatric-specific side effects were reported,” said Dr. Abdel-Mannan. The newer DMTs had similar short-term safety, tolerability, and side-effect profiles in these children as in adult patients.

The study was conducted on behalf of the UK Childhood Inflammatory Demyelination Network. Dr. Abdel-Mannan had no relevant disclosures.

[email protected]

SOURCE: Abdel-Mannan O et al. CNS-ICNA 2020, Abstract PL10.

Key clinical point: Both rituximab and glatiramer acetate failed to stop disability progression in patients with secondary progressive multiple sclerosis (SPMS). They were equally effective in relapse control.

Major finding: The mean Expanded Disability Status Scale (EDSS) score increased from 3.05 to 4.14 in the rituximab group and from 3.22 to 4.60 in the glatiramer acetate group (P less than .001 for both). EDSS score showed no statistically significant difference between 2 groups (P = .071). Annualized relapse rate decreased in both groups with no significant difference between them (P = .534).

Study details: An open randomized clinical trial of 84 patients with SPMS assigned to receive rituximab (n = 43) or glatiramer acetate (n = 41) for 12 months.

Disclosures: The study was funded by vice-chancellor for research and technology of Isfahan University of Medical Sciences. The authors declared no conflicts of interest.

Citation: Cheshmavar M et al. Acta Neurol Scand. 2020 Sep 8. doi: 10.1111/ane.13344.

Key clinical point: Both rituximab and glatiramer acetate failed to stop disability progression in patients with secondary progressive multiple sclerosis (SPMS). They were equally effective in relapse control.

Major finding: The mean Expanded Disability Status Scale (EDSS) score increased from 3.05 to 4.14 in the rituximab group and from 3.22 to 4.60 in the glatiramer acetate group (P less than .001 for both). EDSS score showed no statistically significant difference between 2 groups (P = .071). Annualized relapse rate decreased in both groups with no significant difference between them (P = .534).

Study details: An open randomized clinical trial of 84 patients with SPMS assigned to receive rituximab (n = 43) or glatiramer acetate (n = 41) for 12 months.

Disclosures: The study was funded by vice-chancellor for research and technology of Isfahan University of Medical Sciences. The authors declared no conflicts of interest.

Citation: Cheshmavar M et al. Acta Neurol Scand. 2020 Sep 8. doi: 10.1111/ane.13344.

Key clinical point: Both rituximab and glatiramer acetate failed to stop disability progression in patients with secondary progressive multiple sclerosis (SPMS). They were equally effective in relapse control.

Major finding: The mean Expanded Disability Status Scale (EDSS) score increased from 3.05 to 4.14 in the rituximab group and from 3.22 to 4.60 in the glatiramer acetate group (P less than .001 for both). EDSS score showed no statistically significant difference between 2 groups (P = .071). Annualized relapse rate decreased in both groups with no significant difference between them (P = .534).

Study details: An open randomized clinical trial of 84 patients with SPMS assigned to receive rituximab (n = 43) or glatiramer acetate (n = 41) for 12 months.

Disclosures: The study was funded by vice-chancellor for research and technology of Isfahan University of Medical Sciences. The authors declared no conflicts of interest.

Citation: Cheshmavar M et al. Acta Neurol Scand. 2020 Sep 8. doi: 10.1111/ane.13344.

Key clinical point: Ofatumumab is associated with lower annualized relapse rates than teriflunomide in patients with relapsing multiple sclerosis (MS).

Major finding: Annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in ASCLEPIOS I trial (difference, −0.11; P less than .001) and 0.10 and 0.25, respectively, in ASCLEPIOS II trial (difference, −0.15; P less than .001). The percentage of patients with disability worsening at 3 months and at 6 months was higher in the teriflunomide group, whereas the percentage of patients with disability improvement at 6 months was higher in ofatumumab group.

Study details: In 2 double-blind, double-dummy, phase 3 trials (ASCLEPIOS I and II), patients with relapsing MS were randomly assigned to receive subcutaneous ofatumumab (n = 946) or oral teriflunomide (n = 936) for up to 30 months and were followed for a median of 1.6 years.

Disclosures: The study was supported by Novartis Pharma. Dr. Hauser reported ties with various pharmaceutical companies and travel grant from Novartis.

Citation: Hauser SL et al. N Engl J Med. 2020 Aug 6. doi: 10.1056/NEJMoa1917246.

Key clinical point: Ofatumumab is associated with lower annualized relapse rates than teriflunomide in patients with relapsing multiple sclerosis (MS).

Major finding: Annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in ASCLEPIOS I trial (difference, −0.11; P less than .001) and 0.10 and 0.25, respectively, in ASCLEPIOS II trial (difference, −0.15; P less than .001). The percentage of patients with disability worsening at 3 months and at 6 months was higher in the teriflunomide group, whereas the percentage of patients with disability improvement at 6 months was higher in ofatumumab group.

Study details: In 2 double-blind, double-dummy, phase 3 trials (ASCLEPIOS I and II), patients with relapsing MS were randomly assigned to receive subcutaneous ofatumumab (n = 946) or oral teriflunomide (n = 936) for up to 30 months and were followed for a median of 1.6 years.

Disclosures: The study was supported by Novartis Pharma. Dr. Hauser reported ties with various pharmaceutical companies and travel grant from Novartis.

Citation: Hauser SL et al. N Engl J Med. 2020 Aug 6. doi: 10.1056/NEJMoa1917246.

Key clinical point: Ofatumumab is associated with lower annualized relapse rates than teriflunomide in patients with relapsing multiple sclerosis (MS).

Major finding: Annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in ASCLEPIOS I trial (difference, −0.11; P less than .001) and 0.10 and 0.25, respectively, in ASCLEPIOS II trial (difference, −0.15; P less than .001). The percentage of patients with disability worsening at 3 months and at 6 months was higher in the teriflunomide group, whereas the percentage of patients with disability improvement at 6 months was higher in ofatumumab group.

Study details: In 2 double-blind, double-dummy, phase 3 trials (ASCLEPIOS I and II), patients with relapsing MS were randomly assigned to receive subcutaneous ofatumumab (n = 946) or oral teriflunomide (n = 936) for up to 30 months and were followed for a median of 1.6 years.

Disclosures: The study was supported by Novartis Pharma. Dr. Hauser reported ties with various pharmaceutical companies and travel grant from Novartis.

Citation: Hauser SL et al. N Engl J Med. 2020 Aug 6. doi: 10.1056/NEJMoa1917246.

Key clinical point: Natalizumab is effective on the inflammatory phase of relapsing-remitting multiple sclerosis (RRMS). The frequency of poor outcomes is low and are predicted by disease activity criteria.

Major finding: At 10 years, the cumulative probabilities for secondary progressive multiple sclerosis (SPMS) conversion, Expanded Disability Status Scale (EDSS) worsening, reaching EDSS-4 and EDSS-6 were 23.7%, 30.4%, 25.1%, and 12.4%, respectively with natalizumab. The mean reduction in annualized relapsed rate at 10 years was 97.5% (P less than .0001). Factors predictive of disability at the long-term were not reaching ‘no evidence of disease activity’ (NEDA)-3, MRI worsening, increased EDSS score, and to a lesser extent the occurrence of relapse.

Study details: TYSTEN was a real-life observational study that assessed 770 patients with RRMS starting Natalizumab between 2007 and 2012. The mean follow-up duration was 97.2 months and mean treatment duration for natalizumab was 66 months.

Disclosures: The study received no funding. The presenting author had no disclosures. Some of his coinvestigators reported ties with Biogen Idec.

Citation: Bigaut K et al. Mult Scler. 2020 Jul 9. doi: 10.1177/1352458520936239.

Key clinical point: Natalizumab is effective on the inflammatory phase of relapsing-remitting multiple sclerosis (RRMS). The frequency of poor outcomes is low and are predicted by disease activity criteria.

Major finding: At 10 years, the cumulative probabilities for secondary progressive multiple sclerosis (SPMS) conversion, Expanded Disability Status Scale (EDSS) worsening, reaching EDSS-4 and EDSS-6 were 23.7%, 30.4%, 25.1%, and 12.4%, respectively with natalizumab. The mean reduction in annualized relapsed rate at 10 years was 97.5% (P less than .0001). Factors predictive of disability at the long-term were not reaching ‘no evidence of disease activity’ (NEDA)-3, MRI worsening, increased EDSS score, and to a lesser extent the occurrence of relapse.

Study details: TYSTEN was a real-life observational study that assessed 770 patients with RRMS starting Natalizumab between 2007 and 2012. The mean follow-up duration was 97.2 months and mean treatment duration for natalizumab was 66 months.

Disclosures: The study received no funding. The presenting author had no disclosures. Some of his coinvestigators reported ties with Biogen Idec.

Citation: Bigaut K et al. Mult Scler. 2020 Jul 9. doi: 10.1177/1352458520936239.

Key clinical point: Natalizumab is effective on the inflammatory phase of relapsing-remitting multiple sclerosis (RRMS). The frequency of poor outcomes is low and are predicted by disease activity criteria.

Major finding: At 10 years, the cumulative probabilities for secondary progressive multiple sclerosis (SPMS) conversion, Expanded Disability Status Scale (EDSS) worsening, reaching EDSS-4 and EDSS-6 were 23.7%, 30.4%, 25.1%, and 12.4%, respectively with natalizumab. The mean reduction in annualized relapsed rate at 10 years was 97.5% (P less than .0001). Factors predictive of disability at the long-term were not reaching ‘no evidence of disease activity’ (NEDA)-3, MRI worsening, increased EDSS score, and to a lesser extent the occurrence of relapse.

Study details: TYSTEN was a real-life observational study that assessed 770 patients with RRMS starting Natalizumab between 2007 and 2012. The mean follow-up duration was 97.2 months and mean treatment duration for natalizumab was 66 months.

Disclosures: The study received no funding. The presenting author had no disclosures. Some of his coinvestigators reported ties with Biogen Idec.

Citation: Bigaut K et al. Mult Scler. 2020 Jul 9. doi: 10.1177/1352458520936239.

Key clinical point: Stressful life events are associated with an increased risk of developing multiple sclerosis (MS).

Major finding: Stressful major life events that happened prior to disease onset significantly increased the risk by 17%-30%. Women were more vulnerable than men under certain stressful scenarios such as conflict at work or within families, marriage, sickness, or accident of family members.

Study details: A large Swedish case-control study of 2,930 patients with MS and 6,170 control participants.

Disclosures: Dr. Jiang was supported by a starting package from the Swedish Research Council.

Citation: Jiang X et al. Eur J Neurol. 2020 Aug 2. doi: 10.1111/ene.14458.

Key clinical point: Stressful life events are associated with an increased risk of developing multiple sclerosis (MS).

Major finding: Stressful major life events that happened prior to disease onset significantly increased the risk by 17%-30%. Women were more vulnerable than men under certain stressful scenarios such as conflict at work or within families, marriage, sickness, or accident of family members.

Study details: A large Swedish case-control study of 2,930 patients with MS and 6,170 control participants.

Disclosures: Dr. Jiang was supported by a starting package from the Swedish Research Council.

Citation: Jiang X et al. Eur J Neurol. 2020 Aug 2. doi: 10.1111/ene.14458.

Key clinical point: Stressful life events are associated with an increased risk of developing multiple sclerosis (MS).

Major finding: Stressful major life events that happened prior to disease onset significantly increased the risk by 17%-30%. Women were more vulnerable than men under certain stressful scenarios such as conflict at work or within families, marriage, sickness, or accident of family members.

Study details: A large Swedish case-control study of 2,930 patients with MS and 6,170 control participants.

Disclosures: Dr. Jiang was supported by a starting package from the Swedish Research Council.

Citation: Jiang X et al. Eur J Neurol. 2020 Aug 2. doi: 10.1111/ene.14458.

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
 

Biomarkers had high AUC

Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
 

Biomarkers may predict attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.

“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”

Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

[email protected]

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
 

Biomarkers had high AUC

Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
 

Biomarkers may predict attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.

“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”

Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

[email protected]

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
 

Biomarkers had high AUC

Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
 

Biomarkers may predict attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.

“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”

Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

[email protected]

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

I had the privilege of attending and speaking at the recent MSVirtual2020—the 8^th Joint ACTRIMS-ECTRIMS Meeting. I came away with a wealth of knowledge, much of which can be put to immediate use in practice, and some that shows the promise of eventual clinical utility.

Dr. Helen Tremlett, PhD, kicked off the meeting with a keynote address covering her important work on the MS prodrome.  The Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia summarized her team’s research to date and offered her thoughts on clinical implications.

Dr. Tremlett’s group has observed that in the five years before an MS symptom onset, individuals who would ultimately be diagnosed tended to experience more hospitalizations, visit their provider more, and fill more prescriptions than did those in the general population. The team dug deeper and found that these individuals experienced a range of issues prior to symptom onset, including pain, headache, migraine, fibromyalgia, irritable bowel syndrome, sleep disturbances, depression/anxiety, and dermatologic issues.

Interestingly, females in this group were less likely to become pregnant and more likely than healthy females to fill an oral contraceptive prescription, suggesting that they were trying to delay pregnancy due to these prodromal symptoms.

Dr. Tremlett noted that the more immediate implications of her group’s work are for clinical researchers, who can now use these findings to understand that there is a prodromal stage as they conduct clinical trials. The ultimate aim is to use this work to develop a diagnostic tool, but that will take more time and study.

COVID-19’s Impact on MS

The impact on COVID-19 on individuals with MS was addressed in a number of sessions. I presented data that clearly shows the risk of infection from COVID-19 is similar to that of the population at large.

• A critical evaluation of MS disease modifying therapies (DMTs) and their potential effects on COVID-19 that I published with my colleagues at the University of Pennsylvania suggested that DMTs might not increase the risk of morbidity and mortality associated with COVID-19 as some had feared. We based this conclusion on an evaluation of pathogenesis of COVID, the importance of the innate immune system in control of exposure to a novel pathogen, and the likely effects, both salutary and pernicious, of DMTs on COVID morbidity and mortality.
•  Investigators from Italy looked at 232 patients from 38 centers with MS and confirmed or suspected COVID and found that the vast majority of them (96%) had mild disease consisting of no or mild pneumonia. The remainder had either severe (2%) or critical (3%) disease.  These investigators have since expanded their observations and suggested that anti-CD20 monoclonal antibody treatment may be associated with a higher risk of hospitalization, though there did not appear to be an increase in the risk of death with their use.  Importantly, the anti-CD20 monoclonal antibody therapies are the DMTs routinely used in patients with progressive MS, generally, the MS population at greatest risk of hospitalization with COVID-19 due to their older age, co-morbidities, and level of debility.
• Recently, French researchers evaluated 347 individuals with MS and COVID by COVID disease severity. They found that there was a higher proportion of patients with severe COVID not receiving DMT compared with individuals receiving treatment (46% and 15%, respectively).

The Increasing Importance of sNfL Concentration

Serum neurofilament light chain (sNfL) concentration continues to be a hot topic. Dr. Jens Kuhle, head of the Multiple Sclerosis Centre at the University of Basel, and colleagues have demonstrated that sNfL levels can play a role in monitoring MS treatment in practice. They evaluated more than 1000 individuals who were taking DMTs, measuring sNfL and deriving a score that reflected how participants fared relative to healthy controls of the same age. Among their findings:

• The resulting score predicted clinical events in the following year, with the effect escalating in magnitude in those whose scores were higher.
• This same predictive effect was seen with respect to future new/enlarging T2 lesions and brain volume loss.
• Score change in patients with NEDA-03 status was linked with a 37% increased risk of clinical events in the following year.

New Radiologic Techniques

Encouraging findings on new radiologic techniques were presented. I found three studies extremely informative. The first two have immediate or near-immediate clinical implications, and the third shows promise.

• In a comparison of patients with MS and healthy individuals who underwent brain 3T MRI to assess lesions and atrophy, R. Bonacchi and colleagues from Milan, Italy found that cardiovascular (CV) risk factors are linked with brain atrophy in patients with MS, even those <50 years of age. Specifically, the presence of at least two CV risk factors was linked with reduced normalized grey matter volume, white matter volume, and brain volume.
• Another comparison of individuals with MS and healthy controls—this one from O. Al-Louzi and colleagues at the National Institute of Neurological Disorders and Stroke—looked at the central vein sign (CVS) biomarker and determined that excluding lesions only if all dimensions of 3T MRI results were less than threshold (versus if any dimension was less than threshold) led to the inclusion of more CVS-positive lesions. Investigators suggested this work could lead to modified clinical guidelines.
• In an evaluation of patients with MS using 3T MRI, F. LaRosa and colleagues from Lausanne, Switzerland reported that RimNet, a prototype built upon two convolutional neural networks, was better than two alternative methods at detecting pragmatic rim lesions, which are linked with higher disease burden. Compared with expert raters, RimNet had higher sensitivity (87% vs 76%) but lower specificity (91% vs 99%).

There were many other valuable presentations at MSVirtual2020, but perhaps the most appreciated experience was the ability to hear more experts deliver their important work. Unlike a live meeting, I was able to easily attend parallel sessions and to do so at my leisure. ECTRIMS has become so big that I often left the live meeting feeling as if I missed out on a lot. Not this year. I heard almost all of it and came away with a greater appreciation of the breadth and depth of the meeting.  I hope that in the future, even following the return of in-person meetings, a virtual format coexists to afford attendees and those unable to attend live the opportunity to experience the totality of the meeting.

I had the privilege of attending and speaking at the recent MSVirtual2020—the 8^th Joint ACTRIMS-ECTRIMS Meeting. I came away with a wealth of knowledge, much of which can be put to immediate use in practice, and some that shows the promise of eventual clinical utility.

Dr. Helen Tremlett, PhD, kicked off the meeting with a keynote address covering her important work on the MS prodrome.  The Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia summarized her team’s research to date and offered her thoughts on clinical implications.

Dr. Tremlett’s group has observed that in the five years before an MS symptom onset, individuals who would ultimately be diagnosed tended to experience more hospitalizations, visit their provider more, and fill more prescriptions than did those in the general population. The team dug deeper and found that these individuals experienced a range of issues prior to symptom onset, including pain, headache, migraine, fibromyalgia, irritable bowel syndrome, sleep disturbances, depression/anxiety, and dermatologic issues.

Interestingly, females in this group were less likely to become pregnant and more likely than healthy females to fill an oral contraceptive prescription, suggesting that they were trying to delay pregnancy due to these prodromal symptoms.

Dr. Tremlett noted that the more immediate implications of her group’s work are for clinical researchers, who can now use these findings to understand that there is a prodromal stage as they conduct clinical trials. The ultimate aim is to use this work to develop a diagnostic tool, but that will take more time and study.

COVID-19’s Impact on MS

The impact on COVID-19 on individuals with MS was addressed in a number of sessions. I presented data that clearly shows the risk of infection from COVID-19 is similar to that of the population at large.

• A critical evaluation of MS disease modifying therapies (DMTs) and their potential effects on COVID-19 that I published with my colleagues at the University of Pennsylvania suggested that DMTs might not increase the risk of morbidity and mortality associated with COVID-19 as some had feared. We based this conclusion on an evaluation of pathogenesis of COVID, the importance of the innate immune system in control of exposure to a novel pathogen, and the likely effects, both salutary and pernicious, of DMTs on COVID morbidity and mortality.
•  Investigators from Italy looked at 232 patients from 38 centers with MS and confirmed or suspected COVID and found that the vast majority of them (96%) had mild disease consisting of no or mild pneumonia. The remainder had either severe (2%) or critical (3%) disease.  These investigators have since expanded their observations and suggested that anti-CD20 monoclonal antibody treatment may be associated with a higher risk of hospitalization, though there did not appear to be an increase in the risk of death with their use.  Importantly, the anti-CD20 monoclonal antibody therapies are the DMTs routinely used in patients with progressive MS, generally, the MS population at greatest risk of hospitalization with COVID-19 due to their older age, co-morbidities, and level of debility.
• Recently, French researchers evaluated 347 individuals with MS and COVID by COVID disease severity. They found that there was a higher proportion of patients with severe COVID not receiving DMT compared with individuals receiving treatment (46% and 15%, respectively).

The Increasing Importance of sNfL Concentration

Serum neurofilament light chain (sNfL) concentration continues to be a hot topic. Dr. Jens Kuhle, head of the Multiple Sclerosis Centre at the University of Basel, and colleagues have demonstrated that sNfL levels can play a role in monitoring MS treatment in practice. They evaluated more than 1000 individuals who were taking DMTs, measuring sNfL and deriving a score that reflected how participants fared relative to healthy controls of the same age. Among their findings:

• The resulting score predicted clinical events in the following year, with the effect escalating in magnitude in those whose scores were higher.
• This same predictive effect was seen with respect to future new/enlarging T2 lesions and brain volume loss.
• Score change in patients with NEDA-03 status was linked with a 37% increased risk of clinical events in the following year.

New Radiologic Techniques

Encouraging findings on new radiologic techniques were presented. I found three studies extremely informative. The first two have immediate or near-immediate clinical implications, and the third shows promise.

• In a comparison of patients with MS and healthy individuals who underwent brain 3T MRI to assess lesions and atrophy, R. Bonacchi and colleagues from Milan, Italy found that cardiovascular (CV) risk factors are linked with brain atrophy in patients with MS, even those <50 years of age. Specifically, the presence of at least two CV risk factors was linked with reduced normalized grey matter volume, white matter volume, and brain volume.
• Another comparison of individuals with MS and healthy controls—this one from O. Al-Louzi and colleagues at the National Institute of Neurological Disorders and Stroke—looked at the central vein sign (CVS) biomarker and determined that excluding lesions only if all dimensions of 3T MRI results were less than threshold (versus if any dimension was less than threshold) led to the inclusion of more CVS-positive lesions. Investigators suggested this work could lead to modified clinical guidelines.
• In an evaluation of patients with MS using 3T MRI, F. LaRosa and colleagues from Lausanne, Switzerland reported that RimNet, a prototype built upon two convolutional neural networks, was better than two alternative methods at detecting pragmatic rim lesions, which are linked with higher disease burden. Compared with expert raters, RimNet had higher sensitivity (87% vs 76%) but lower specificity (91% vs 99%).

There were many other valuable presentations at MSVirtual2020, but perhaps the most appreciated experience was the ability to hear more experts deliver their important work. Unlike a live meeting, I was able to easily attend parallel sessions and to do so at my leisure. ECTRIMS has become so big that I often left the live meeting feeling as if I missed out on a lot. Not this year. I heard almost all of it and came away with a greater appreciation of the breadth and depth of the meeting.  I hope that in the future, even following the return of in-person meetings, a virtual format coexists to afford attendees and those unable to attend live the opportunity to experience the totality of the meeting.

I had the privilege of attending and speaking at the recent MSVirtual2020—the 8^th Joint ACTRIMS-ECTRIMS Meeting. I came away with a wealth of knowledge, much of which can be put to immediate use in practice, and some that shows the promise of eventual clinical utility.

Dr. Helen Tremlett, PhD, kicked off the meeting with a keynote address covering her important work on the MS prodrome.  The Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia summarized her team’s research to date and offered her thoughts on clinical implications.

Dr. Tremlett’s group has observed that in the five years before an MS symptom onset, individuals who would ultimately be diagnosed tended to experience more hospitalizations, visit their provider more, and fill more prescriptions than did those in the general population. The team dug deeper and found that these individuals experienced a range of issues prior to symptom onset, including pain, headache, migraine, fibromyalgia, irritable bowel syndrome, sleep disturbances, depression/anxiety, and dermatologic issues.

Interestingly, females in this group were less likely to become pregnant and more likely than healthy females to fill an oral contraceptive prescription, suggesting that they were trying to delay pregnancy due to these prodromal symptoms.

Dr. Tremlett noted that the more immediate implications of her group’s work are for clinical researchers, who can now use these findings to understand that there is a prodromal stage as they conduct clinical trials. The ultimate aim is to use this work to develop a diagnostic tool, but that will take more time and study.

COVID-19’s Impact on MS

The impact on COVID-19 on individuals with MS was addressed in a number of sessions. I presented data that clearly shows the risk of infection from COVID-19 is similar to that of the population at large.

• A critical evaluation of MS disease modifying therapies (DMTs) and their potential effects on COVID-19 that I published with my colleagues at the University of Pennsylvania suggested that DMTs might not increase the risk of morbidity and mortality associated with COVID-19 as some had feared. We based this conclusion on an evaluation of pathogenesis of COVID, the importance of the innate immune system in control of exposure to a novel pathogen, and the likely effects, both salutary and pernicious, of DMTs on COVID morbidity and mortality.
•  Investigators from Italy looked at 232 patients from 38 centers with MS and confirmed or suspected COVID and found that the vast majority of them (96%) had mild disease consisting of no or mild pneumonia. The remainder had either severe (2%) or critical (3%) disease.  These investigators have since expanded their observations and suggested that anti-CD20 monoclonal antibody treatment may be associated with a higher risk of hospitalization, though there did not appear to be an increase in the risk of death with their use.  Importantly, the anti-CD20 monoclonal antibody therapies are the DMTs routinely used in patients with progressive MS, generally, the MS population at greatest risk of hospitalization with COVID-19 due to their older age, co-morbidities, and level of debility.
• Recently, French researchers evaluated 347 individuals with MS and COVID by COVID disease severity. They found that there was a higher proportion of patients with severe COVID not receiving DMT compared with individuals receiving treatment (46% and 15%, respectively).

The Increasing Importance of sNfL Concentration

Serum neurofilament light chain (sNfL) concentration continues to be a hot topic. Dr. Jens Kuhle, head of the Multiple Sclerosis Centre at the University of Basel, and colleagues have demonstrated that sNfL levels can play a role in monitoring MS treatment in practice. They evaluated more than 1000 individuals who were taking DMTs, measuring sNfL and deriving a score that reflected how participants fared relative to healthy controls of the same age. Among their findings:

• The resulting score predicted clinical events in the following year, with the effect escalating in magnitude in those whose scores were higher.
• This same predictive effect was seen with respect to future new/enlarging T2 lesions and brain volume loss.
• Score change in patients with NEDA-03 status was linked with a 37% increased risk of clinical events in the following year.

New Radiologic Techniques

Encouraging findings on new radiologic techniques were presented. I found three studies extremely informative. The first two have immediate or near-immediate clinical implications, and the third shows promise.

• In a comparison of patients with MS and healthy individuals who underwent brain 3T MRI to assess lesions and atrophy, R. Bonacchi and colleagues from Milan, Italy found that cardiovascular (CV) risk factors are linked with brain atrophy in patients with MS, even those <50 years of age. Specifically, the presence of at least two CV risk factors was linked with reduced normalized grey matter volume, white matter volume, and brain volume.
• Another comparison of individuals with MS and healthy controls—this one from O. Al-Louzi and colleagues at the National Institute of Neurological Disorders and Stroke—looked at the central vein sign (CVS) biomarker and determined that excluding lesions only if all dimensions of 3T MRI results were less than threshold (versus if any dimension was less than threshold) led to the inclusion of more CVS-positive lesions. Investigators suggested this work could lead to modified clinical guidelines.
• In an evaluation of patients with MS using 3T MRI, F. LaRosa and colleagues from Lausanne, Switzerland reported that RimNet, a prototype built upon two convolutional neural networks, was better than two alternative methods at detecting pragmatic rim lesions, which are linked with higher disease burden. Compared with expert raters, RimNet had higher sensitivity (87% vs 76%) but lower specificity (91% vs 99%).

There were many other valuable presentations at MSVirtual2020, but perhaps the most appreciated experience was the ability to hear more experts deliver their important work. Unlike a live meeting, I was able to easily attend parallel sessions and to do so at my leisure. ECTRIMS has become so big that I often left the live meeting feeling as if I missed out on a lot. Not this year. I heard almost all of it and came away with a greater appreciation of the breadth and depth of the meeting.  I hope that in the future, even following the return of in-person meetings, a virtual format coexists to afford attendees and those unable to attend live the opportunity to experience the totality of the meeting.

Promising phase 3 trial results from French researchers indicate that the first-in-class oral TKI masitinib may provide a new treatment option for patients with primary progressive multiple sclerosis (PPMS) or nonactive secondary progressive MS (SPMS).

The masitinib study was noted by Dr Mark Freedman, professor of neurology at the University of Ottawa, as among the key findings on PPMS presented at ACTRIMS-ECTRIMS 2020. The French study reported that patients receiving masitinib over 96 weeks experienced significant delay in disability progression.

Dr Freedman explains how an analysis done by Mellon Center researchers may change how clinicians counsel patients about the risk for progressive multifocal leukoencephalopathy (PML) related to fingolimod treatment. Their research shows the incidence rate of PML among patients receiving fingolimod to be very low — in fact, fewer than 40 times that of patients receiving natalizumab.

Finally, Dr Freedman discuses an ad hoc analysis presented by leading MS researchers from University Hospital in Basel, Switzerland, which points to plasma glial fibrillary acidic protein (GFAP) levels as a prognostic biomarker of increased risk for worsening disability. Using data from the EXPAND trial, researchers found significant risk for increased disability among patients with nonactive SPMS who had elevated baseline GFAP.

Professor, Department of Neurology, University of Ottawa and The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada.

Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships: Serve(d) on the advisory board, board of directors, or other similar groups for: Actelion (Janssen/Johnson & Johnson); Alexion; Atara Biotherapeutics; BayerHealthcare; BiogenIdec; Celgene; Clene Nanomedicine; GRI Bio; Hoffman La-Roche; Magenta Therapeutics; Merck Serono; MedDay; Novartis; Sanofi-Genzyme; Teva Canada Innovation. Serve(d) as a member of a speakers bureau for: Sanofi-Genzyme; EMD Serono. Received honoraria or consultation fees for: Actelion (Janssen/Johnson & Johnson); Alexion; BiogenIdec; Celgene (BMS); EMD Inc; Sanofi-Genzyme; Hoffman La-Roche; Merck Serono; Novartis; Teva Canada Innovation­. Received research or educational grants from: Sanofi-Genzyme Canada; Hoffman-La Roche; EMD Inc.

Promising phase 3 trial results from French researchers indicate that the first-in-class oral TKI masitinib may provide a new treatment option for patients with primary progressive multiple sclerosis (PPMS) or nonactive secondary progressive MS (SPMS).

The masitinib study was noted by Dr Mark Freedman, professor of neurology at the University of Ottawa, as among the key findings on PPMS presented at ACTRIMS-ECTRIMS 2020. The French study reported that patients receiving masitinib over 96 weeks experienced significant delay in disability progression.

Dr Freedman explains how an analysis done by Mellon Center researchers may change how clinicians counsel patients about the risk for progressive multifocal leukoencephalopathy (PML) related to fingolimod treatment. Their research shows the incidence rate of PML among patients receiving fingolimod to be very low — in fact, fewer than 40 times that of patients receiving natalizumab.

Finally, Dr Freedman discuses an ad hoc analysis presented by leading MS researchers from University Hospital in Basel, Switzerland, which points to plasma glial fibrillary acidic protein (GFAP) levels as a prognostic biomarker of increased risk for worsening disability. Using data from the EXPAND trial, researchers found significant risk for increased disability among patients with nonactive SPMS who had elevated baseline GFAP.

Professor, Department of Neurology, University of Ottawa and The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada.

Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships: Serve(d) on the advisory board, board of directors, or other similar groups for: Actelion (Janssen/Johnson & Johnson); Alexion; Atara Biotherapeutics; BayerHealthcare; BiogenIdec; Celgene; Clene Nanomedicine; GRI Bio; Hoffman La-Roche; Magenta Therapeutics; Merck Serono; MedDay; Novartis; Sanofi-Genzyme; Teva Canada Innovation. Serve(d) as a member of a speakers bureau for: Sanofi-Genzyme; EMD Serono. Received honoraria or consultation fees for: Actelion (Janssen/Johnson & Johnson); Alexion; BiogenIdec; Celgene (BMS); EMD Inc; Sanofi-Genzyme; Hoffman La-Roche; Merck Serono; Novartis; Teva Canada Innovation­. Received research or educational grants from: Sanofi-Genzyme Canada; Hoffman-La Roche; EMD Inc.

Promising phase 3 trial results from French researchers indicate that the first-in-class oral TKI masitinib may provide a new treatment option for patients with primary progressive multiple sclerosis (PPMS) or nonactive secondary progressive MS (SPMS).

The masitinib study was noted by Dr Mark Freedman, professor of neurology at the University of Ottawa, as among the key findings on PPMS presented at ACTRIMS-ECTRIMS 2020. The French study reported that patients receiving masitinib over 96 weeks experienced significant delay in disability progression.

Dr Freedman explains how an analysis done by Mellon Center researchers may change how clinicians counsel patients about the risk for progressive multifocal leukoencephalopathy (PML) related to fingolimod treatment. Their research shows the incidence rate of PML among patients receiving fingolimod to be very low — in fact, fewer than 40 times that of patients receiving natalizumab.

Finally, Dr Freedman discuses an ad hoc analysis presented by leading MS researchers from University Hospital in Basel, Switzerland, which points to plasma glial fibrillary acidic protein (GFAP) levels as a prognostic biomarker of increased risk for worsening disability. Using data from the EXPAND trial, researchers found significant risk for increased disability among patients with nonactive SPMS who had elevated baseline GFAP.

Professor, Department of Neurology, University of Ottawa and The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada.

Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships: Serve(d) on the advisory board, board of directors, or other similar groups for: Actelion (Janssen/Johnson & Johnson); Alexion; Atara Biotherapeutics; BayerHealthcare; BiogenIdec; Celgene; Clene Nanomedicine; GRI Bio; Hoffman La-Roche; Magenta Therapeutics; Merck Serono; MedDay; Novartis; Sanofi-Genzyme; Teva Canada Innovation. Serve(d) as a member of a speakers bureau for: Sanofi-Genzyme; EMD Serono. Received honoraria or consultation fees for: Actelion (Janssen/Johnson & Johnson); Alexion; BiogenIdec; Celgene (BMS); EMD Inc; Sanofi-Genzyme; Hoffman La-Roche; Merck Serono; Novartis; Teva Canada Innovation­. Received research or educational grants from: Sanofi-Genzyme Canada; Hoffman-La Roche; EMD Inc.