Multiple Sclerosis

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.

A shift in managing symptoms for patients with relapsing-remitting multiple sclerosis (RRMS) may be in order as new research questions the efficacy of three commonly used drugs for MS-related fatigue. Results of a study from Johns Hopkins University show that amantadine, modafinil, and methylphenidate were not superior to placebo. As Dr Mark Freedman reports in this ReCAP, the study suggests that clinicians consider focusing more on patient sleep quality rather than tiredness in their evaluation of fatigue.

This study was presented during the 8th Joint Meeting of ACTRIMS-ECTRIMS, this year branded MSVirtual2020. Dr Freedman, a recognized neurologist from the University of Ottawa, shares key highlights from the online conference.

He explains the significance of new evidence that points to the potential for a selective retinoid X receptor agonist to promote remyelination in relapsing disease. He also discusses a study by researchers at the University of Melbourne that looked at data from the largest cohort of MS patients with COVID-19 and drew troubling conclusions.

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.

A shift in managing symptoms for patients with relapsing-remitting multiple sclerosis (RRMS) may be in order as new research questions the efficacy of three commonly used drugs for MS-related fatigue. Results of a study from Johns Hopkins University show that amantadine, modafinil, and methylphenidate were not superior to placebo. As Dr Mark Freedman reports in this ReCAP, the study suggests that clinicians consider focusing more on patient sleep quality rather than tiredness in their evaluation of fatigue.

This study was presented during the 8th Joint Meeting of ACTRIMS-ECTRIMS, this year branded MSVirtual2020. Dr Freedman, a recognized neurologist from the University of Ottawa, shares key highlights from the online conference.

He explains the significance of new evidence that points to the potential for a selective retinoid X receptor agonist to promote remyelination in relapsing disease. He also discusses a study by researchers at the University of Melbourne that looked at data from the largest cohort of MS patients with COVID-19 and drew troubling conclusions.

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.

A shift in managing symptoms for patients with relapsing-remitting multiple sclerosis (RRMS) may be in order as new research questions the efficacy of three commonly used drugs for MS-related fatigue. Results of a study from Johns Hopkins University show that amantadine, modafinil, and methylphenidate were not superior to placebo. As Dr Mark Freedman reports in this ReCAP, the study suggests that clinicians consider focusing more on patient sleep quality rather than tiredness in their evaluation of fatigue.

This study was presented during the 8th Joint Meeting of ACTRIMS-ECTRIMS, this year branded MSVirtual2020. Dr Freedman, a recognized neurologist from the University of Ottawa, shares key highlights from the online conference.

He explains the significance of new evidence that points to the potential for a selective retinoid X receptor agonist to promote remyelination in relapsing disease. He also discusses a study by researchers at the University of Melbourne that looked at data from the largest cohort of MS patients with COVID-19 and drew troubling conclusions.

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.

In relapsing-remitting multiple sclerosis (RRMS), MRI has provided a key indication of disease presence and activity. With the availability of serum neurofilament (sNfL) assays, disease activity can be correlated with sNfL levels.

Dr Tobias Derfuss, from University Hospital Basel in Basel, Switzerland, discusses emerging research reported at the ACTRIMS/ECTRIMS 2020 Virtual Meeting, focusing on the use of sNfL as a biomarker for monitoring treatment response and disease activity in RRMS.

Dr Derfuss highlights one study in which longitudinal observations showed that high levels of sNfL at baseline are associated with a high risk for gadolinium-enhancing lesions; the study authors suggest that quarterly monitoring may be adequate for surveillance of subclinical disease.

In another study, higher sNfL levels at baseline were linked to a higher risk for T2 lesions and a more pronounced brain atrophy rate, but disability progression was not correlated to baseline sNfL levels.

Finally, Dr Derfuss reports on a real-world, large cohort study supporting the value of sNfL to capture and predict disability progression independent of relapses.

Tobias J. Derfuss, MD, Professor, Head of Outpatient Clinic, Department of Neurology, University Hospital Board, Basel, Switzerland

Tobias J. Derfuss, MD, has disclosed the following relevant financial relationships:­ Received financial compensation for his activities in advisory boards, steering committees, data safety monitoring boards, and consultation for: Novartis; Merck; Biogen; Celgene; Actelion; Mitsubishi Pharma; MedDay; Roche; Sanofi Genzyme. Received research grant from: Novartis; Biogen; Roche; Swiss National Science Foundation; European Union; Swiss MS Society. Spouse is an employee of and holds stock options in: Novartis

In relapsing-remitting multiple sclerosis (RRMS), MRI has provided a key indication of disease presence and activity. With the availability of serum neurofilament (sNfL) assays, disease activity can be correlated with sNfL levels.

Dr Tobias Derfuss, from University Hospital Basel in Basel, Switzerland, discusses emerging research reported at the ACTRIMS/ECTRIMS 2020 Virtual Meeting, focusing on the use of sNfL as a biomarker for monitoring treatment response and disease activity in RRMS.

Dr Derfuss highlights one study in which longitudinal observations showed that high levels of sNfL at baseline are associated with a high risk for gadolinium-enhancing lesions; the study authors suggest that quarterly monitoring may be adequate for surveillance of subclinical disease.

In another study, higher sNfL levels at baseline were linked to a higher risk for T2 lesions and a more pronounced brain atrophy rate, but disability progression was not correlated to baseline sNfL levels.

Finally, Dr Derfuss reports on a real-world, large cohort study supporting the value of sNfL to capture and predict disability progression independent of relapses.

Tobias J. Derfuss, MD, Professor, Head of Outpatient Clinic, Department of Neurology, University Hospital Board, Basel, Switzerland

Tobias J. Derfuss, MD, has disclosed the following relevant financial relationships:­ Received financial compensation for his activities in advisory boards, steering committees, data safety monitoring boards, and consultation for: Novartis; Merck; Biogen; Celgene; Actelion; Mitsubishi Pharma; MedDay; Roche; Sanofi Genzyme. Received research grant from: Novartis; Biogen; Roche; Swiss National Science Foundation; European Union; Swiss MS Society. Spouse is an employee of and holds stock options in: Novartis

In relapsing-remitting multiple sclerosis (RRMS), MRI has provided a key indication of disease presence and activity. With the availability of serum neurofilament (sNfL) assays, disease activity can be correlated with sNfL levels.

Dr Tobias Derfuss, from University Hospital Basel in Basel, Switzerland, discusses emerging research reported at the ACTRIMS/ECTRIMS 2020 Virtual Meeting, focusing on the use of sNfL as a biomarker for monitoring treatment response and disease activity in RRMS.

Dr Derfuss highlights one study in which longitudinal observations showed that high levels of sNfL at baseline are associated with a high risk for gadolinium-enhancing lesions; the study authors suggest that quarterly monitoring may be adequate for surveillance of subclinical disease.

In another study, higher sNfL levels at baseline were linked to a higher risk for T2 lesions and a more pronounced brain atrophy rate, but disability progression was not correlated to baseline sNfL levels.

Finally, Dr Derfuss reports on a real-world, large cohort study supporting the value of sNfL to capture and predict disability progression independent of relapses.

Tobias J. Derfuss, MD, Professor, Head of Outpatient Clinic, Department of Neurology, University Hospital Board, Basel, Switzerland

Tobias J. Derfuss, MD, has disclosed the following relevant financial relationships:­ Received financial compensation for his activities in advisory boards, steering committees, data safety monitoring boards, and consultation for: Novartis; Merck; Biogen; Celgene; Actelion; Mitsubishi Pharma; MedDay; Roche; Sanofi Genzyme. Received research grant from: Novartis; Biogen; Roche; Swiss National Science Foundation; European Union; Swiss MS Society. Spouse is an employee of and holds stock options in: Novartis

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented 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.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented 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.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented 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.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.