ICYMI Multiple Sclerosis

Key clinical point: Cladribine tablets had lower annualized relapse rate (ARR) vs. interferon, glatiramer acetate, and dimethyl fumarate for relapsing-remitting multiple sclerosis (RRMS) in the first 2 years; a similar ARR vs. fingolimod; and a higher ARR vs. natalizumab.

Major finding: Cladribine demonstrated significantly lower ARR vs. interferon (relapse ratio [RR], 0.48; P less than .001), glatiramer acetate (RR, 0.49; P less than .001), and dimethyl fumarate (RR, 0.6; P = .001). No significant differences in ARR were observed when compared with fingolimod (RR = 0.74; P = .24), whereas higher ARR was observed vs. natalizumab (RR, 2.13; P = .014).

Study details: This study compared the efficacy of cladribine vs. other approved drugs in patients with RRMS by matching randomized controlled trial (CLARITY trial; cladribine tablets vs. placebo; n = 945) to observational data (Italian multicenter database i-MuST; n = 2,204).

Disclosures: The study was sponsored by Merck Serono S.p.A., Rome, Italy; an affiliate of Merck KGaA, Darmstadt, Germany. Dr. Signori had no disclosures. Dr. Visconti is an employee at Merck Serono, Italy, and Dr. Sormani received consulting fees from various pharmaceutical companies including Merck KGaA.

Citation: Signori A et al. Neurol Neuroimmunol Neuroinflamm. 2020 Aug 14. doi: 10.1212/NXI.0000000000000878.

Key clinical point: Cladribine tablets had lower annualized relapse rate (ARR) vs. interferon, glatiramer acetate, and dimethyl fumarate for relapsing-remitting multiple sclerosis (RRMS) in the first 2 years; a similar ARR vs. fingolimod; and a higher ARR vs. natalizumab.

Major finding: Cladribine demonstrated significantly lower ARR vs. interferon (relapse ratio [RR], 0.48; P less than .001), glatiramer acetate (RR, 0.49; P less than .001), and dimethyl fumarate (RR, 0.6; P = .001). No significant differences in ARR were observed when compared with fingolimod (RR = 0.74; P = .24), whereas higher ARR was observed vs. natalizumab (RR, 2.13; P = .014).

Study details: This study compared the efficacy of cladribine vs. other approved drugs in patients with RRMS by matching randomized controlled trial (CLARITY trial; cladribine tablets vs. placebo; n = 945) to observational data (Italian multicenter database i-MuST; n = 2,204).

Disclosures: The study was sponsored by Merck Serono S.p.A., Rome, Italy; an affiliate of Merck KGaA, Darmstadt, Germany. Dr. Signori had no disclosures. Dr. Visconti is an employee at Merck Serono, Italy, and Dr. Sormani received consulting fees from various pharmaceutical companies including Merck KGaA.

Citation: Signori A et al. Neurol Neuroimmunol Neuroinflamm. 2020 Aug 14. doi: 10.1212/NXI.0000000000000878.

Key clinical point: Cladribine tablets had lower annualized relapse rate (ARR) vs. interferon, glatiramer acetate, and dimethyl fumarate for relapsing-remitting multiple sclerosis (RRMS) in the first 2 years; a similar ARR vs. fingolimod; and a higher ARR vs. natalizumab.

Major finding: Cladribine demonstrated significantly lower ARR vs. interferon (relapse ratio [RR], 0.48; P less than .001), glatiramer acetate (RR, 0.49; P less than .001), and dimethyl fumarate (RR, 0.6; P = .001). No significant differences in ARR were observed when compared with fingolimod (RR = 0.74; P = .24), whereas higher ARR was observed vs. natalizumab (RR, 2.13; P = .014).

Study details: This study compared the efficacy of cladribine vs. other approved drugs in patients with RRMS by matching randomized controlled trial (CLARITY trial; cladribine tablets vs. placebo; n = 945) to observational data (Italian multicenter database i-MuST; n = 2,204).

Disclosures: The study was sponsored by Merck Serono S.p.A., Rome, Italy; an affiliate of Merck KGaA, Darmstadt, Germany. Dr. Signori had no disclosures. Dr. Visconti is an employee at Merck Serono, Italy, and Dr. Sormani received consulting fees from various pharmaceutical companies including Merck KGaA.

Citation: Signori A et al. Neurol Neuroimmunol Neuroinflamm. 2020 Aug 14. doi: 10.1212/NXI.0000000000000878.

Key clinical point: Pregnancy and childbirth seem to delay the onset of multiple sclerosis by more than 3 years. However, having more pregnancies is not associated with later onset.

Major finding: Onset of clinically isolated syndrome (CIS) was later in women with previous pregnancies and childbirths vs. those without pregnancies and childbirths (hazard ratio, 0.68; P less than .001), with a median delay of 3.3 years. No association was seen between higher number of pregnancies and childbirths and delay in CIS onset.

Study details: The findings are based on a multicenter cohort study of 2,557 women with CIS (mean age at CIS onset, 31.5 years) from the MSBase Registry.

Disclosures: The study was supported by a postgraduate scholarship and Ian Ballard Travel Award from MS Research Australia, an Australian Government Research Training Program Scholarship, and a grant from the National Health and Medical Research Council. The lead author reported receiving grants from MS Research Australia during the conduct of the study; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Genzyme-Sanofi outside the submitted work.

Citation: Nguyen AL et al. JAMA Neurol. 2020 Sep 14. doi: 10.1001/jamaneurol.2020.3324.

Key clinical point: Pregnancy and childbirth seem to delay the onset of multiple sclerosis by more than 3 years. However, having more pregnancies is not associated with later onset.

Major finding: Onset of clinically isolated syndrome (CIS) was later in women with previous pregnancies and childbirths vs. those without pregnancies and childbirths (hazard ratio, 0.68; P less than .001), with a median delay of 3.3 years. No association was seen between higher number of pregnancies and childbirths and delay in CIS onset.

Study details: The findings are based on a multicenter cohort study of 2,557 women with CIS (mean age at CIS onset, 31.5 years) from the MSBase Registry.

Disclosures: The study was supported by a postgraduate scholarship and Ian Ballard Travel Award from MS Research Australia, an Australian Government Research Training Program Scholarship, and a grant from the National Health and Medical Research Council. The lead author reported receiving grants from MS Research Australia during the conduct of the study; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Genzyme-Sanofi outside the submitted work.

Citation: Nguyen AL et al. JAMA Neurol. 2020 Sep 14. doi: 10.1001/jamaneurol.2020.3324.

Key clinical point: Pregnancy and childbirth seem to delay the onset of multiple sclerosis by more than 3 years. However, having more pregnancies is not associated with later onset.

Major finding: Onset of clinically isolated syndrome (CIS) was later in women with previous pregnancies and childbirths vs. those without pregnancies and childbirths (hazard ratio, 0.68; P less than .001), with a median delay of 3.3 years. No association was seen between higher number of pregnancies and childbirths and delay in CIS onset.

Study details: The findings are based on a multicenter cohort study of 2,557 women with CIS (mean age at CIS onset, 31.5 years) from the MSBase Registry.

Disclosures: The study was supported by a postgraduate scholarship and Ian Ballard Travel Award from MS Research Australia, an Australian Government Research Training Program Scholarship, and a grant from the National Health and Medical Research Council. The lead author reported receiving grants from MS Research Australia during the conduct of the study; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Genzyme-Sanofi outside the submitted work.

Citation: Nguyen AL et al. JAMA Neurol. 2020 Sep 14. doi: 10.1001/jamaneurol.2020.3324.

Measuring serum levels of neurofilament light chain (NfL) is an effective way of detecting disease activity and the need to optimize treatment in patients with multiple sclerosis (MS), independent of relapse and MRI activity, a new study has shown. 

The study found that current serum NfL levels predicted relapses, disability worsening, and MRI activity in the following year independent of standard metrics for treatment monitoring, such as relapse rate, disability worsening, and MRI findings. The biomarker also detected subclinical disease activity in patients with no evidence of disease activity (NEDA3), as measured by absence of previous relapses, worsening score on the Expanded Disability Status Scale (EDSS), or brain lesion formation on MRI. 

“Our data in this well-characterized large real-world cohort supports the value of serum NfL levels for treatment monitoring in MS clinical practice,” lead author Özgür Yaldizli, MD, concluded.

Dr. Yaldizli, who is a consultant neurologist at University Hospital Basel (Switzerland), presented the findings 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.

“This is the first study to compare NfL simultaneously with other markers of disease progression, such as MRI lesions and relapse rate in treated patients. We show that NfL gives a unique signal that is not captured by other markers,” Dr. Yaldizli said.

“This is likely the largest study of NfL in MS to date, with more than 7,000 samples from well-characterized MS patients followed longitudinally for more than 5 years of sampling and including high quality data on MRI and clinical examinations. It is the first time all these factors have been combined so that we can see how NfL compares with other markers of disease progression in predicting clinical events and monitoring treatment efficacy,” said senior author Jens Kuhle, MD, PhD, also from University Hospital Basel. 
 

Large normative database for reference

The researchers also reported a large normative database of NfL values with data from more than 8,000 healthy controls. “This is the largest normative database to date, that gives us reliable reference values for NfL across a range of ages and comorbidities,” Dr. Kuhle noted.

In his presentation, Dr. Yaldizli explained that NfL is a neuronal cytoskeletal protein released into the cerebrospinal fluid and blood following neuroaxonal injury. Although numerous studies have shown that serum NfL is associated with clinical and MRI disease activity and treatment response, it is not clear whether serum NfL under established disease-modifying therapy (DMT) can identify patients with suboptimal treatment response, compared with standard clinical and MRI activity measures.

This study addressed that question in the large real-world Swiss MS cohort.

The study involved 1,366 patients (88.8% with relapsing remitting MS [RRMS], 5.4% with secondary progressive MS, and 5.8% with primary progressive MS) receiving DMT for at least 3 months from seven MS centers. The median disease duration was 7.2 years. Serum NfL was measured every 6 or 12 months with NF-Light assay on the latest-generation HDX platform (blinded for clinical and MRI data). The median follow-up was 4.9 years. There was an average of five samples per patient, with a total of 7462 samples.

Results showed that NfL levels were higher in older patients (14.5% per 10 years), those with secondary progressive MS (12.4% vs. RRMS), those with primary progressive MS (14.4% vs. RRMS), and in those who had a relapse in the last 4 months (53.4%).

NfL levels were 13.4% lower in patients receiving oral DMT (vs. untreated patients) and 17.7% in patients receiving monoclonal antibodies (vs. untreated patients).

In the large cohort of healthy controls, NfL levels also increased with age, but levels in patients with MS were higher than in controls across the whole age spectrum.

To obtain a measure of deviation from normal, the authors converted NfL levels to z score, which express how much (in terms of number of standard deviations) a measurement differs from mean values found in healthy controls of the same age. Effects were more pronounced with use of z score derived from the normative database than with use of absolute NfL levels even after adjustment for age.

In the univariate analysis, serum NfL z score predicted relapse or EDSS worsening in the following year: The higher the z score, the higher the risk for relapse or EDSS worsening. Patients with an NfL z score greater than 1 had a 41% higher risk for relapse or EDSS worsening in the following year, compared with those whose z score was less than 1 (odds ratio, 1.41).

Patients with an NfL z score exceeding 1.5 had an 80% higher risk for relapse or EDSS worsening in the following year than did those whose score was below 1.5 (OR, 1.8).

Patients with an NfL z score greater than 2 had a 2.3 times higher risk for relapse or EDSS worsening in the following year versus those with a score below 2. (P < 0.001 for all comparisons.)

A screen for nervous system conditions?

Dr, Kuhle reported that NfL is being used on an individual basis in clinical practice at present – at certain MS centers. “One of the problems is not having reliable reference values, so this database of normative values will be very helpful in developing those,” he said. “We see an increase in NfL with age in healthy controls. In order to know what pathological levels are, we need to know what normal levels are in controls throughout the spectrum of ages and other comorbidities, which also play a role. If we normalize these, then we can work out the MS signal in a more efficient way.”

Dr. Kuhle believes that, in the future, NfL may be used to screen for nervous system disease. “NfL is a measure of neuronal health independent of MS. If we have increased levels, we should be worried.”

There is a “high level of energy in this field,” he added. “In future, it could be like having a cholesterol test at present – picking up that something is not right and indicating the need for more tests.”

Dr. Yaldizli suggested that NfL monitoring could also help to individualize and optimize use of MS treatments. “There is a huge unmet need in MS. While we have a plethora of treatment options, we are struggling to individualize and monitor treatments. If NfL levels increase, this is likely a strong indication to change treatment even if there are no other overt symptoms.”

Commenting on the current study, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, called it “an important study.” 

“NfL clearly can detect disease activity and distinguish efficacy of DMT in groups of patients,” Dr. Cohen said.  

“This study shows that NfL can be used to monitor DMT efficacy in individual patients and can detect suboptimal treatment response in patients with NEDA (i.e., who appear stable by the measures we typically employ in practice),” he added.

Dr. Yaldizli sits on advisory boards for Sanofi Genzyme, Novartis, Biogen, and Novartis. Dr. Kuhle reported no relevant disclosures.

This article first appeared on Medscape.com.

Measuring serum levels of neurofilament light chain (NfL) is an effective way of detecting disease activity and the need to optimize treatment in patients with multiple sclerosis (MS), independent of relapse and MRI activity, a new study has shown. 

The study found that current serum NfL levels predicted relapses, disability worsening, and MRI activity in the following year independent of standard metrics for treatment monitoring, such as relapse rate, disability worsening, and MRI findings. The biomarker also detected subclinical disease activity in patients with no evidence of disease activity (NEDA3), as measured by absence of previous relapses, worsening score on the Expanded Disability Status Scale (EDSS), or brain lesion formation on MRI. 

“Our data in this well-characterized large real-world cohort supports the value of serum NfL levels for treatment monitoring in MS clinical practice,” lead author Özgür Yaldizli, MD, concluded.

Dr. Yaldizli, who is a consultant neurologist at University Hospital Basel (Switzerland), presented the findings 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.

“This is the first study to compare NfL simultaneously with other markers of disease progression, such as MRI lesions and relapse rate in treated patients. We show that NfL gives a unique signal that is not captured by other markers,” Dr. Yaldizli said.

“This is likely the largest study of NfL in MS to date, with more than 7,000 samples from well-characterized MS patients followed longitudinally for more than 5 years of sampling and including high quality data on MRI and clinical examinations. It is the first time all these factors have been combined so that we can see how NfL compares with other markers of disease progression in predicting clinical events and monitoring treatment efficacy,” said senior author Jens Kuhle, MD, PhD, also from University Hospital Basel. 
 

Large normative database for reference

The researchers also reported a large normative database of NfL values with data from more than 8,000 healthy controls. “This is the largest normative database to date, that gives us reliable reference values for NfL across a range of ages and comorbidities,” Dr. Kuhle noted.

In his presentation, Dr. Yaldizli explained that NfL is a neuronal cytoskeletal protein released into the cerebrospinal fluid and blood following neuroaxonal injury. Although numerous studies have shown that serum NfL is associated with clinical and MRI disease activity and treatment response, it is not clear whether serum NfL under established disease-modifying therapy (DMT) can identify patients with suboptimal treatment response, compared with standard clinical and MRI activity measures.

This study addressed that question in the large real-world Swiss MS cohort.

The study involved 1,366 patients (88.8% with relapsing remitting MS [RRMS], 5.4% with secondary progressive MS, and 5.8% with primary progressive MS) receiving DMT for at least 3 months from seven MS centers. The median disease duration was 7.2 years. Serum NfL was measured every 6 or 12 months with NF-Light assay on the latest-generation HDX platform (blinded for clinical and MRI data). The median follow-up was 4.9 years. There was an average of five samples per patient, with a total of 7462 samples.

Results showed that NfL levels were higher in older patients (14.5% per 10 years), those with secondary progressive MS (12.4% vs. RRMS), those with primary progressive MS (14.4% vs. RRMS), and in those who had a relapse in the last 4 months (53.4%).

NfL levels were 13.4% lower in patients receiving oral DMT (vs. untreated patients) and 17.7% in patients receiving monoclonal antibodies (vs. untreated patients).

In the large cohort of healthy controls, NfL levels also increased with age, but levels in patients with MS were higher than in controls across the whole age spectrum.

To obtain a measure of deviation from normal, the authors converted NfL levels to z score, which express how much (in terms of number of standard deviations) a measurement differs from mean values found in healthy controls of the same age. Effects were more pronounced with use of z score derived from the normative database than with use of absolute NfL levels even after adjustment for age.

In the univariate analysis, serum NfL z score predicted relapse or EDSS worsening in the following year: The higher the z score, the higher the risk for relapse or EDSS worsening. Patients with an NfL z score greater than 1 had a 41% higher risk for relapse or EDSS worsening in the following year, compared with those whose z score was less than 1 (odds ratio, 1.41).

Patients with an NfL z score exceeding 1.5 had an 80% higher risk for relapse or EDSS worsening in the following year than did those whose score was below 1.5 (OR, 1.8).

Patients with an NfL z score greater than 2 had a 2.3 times higher risk for relapse or EDSS worsening in the following year versus those with a score below 2. (P < 0.001 for all comparisons.)

A screen for nervous system conditions?

Dr, Kuhle reported that NfL is being used on an individual basis in clinical practice at present – at certain MS centers. “One of the problems is not having reliable reference values, so this database of normative values will be very helpful in developing those,” he said. “We see an increase in NfL with age in healthy controls. In order to know what pathological levels are, we need to know what normal levels are in controls throughout the spectrum of ages and other comorbidities, which also play a role. If we normalize these, then we can work out the MS signal in a more efficient way.”

Dr. Kuhle believes that, in the future, NfL may be used to screen for nervous system disease. “NfL is a measure of neuronal health independent of MS. If we have increased levels, we should be worried.”

There is a “high level of energy in this field,” he added. “In future, it could be like having a cholesterol test at present – picking up that something is not right and indicating the need for more tests.”

Dr. Yaldizli suggested that NfL monitoring could also help to individualize and optimize use of MS treatments. “There is a huge unmet need in MS. While we have a plethora of treatment options, we are struggling to individualize and monitor treatments. If NfL levels increase, this is likely a strong indication to change treatment even if there are no other overt symptoms.”

Commenting on the current study, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, called it “an important study.” 

“NfL clearly can detect disease activity and distinguish efficacy of DMT in groups of patients,” Dr. Cohen said.  

“This study shows that NfL can be used to monitor DMT efficacy in individual patients and can detect suboptimal treatment response in patients with NEDA (i.e., who appear stable by the measures we typically employ in practice),” he added.

Dr. Yaldizli sits on advisory boards for Sanofi Genzyme, Novartis, Biogen, and Novartis. Dr. Kuhle reported no relevant disclosures.

This article first appeared on Medscape.com.

Measuring serum levels of neurofilament light chain (NfL) is an effective way of detecting disease activity and the need to optimize treatment in patients with multiple sclerosis (MS), independent of relapse and MRI activity, a new study has shown. 

The study found that current serum NfL levels predicted relapses, disability worsening, and MRI activity in the following year independent of standard metrics for treatment monitoring, such as relapse rate, disability worsening, and MRI findings. The biomarker also detected subclinical disease activity in patients with no evidence of disease activity (NEDA3), as measured by absence of previous relapses, worsening score on the Expanded Disability Status Scale (EDSS), or brain lesion formation on MRI. 

“Our data in this well-characterized large real-world cohort supports the value of serum NfL levels for treatment monitoring in MS clinical practice,” lead author Özgür Yaldizli, MD, concluded.

Dr. Yaldizli, who is a consultant neurologist at University Hospital Basel (Switzerland), presented the findings 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.

“This is the first study to compare NfL simultaneously with other markers of disease progression, such as MRI lesions and relapse rate in treated patients. We show that NfL gives a unique signal that is not captured by other markers,” Dr. Yaldizli said.

“This is likely the largest study of NfL in MS to date, with more than 7,000 samples from well-characterized MS patients followed longitudinally for more than 5 years of sampling and including high quality data on MRI and clinical examinations. It is the first time all these factors have been combined so that we can see how NfL compares with other markers of disease progression in predicting clinical events and monitoring treatment efficacy,” said senior author Jens Kuhle, MD, PhD, also from University Hospital Basel. 
 

Large normative database for reference

The researchers also reported a large normative database of NfL values with data from more than 8,000 healthy controls. “This is the largest normative database to date, that gives us reliable reference values for NfL across a range of ages and comorbidities,” Dr. Kuhle noted.

In his presentation, Dr. Yaldizli explained that NfL is a neuronal cytoskeletal protein released into the cerebrospinal fluid and blood following neuroaxonal injury. Although numerous studies have shown that serum NfL is associated with clinical and MRI disease activity and treatment response, it is not clear whether serum NfL under established disease-modifying therapy (DMT) can identify patients with suboptimal treatment response, compared with standard clinical and MRI activity measures.

This study addressed that question in the large real-world Swiss MS cohort.

The study involved 1,366 patients (88.8% with relapsing remitting MS [RRMS], 5.4% with secondary progressive MS, and 5.8% with primary progressive MS) receiving DMT for at least 3 months from seven MS centers. The median disease duration was 7.2 years. Serum NfL was measured every 6 or 12 months with NF-Light assay on the latest-generation HDX platform (blinded for clinical and MRI data). The median follow-up was 4.9 years. There was an average of five samples per patient, with a total of 7462 samples.

Results showed that NfL levels were higher in older patients (14.5% per 10 years), those with secondary progressive MS (12.4% vs. RRMS), those with primary progressive MS (14.4% vs. RRMS), and in those who had a relapse in the last 4 months (53.4%).

NfL levels were 13.4% lower in patients receiving oral DMT (vs. untreated patients) and 17.7% in patients receiving monoclonal antibodies (vs. untreated patients).

In the large cohort of healthy controls, NfL levels also increased with age, but levels in patients with MS were higher than in controls across the whole age spectrum.

To obtain a measure of deviation from normal, the authors converted NfL levels to z score, which express how much (in terms of number of standard deviations) a measurement differs from mean values found in healthy controls of the same age. Effects were more pronounced with use of z score derived from the normative database than with use of absolute NfL levels even after adjustment for age.

In the univariate analysis, serum NfL z score predicted relapse or EDSS worsening in the following year: The higher the z score, the higher the risk for relapse or EDSS worsening. Patients with an NfL z score greater than 1 had a 41% higher risk for relapse or EDSS worsening in the following year, compared with those whose z score was less than 1 (odds ratio, 1.41).

Patients with an NfL z score exceeding 1.5 had an 80% higher risk for relapse or EDSS worsening in the following year than did those whose score was below 1.5 (OR, 1.8).

Patients with an NfL z score greater than 2 had a 2.3 times higher risk for relapse or EDSS worsening in the following year versus those with a score below 2. (P < 0.001 for all comparisons.)

A screen for nervous system conditions?

Dr, Kuhle reported that NfL is being used on an individual basis in clinical practice at present – at certain MS centers. “One of the problems is not having reliable reference values, so this database of normative values will be very helpful in developing those,” he said. “We see an increase in NfL with age in healthy controls. In order to know what pathological levels are, we need to know what normal levels are in controls throughout the spectrum of ages and other comorbidities, which also play a role. If we normalize these, then we can work out the MS signal in a more efficient way.”

Dr. Kuhle believes that, in the future, NfL may be used to screen for nervous system disease. “NfL is a measure of neuronal health independent of MS. If we have increased levels, we should be worried.”

There is a “high level of energy in this field,” he added. “In future, it could be like having a cholesterol test at present – picking up that something is not right and indicating the need for more tests.”

Dr. Yaldizli suggested that NfL monitoring could also help to individualize and optimize use of MS treatments. “There is a huge unmet need in MS. While we have a plethora of treatment options, we are struggling to individualize and monitor treatments. If NfL levels increase, this is likely a strong indication to change treatment even if there are no other overt symptoms.”

Commenting on the current study, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, called it “an important study.” 

“NfL clearly can detect disease activity and distinguish efficacy of DMT in groups of patients,” Dr. Cohen said.  

“This study shows that NfL can be used to monitor DMT efficacy in individual patients and can detect suboptimal treatment response in patients with NEDA (i.e., who appear stable by the measures we typically employ in practice),” he added.

Dr. Yaldizli sits on advisory boards for Sanofi Genzyme, Novartis, Biogen, and Novartis. Dr. Kuhle reported no relevant disclosures.

This article first appeared on Medscape.com.

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

What kind of impact will breastfeeding have on my child?

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

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

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

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

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

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

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

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

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

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

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

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

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

What kind of impact will breastfeeding have on my child?

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

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

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

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

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

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

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

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

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

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

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

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

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

What kind of impact will breastfeeding have on my child?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

An examination of medical records

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

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

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

Most patients initiated injectable DMTs

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

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

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

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

[email protected]

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

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

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

An examination of medical records

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

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

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

Most patients initiated injectable DMTs

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

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

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

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

[email protected]

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

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

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

An examination of medical records

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

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

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

Most patients initiated injectable DMTs

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Biomarkers had high AUC

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

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

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

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

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

Biomarkers may predict attacks

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

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

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

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

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

[email protected]

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

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

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

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

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

Biomarkers had high AUC

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

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

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

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

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

Biomarkers may predict attacks

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

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

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

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

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

[email protected]

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

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

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

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

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

Biomarkers had high AUC

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

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

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

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

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

Biomarkers may predict attacks

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

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

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

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

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

[email protected]

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