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Researchers examine vitamin D, skin pigmentation, and outcomes of pediatric MS
PHILADELPHIA – according to research described at the annual meeting of the American Academy of Neurology. Future research will be required to understand the interactions between dietary vitamin D ingestion, sun exposure, pigmentation of sun-exposed skin, seasonal vitamin D concentrations, and the genetic influences of vitamin D pathways with MS risk.
Race, vitamin D status, HLA-DRB1*15 genotype, and place of residence during childhood all affect the risk of MS. The place of residence also can affect exposure to ultraviolet radiation and, thus, dermal pigmentation.
Candice Dunn, a clinical research coordinator at the Children’s Hospital of Philadelphia, and colleagues conducted a prospective study to determine whether HLA-DRB1*15 status, 25-hydroxyvitamin D (25[OH]D) levels measured at baseline, and skin tone are associated with MS outcome in children with ADS. They enrolled 259 children with incident ADS in a multisite study in Toronto and Philadelphia (latitudes 43° to 51°). The investigators measured non–sun-exposed upper inner arm melanin content using the DSM II ColorMeter device. They measured 25(OH)D concentrations in serum obtained within 60 days of symptom onset and compared them with laboratory-reported normative values. Vitamin D insufficiency was defined as 25(OH)D less than 75 nmol/L. Ms. Dunn and colleagues quantified HLA-DRB1*15 alleles using allele-specific polymerase chain reaction amplification. Statistical analysis was performed using Spearman correlation models and Wilcoxon or Kruskal-Wallis tests as appropriate.
In all, 68 children were diagnosed with MS, 191 remained monophasic (monoADS). Approximately 46% of children with MS were HLA-DRB1*15-positive, compared with 29.9% of monoADS children. In addition, children with MS had significantly lower 25(OH)D levels (mean, 45.4 nmol/L) than monoADS children (mean, 61.9 nmol/L) at baseline. Non–sun-exposed skin tone measured in the upper inner arm did not differ between children diagnosed with MS (mean melanin index, 46.4) and monoADS (mean melanin index, 43.5). Furthermore, 25(OH)D levels correlated with upper inner arm melanin index in the MS group, but not in children with monoADS.
Ms. Dunn had nothing to disclose, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
SOURCE: Dunn C et al. AAN 2019, Abstract S19.007.
PHILADELPHIA – according to research described at the annual meeting of the American Academy of Neurology. Future research will be required to understand the interactions between dietary vitamin D ingestion, sun exposure, pigmentation of sun-exposed skin, seasonal vitamin D concentrations, and the genetic influences of vitamin D pathways with MS risk.
Race, vitamin D status, HLA-DRB1*15 genotype, and place of residence during childhood all affect the risk of MS. The place of residence also can affect exposure to ultraviolet radiation and, thus, dermal pigmentation.
Candice Dunn, a clinical research coordinator at the Children’s Hospital of Philadelphia, and colleagues conducted a prospective study to determine whether HLA-DRB1*15 status, 25-hydroxyvitamin D (25[OH]D) levels measured at baseline, and skin tone are associated with MS outcome in children with ADS. They enrolled 259 children with incident ADS in a multisite study in Toronto and Philadelphia (latitudes 43° to 51°). The investigators measured non–sun-exposed upper inner arm melanin content using the DSM II ColorMeter device. They measured 25(OH)D concentrations in serum obtained within 60 days of symptom onset and compared them with laboratory-reported normative values. Vitamin D insufficiency was defined as 25(OH)D less than 75 nmol/L. Ms. Dunn and colleagues quantified HLA-DRB1*15 alleles using allele-specific polymerase chain reaction amplification. Statistical analysis was performed using Spearman correlation models and Wilcoxon or Kruskal-Wallis tests as appropriate.
In all, 68 children were diagnosed with MS, 191 remained monophasic (monoADS). Approximately 46% of children with MS were HLA-DRB1*15-positive, compared with 29.9% of monoADS children. In addition, children with MS had significantly lower 25(OH)D levels (mean, 45.4 nmol/L) than monoADS children (mean, 61.9 nmol/L) at baseline. Non–sun-exposed skin tone measured in the upper inner arm did not differ between children diagnosed with MS (mean melanin index, 46.4) and monoADS (mean melanin index, 43.5). Furthermore, 25(OH)D levels correlated with upper inner arm melanin index in the MS group, but not in children with monoADS.
Ms. Dunn had nothing to disclose, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
SOURCE: Dunn C et al. AAN 2019, Abstract S19.007.
PHILADELPHIA – according to research described at the annual meeting of the American Academy of Neurology. Future research will be required to understand the interactions between dietary vitamin D ingestion, sun exposure, pigmentation of sun-exposed skin, seasonal vitamin D concentrations, and the genetic influences of vitamin D pathways with MS risk.
Race, vitamin D status, HLA-DRB1*15 genotype, and place of residence during childhood all affect the risk of MS. The place of residence also can affect exposure to ultraviolet radiation and, thus, dermal pigmentation.
Candice Dunn, a clinical research coordinator at the Children’s Hospital of Philadelphia, and colleagues conducted a prospective study to determine whether HLA-DRB1*15 status, 25-hydroxyvitamin D (25[OH]D) levels measured at baseline, and skin tone are associated with MS outcome in children with ADS. They enrolled 259 children with incident ADS in a multisite study in Toronto and Philadelphia (latitudes 43° to 51°). The investigators measured non–sun-exposed upper inner arm melanin content using the DSM II ColorMeter device. They measured 25(OH)D concentrations in serum obtained within 60 days of symptom onset and compared them with laboratory-reported normative values. Vitamin D insufficiency was defined as 25(OH)D less than 75 nmol/L. Ms. Dunn and colleagues quantified HLA-DRB1*15 alleles using allele-specific polymerase chain reaction amplification. Statistical analysis was performed using Spearman correlation models and Wilcoxon or Kruskal-Wallis tests as appropriate.
In all, 68 children were diagnosed with MS, 191 remained monophasic (monoADS). Approximately 46% of children with MS were HLA-DRB1*15-positive, compared with 29.9% of monoADS children. In addition, children with MS had significantly lower 25(OH)D levels (mean, 45.4 nmol/L) than monoADS children (mean, 61.9 nmol/L) at baseline. Non–sun-exposed skin tone measured in the upper inner arm did not differ between children diagnosed with MS (mean melanin index, 46.4) and monoADS (mean melanin index, 43.5). Furthermore, 25(OH)D levels correlated with upper inner arm melanin index in the MS group, but not in children with monoADS.
Ms. Dunn had nothing to disclose, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
SOURCE: Dunn C et al. AAN 2019, Abstract S19.007.
REPORTING FROM AAN 2019
Key clinical point: The relationship between vitamin D status and MS outcome in children relates to skin pigmentation.
Major finding: About 46% of children with MS were HLA-DRB1*15 positive.
Study details: A multisite, prospective study of 259 children with MS.
Disclosures: Ms. Dunn had no disclosures, but various coauthors have received compensation from companies such as Novartis, Merck, Teva, Celgene, and Genentech.
Source: Dunn C et al. AAN 2019, Abstract S19.007.
Criterion based on the central vein sign distinguishes between MS and mimics
PHILADELPHIA – according to research presented at the annual meeting of the American Academy of Neurology. Using this criterion in clinical practice is feasible, the researchers added.
Several years ago, researchers proposed the central vein sign as a specific and sensitive imaging biomarker for distinguishing between multiple sclerosis (MS) and its imaging mimics. Recent studies have proposed criteria for this distinction that are based on the proportion of lesions with the central vein sign. Criteria that are based on the absolute numbers of lesions with the central vein sign, however, may be more applicable in clinical practice, said Tim Sinnecker, MD, research associate at the University of Basel (Switzerland).
Dr. Sinnecker and colleagues conducted a multicenter study to evaluate the sensitivity and specificity of criteria that are based on the absolute numbers of lesions with the central vein sign (CVS) in distinguishing MS from non-MS conditions on clinical 3T brain MRI. They analyzed 606 participants with clinically isolated syndrome (CIS; n = 117), relapsing remitting MS (RRMS; n = 236, of whom 108 had a disease duration shorter than 5 years), aquaporin 4 antibody–positive neuromyelitis optica spectrum disorder (n = 32), systemic lupus erythematosus (n = 25), migraine (n = 29), cluster headache (n = 5), diabetes mellitus (n = 20), or other types of small-vessel disease (n = 142). Raters blinded to clinical data and lesion distribution determined the occurrence of CVS on 3T T2*-weighted or susceptibility-weighted imaging. The researchers assessed the sensitivity and specificity of different CVS lesion criteria that were defined according to the absolute numbers of lesions with CVS.
In total, Dr. Sinnecker and colleagues analyzed 4,447 lesions. The “two-CVS-lesions criterion” (two or more lesions with CVS) had a sensitivity and specificity of 76.2% and 79.3%, respectively, in distinguishing between RRMS/CIS and non-MS. The “three-CVS-lesions criterion” (three or more lesions with CVS) had a sensitivity and specificity of 61.9% and 89.0%, respectively. The observed sensitivity and specificity values were consistent across all disease subgroups examined in the study, including CIS and early RRMS. These results indicate that positive criteria based on CVS could be used to support the diagnosis of MS, Dr. Sinnecker said.
Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
SOURCE: Sinnecker T et al. AAN 2019, Abstract S6.002.
PHILADELPHIA – according to research presented at the annual meeting of the American Academy of Neurology. Using this criterion in clinical practice is feasible, the researchers added.
Several years ago, researchers proposed the central vein sign as a specific and sensitive imaging biomarker for distinguishing between multiple sclerosis (MS) and its imaging mimics. Recent studies have proposed criteria for this distinction that are based on the proportion of lesions with the central vein sign. Criteria that are based on the absolute numbers of lesions with the central vein sign, however, may be more applicable in clinical practice, said Tim Sinnecker, MD, research associate at the University of Basel (Switzerland).
Dr. Sinnecker and colleagues conducted a multicenter study to evaluate the sensitivity and specificity of criteria that are based on the absolute numbers of lesions with the central vein sign (CVS) in distinguishing MS from non-MS conditions on clinical 3T brain MRI. They analyzed 606 participants with clinically isolated syndrome (CIS; n = 117), relapsing remitting MS (RRMS; n = 236, of whom 108 had a disease duration shorter than 5 years), aquaporin 4 antibody–positive neuromyelitis optica spectrum disorder (n = 32), systemic lupus erythematosus (n = 25), migraine (n = 29), cluster headache (n = 5), diabetes mellitus (n = 20), or other types of small-vessel disease (n = 142). Raters blinded to clinical data and lesion distribution determined the occurrence of CVS on 3T T2*-weighted or susceptibility-weighted imaging. The researchers assessed the sensitivity and specificity of different CVS lesion criteria that were defined according to the absolute numbers of lesions with CVS.
In total, Dr. Sinnecker and colleagues analyzed 4,447 lesions. The “two-CVS-lesions criterion” (two or more lesions with CVS) had a sensitivity and specificity of 76.2% and 79.3%, respectively, in distinguishing between RRMS/CIS and non-MS. The “three-CVS-lesions criterion” (three or more lesions with CVS) had a sensitivity and specificity of 61.9% and 89.0%, respectively. The observed sensitivity and specificity values were consistent across all disease subgroups examined in the study, including CIS and early RRMS. These results indicate that positive criteria based on CVS could be used to support the diagnosis of MS, Dr. Sinnecker said.
Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
SOURCE: Sinnecker T et al. AAN 2019, Abstract S6.002.
PHILADELPHIA – according to research presented at the annual meeting of the American Academy of Neurology. Using this criterion in clinical practice is feasible, the researchers added.
Several years ago, researchers proposed the central vein sign as a specific and sensitive imaging biomarker for distinguishing between multiple sclerosis (MS) and its imaging mimics. Recent studies have proposed criteria for this distinction that are based on the proportion of lesions with the central vein sign. Criteria that are based on the absolute numbers of lesions with the central vein sign, however, may be more applicable in clinical practice, said Tim Sinnecker, MD, research associate at the University of Basel (Switzerland).
Dr. Sinnecker and colleagues conducted a multicenter study to evaluate the sensitivity and specificity of criteria that are based on the absolute numbers of lesions with the central vein sign (CVS) in distinguishing MS from non-MS conditions on clinical 3T brain MRI. They analyzed 606 participants with clinically isolated syndrome (CIS; n = 117), relapsing remitting MS (RRMS; n = 236, of whom 108 had a disease duration shorter than 5 years), aquaporin 4 antibody–positive neuromyelitis optica spectrum disorder (n = 32), systemic lupus erythematosus (n = 25), migraine (n = 29), cluster headache (n = 5), diabetes mellitus (n = 20), or other types of small-vessel disease (n = 142). Raters blinded to clinical data and lesion distribution determined the occurrence of CVS on 3T T2*-weighted or susceptibility-weighted imaging. The researchers assessed the sensitivity and specificity of different CVS lesion criteria that were defined according to the absolute numbers of lesions with CVS.
In total, Dr. Sinnecker and colleagues analyzed 4,447 lesions. The “two-CVS-lesions criterion” (two or more lesions with CVS) had a sensitivity and specificity of 76.2% and 79.3%, respectively, in distinguishing between RRMS/CIS and non-MS. The “three-CVS-lesions criterion” (three or more lesions with CVS) had a sensitivity and specificity of 61.9% and 89.0%, respectively. The observed sensitivity and specificity values were consistent across all disease subgroups examined in the study, including CIS and early RRMS. These results indicate that positive criteria based on CVS could be used to support the diagnosis of MS, Dr. Sinnecker said.
Dr. Sinnecker reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion.
SOURCE: Sinnecker T et al. AAN 2019, Abstract S6.002.
REPORTING FROM AAN 2019
Eculizumab cuts relapse risk in NMO spectrum disorder
PHILADELPHIA – Treatment with the monoclonal antibody eculizumab substantially reduced the risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica (NMO) spectrum disorder, according to the results of a phase 3 trial reported at the annual meeting of the American Academy of Neurology. Nearly 98% of patients with this autoimmune inflammatory CNS disorder were relapse-free at 48 weeks in the PREVENT trial, according to principal investigator Sean J. Pittock, MD, director of the Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology in Rochester, Minn.
“This was a dramatic result, I think, really showing a significant amount of hope for people with this disease,” Dr. Pittock said in a press conference.
Most cases of NMO are associated with aquaporin-4 antibodies and complement-mediated CNS damage, and eculizumab (Soliris) is an inhibitor of complement protein C5 shown to reduce relapse frequency in a previous, small open-label study, according to Dr. Pittock.
In the current global phase 3 trial, conducted at 70 centers in 18 countries, 143 adult patients with aquaporin-4 positive NMO spectrum disorder were randomized to eculizumab every 2 weeks or placebo. The trial allowed for supportive immunosuppressive therapy and excluded patients who had received rituximab in the past 3 months. A total of 124 patients completed the study, which was stopped after 23 adjudicated relapses had occurred.
Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant effect (P less than .0001) in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse, according to Dr. Pittock and coinvestigators.
At 48 weeks, 97.9% of patients were relapse free in the eculizumab group, versus 63.2% in the placebo group, they added in their report, which was published May 3 online ahead of print in the New England Journal of Medicine (doi: 10.1056/NEJMoa1900866).
Longer-term follow-up showed that, at 144 weeks, 96% of eculizumab-treated patients remained relapse free, while 45% of the placebo group were relapse free, Dr. Pittock said in the press conference.
Most adverse events seen on treatment were mild to moderate, and no meningococcal infections were observed.
One death occurred in the study from pulmonary empyema in an eculizumab-treated patient, but the associated cultures yielded microorganisms not associated with complement deficiency, investigators said in their published report.
“The concept that you can discover a target, understand the immunopathology of a disease, identify a novel mechanism, then identify a precision drug that targets that mechanism, and essentially turn off, or switch off, the disease is very, very exciting,” Dr. Pittock said in the press conference.
The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
SOURCE: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
PHILADELPHIA – Treatment with the monoclonal antibody eculizumab substantially reduced the risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica (NMO) spectrum disorder, according to the results of a phase 3 trial reported at the annual meeting of the American Academy of Neurology. Nearly 98% of patients with this autoimmune inflammatory CNS disorder were relapse-free at 48 weeks in the PREVENT trial, according to principal investigator Sean J. Pittock, MD, director of the Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology in Rochester, Minn.
“This was a dramatic result, I think, really showing a significant amount of hope for people with this disease,” Dr. Pittock said in a press conference.
Most cases of NMO are associated with aquaporin-4 antibodies and complement-mediated CNS damage, and eculizumab (Soliris) is an inhibitor of complement protein C5 shown to reduce relapse frequency in a previous, small open-label study, according to Dr. Pittock.
In the current global phase 3 trial, conducted at 70 centers in 18 countries, 143 adult patients with aquaporin-4 positive NMO spectrum disorder were randomized to eculizumab every 2 weeks or placebo. The trial allowed for supportive immunosuppressive therapy and excluded patients who had received rituximab in the past 3 months. A total of 124 patients completed the study, which was stopped after 23 adjudicated relapses had occurred.
Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant effect (P less than .0001) in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse, according to Dr. Pittock and coinvestigators.
At 48 weeks, 97.9% of patients were relapse free in the eculizumab group, versus 63.2% in the placebo group, they added in their report, which was published May 3 online ahead of print in the New England Journal of Medicine (doi: 10.1056/NEJMoa1900866).
Longer-term follow-up showed that, at 144 weeks, 96% of eculizumab-treated patients remained relapse free, while 45% of the placebo group were relapse free, Dr. Pittock said in the press conference.
Most adverse events seen on treatment were mild to moderate, and no meningococcal infections were observed.
One death occurred in the study from pulmonary empyema in an eculizumab-treated patient, but the associated cultures yielded microorganisms not associated with complement deficiency, investigators said in their published report.
“The concept that you can discover a target, understand the immunopathology of a disease, identify a novel mechanism, then identify a precision drug that targets that mechanism, and essentially turn off, or switch off, the disease is very, very exciting,” Dr. Pittock said in the press conference.
The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
SOURCE: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
PHILADELPHIA – Treatment with the monoclonal antibody eculizumab substantially reduced the risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica (NMO) spectrum disorder, according to the results of a phase 3 trial reported at the annual meeting of the American Academy of Neurology. Nearly 98% of patients with this autoimmune inflammatory CNS disorder were relapse-free at 48 weeks in the PREVENT trial, according to principal investigator Sean J. Pittock, MD, director of the Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology in Rochester, Minn.
“This was a dramatic result, I think, really showing a significant amount of hope for people with this disease,” Dr. Pittock said in a press conference.
Most cases of NMO are associated with aquaporin-4 antibodies and complement-mediated CNS damage, and eculizumab (Soliris) is an inhibitor of complement protein C5 shown to reduce relapse frequency in a previous, small open-label study, according to Dr. Pittock.
In the current global phase 3 trial, conducted at 70 centers in 18 countries, 143 adult patients with aquaporin-4 positive NMO spectrum disorder were randomized to eculizumab every 2 weeks or placebo. The trial allowed for supportive immunosuppressive therapy and excluded patients who had received rituximab in the past 3 months. A total of 124 patients completed the study, which was stopped after 23 adjudicated relapses had occurred.
Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant effect (P less than .0001) in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse, according to Dr. Pittock and coinvestigators.
At 48 weeks, 97.9% of patients were relapse free in the eculizumab group, versus 63.2% in the placebo group, they added in their report, which was published May 3 online ahead of print in the New England Journal of Medicine (doi: 10.1056/NEJMoa1900866).
Longer-term follow-up showed that, at 144 weeks, 96% of eculizumab-treated patients remained relapse free, while 45% of the placebo group were relapse free, Dr. Pittock said in the press conference.
Most adverse events seen on treatment were mild to moderate, and no meningococcal infections were observed.
One death occurred in the study from pulmonary empyema in an eculizumab-treated patient, but the associated cultures yielded microorganisms not associated with complement deficiency, investigators said in their published report.
“The concept that you can discover a target, understand the immunopathology of a disease, identify a novel mechanism, then identify a precision drug that targets that mechanism, and essentially turn off, or switch off, the disease is very, very exciting,” Dr. Pittock said in the press conference.
The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
SOURCE: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
FROM AAN 2019
Key clinical point: Treatment with eculizumab substantially reduced risk of relapse versus placebo in patients with aquaporin-4 positive neuromyelitis optica spectrum disorder.
Major finding: Time to first adjudicated relapse on trial, the primary endpoint of the study, showed a significant (P less than .0001) effect in favor of monoclonal antibody treatment over placebo, with a 94.2% reduction in risk of relapse.
Study details: A phase 3, randomized, double-blind, placebo-controlled, multicenter trial (PREVENT) including 143 adult patients.
Disclosures: The study was supported by Alexion Pharmaceuticals. Dr. Pittock provided disclosures related to Alexion Pharmaceuticals, MedImmune, and Grifols, along with patents related to administration of eculizumab and cancer markers in neuromyelitis optica.
Source: Pittock SJ et al. AAN 2019, Emerging Science Abstract 009.
Multiple sclerosis may not flare up after pregnancy
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
FROM AAN 2019
Damage of the Lateral Geniculate Nucleus in MS
Key clinical point: Lateral geniculate nucleus (LGN) volume loss in multiple sclerosis (MS) indicates structural damage with potential functional relevance.
Major finding: LGN volume was reduced in patients with relapsing-remitting MS vs healthy controls and was associated with ganglion cell-inner plexiform layer (GC-IPL) thickness and correlated with optic radiation (OR) lesion volume.
Study details: A cross-sectional study of 34 patients with relapsing-remitting MS and 33 matched healthy controls.
Disclosures: The lead author received funding for speaker or travel honoraria from Sanofi-Genzyme, Bayer AG, Teva, UCB-Pharma AG, and Hoffmann-La Roche.
Citation: Papadopoulou, et al. Neurology. doi:10.1212/WNL.0000000000007450.
Key clinical point: Lateral geniculate nucleus (LGN) volume loss in multiple sclerosis (MS) indicates structural damage with potential functional relevance.
Major finding: LGN volume was reduced in patients with relapsing-remitting MS vs healthy controls and was associated with ganglion cell-inner plexiform layer (GC-IPL) thickness and correlated with optic radiation (OR) lesion volume.
Study details: A cross-sectional study of 34 patients with relapsing-remitting MS and 33 matched healthy controls.
Disclosures: The lead author received funding for speaker or travel honoraria from Sanofi-Genzyme, Bayer AG, Teva, UCB-Pharma AG, and Hoffmann-La Roche.
Citation: Papadopoulou, et al. Neurology. doi:10.1212/WNL.0000000000007450.
Key clinical point: Lateral geniculate nucleus (LGN) volume loss in multiple sclerosis (MS) indicates structural damage with potential functional relevance.
Major finding: LGN volume was reduced in patients with relapsing-remitting MS vs healthy controls and was associated with ganglion cell-inner plexiform layer (GC-IPL) thickness and correlated with optic radiation (OR) lesion volume.
Study details: A cross-sectional study of 34 patients with relapsing-remitting MS and 33 matched healthy controls.
Disclosures: The lead author received funding for speaker or travel honoraria from Sanofi-Genzyme, Bayer AG, Teva, UCB-Pharma AG, and Hoffmann-La Roche.
Citation: Papadopoulou, et al. Neurology. doi:10.1212/WNL.0000000000007450.
Survey of MS Patients Reveals Pregnancy-Related Concerns
Key clinical point: Patients with multiple sclerosis report a wide range of concerns about family planning and pregnancy.
Major finding: Of the 137 respondents who did not become pregnant following diagnosis, 22 (16%) indicated that their decision was driven by multiple sclerosis–related concerns, including MS worsening with pregnancy (64%).
Study details: A survey of 174 women with confirmed MS diagnosis who received care at the University of Virginia Medical Center.
Disclosures: The study was supported by the ziMS Foundation.
Citation: Engel CE et al. ACTRIMS Forum 2019, Poster 307.
Key clinical point: Patients with multiple sclerosis report a wide range of concerns about family planning and pregnancy.
Major finding: Of the 137 respondents who did not become pregnant following diagnosis, 22 (16%) indicated that their decision was driven by multiple sclerosis–related concerns, including MS worsening with pregnancy (64%).
Study details: A survey of 174 women with confirmed MS diagnosis who received care at the University of Virginia Medical Center.
Disclosures: The study was supported by the ziMS Foundation.
Citation: Engel CE et al. ACTRIMS Forum 2019, Poster 307.
Key clinical point: Patients with multiple sclerosis report a wide range of concerns about family planning and pregnancy.
Major finding: Of the 137 respondents who did not become pregnant following diagnosis, 22 (16%) indicated that their decision was driven by multiple sclerosis–related concerns, including MS worsening with pregnancy (64%).
Study details: A survey of 174 women with confirmed MS diagnosis who received care at the University of Virginia Medical Center.
Disclosures: The study was supported by the ziMS Foundation.
Citation: Engel CE et al. ACTRIMS Forum 2019, Poster 307.
What Happens When RRMS Patients Discontinue Their DMT?
Key clinical point: Patients who discontinued disease-modifying therapy after a period of disease inactivity had a similar time to next event, compared with patients who remained on treatment.
Major finding: Compared with patients aged 45 years and younger, older patients who discontinued disease-modifying therapy had significantly favorable disease course in terms of time to clinical relapse (P = .032), time to MRI event (P = .013), and time to any inflammatory event (P = .0005).
Study details: A single-center study of 140 patients with relapsing remitting multiple sclerosis.
Disclosures: Dr. Yano reported that he has received a research grant from the Yoshida Scholarship Foundation in Japan. His coauthors reported having numerous financial ties to industry.
Citation: Yano H et al. ACTRIMS Forum 2019, Poster 061.
Key clinical point: Patients who discontinued disease-modifying therapy after a period of disease inactivity had a similar time to next event, compared with patients who remained on treatment.
Major finding: Compared with patients aged 45 years and younger, older patients who discontinued disease-modifying therapy had significantly favorable disease course in terms of time to clinical relapse (P = .032), time to MRI event (P = .013), and time to any inflammatory event (P = .0005).
Study details: A single-center study of 140 patients with relapsing remitting multiple sclerosis.
Disclosures: Dr. Yano reported that he has received a research grant from the Yoshida Scholarship Foundation in Japan. His coauthors reported having numerous financial ties to industry.
Citation: Yano H et al. ACTRIMS Forum 2019, Poster 061.
Key clinical point: Patients who discontinued disease-modifying therapy after a period of disease inactivity had a similar time to next event, compared with patients who remained on treatment.
Major finding: Compared with patients aged 45 years and younger, older patients who discontinued disease-modifying therapy had significantly favorable disease course in terms of time to clinical relapse (P = .032), time to MRI event (P = .013), and time to any inflammatory event (P = .0005).
Study details: A single-center study of 140 patients with relapsing remitting multiple sclerosis.
Disclosures: Dr. Yano reported that he has received a research grant from the Yoshida Scholarship Foundation in Japan. His coauthors reported having numerous financial ties to industry.
Citation: Yano H et al. ACTRIMS Forum 2019, Poster 061.
Which Comorbidities Diminish Quality of Life in Patients with MS?
Key clinical point: A higher number of comorbidities was associated with lower quality of life.
Major finding: All comorbidities accounted for 18.09% of the variance of overall health-related quality of life.
Study details: A longitudinal study of 902 patients with MS.
Disclosures: This study was supported by Multiple Sclerosis Research Australia.
Citation: Lo LMP et al. ACTRIMS Forum 2019, Abstract 80.
Key clinical point: A higher number of comorbidities was associated with lower quality of life.
Major finding: All comorbidities accounted for 18.09% of the variance of overall health-related quality of life.
Study details: A longitudinal study of 902 patients with MS.
Disclosures: This study was supported by Multiple Sclerosis Research Australia.
Citation: Lo LMP et al. ACTRIMS Forum 2019, Abstract 80.
Key clinical point: A higher number of comorbidities was associated with lower quality of life.
Major finding: All comorbidities accounted for 18.09% of the variance of overall health-related quality of life.
Study details: A longitudinal study of 902 patients with MS.
Disclosures: This study was supported by Multiple Sclerosis Research Australia.
Citation: Lo LMP et al. ACTRIMS Forum 2019, Abstract 80.
Cerebellar Volume May Predict Disability in Patients With Relapsing-Remitting MS
Key clinical point: In patients with relapsing-remitting MS, cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test.
Major finding: Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months (Beta = –0.172).
Study details: A retrospective analysis of MRI data from 838 patients in the phase 3 CombiRx trial.
Disclosures: The researchers had no disclosures.
Citation: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
Key clinical point: In patients with relapsing-remitting MS, cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test.
Major finding: Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months (Beta = –0.172).
Study details: A retrospective analysis of MRI data from 838 patients in the phase 3 CombiRx trial.
Disclosures: The researchers had no disclosures.
Citation: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
Key clinical point: In patients with relapsing-remitting MS, cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test.
Major finding: Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months (Beta = –0.172).
Study details: A retrospective analysis of MRI data from 838 patients in the phase 3 CombiRx trial.
Disclosures: The researchers had no disclosures.
Citation: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
A blood biomarker for MS: Coming to clinics soon?
DALLAS – Neurologists soon may use a blood biomarker of axonal damage to monitor patients with multiple sclerosis (MS) and guide treatment decisions, according to a lecture delivered at ACTRIMS Forum 2019.
said David Leppert, MD, senior research associate in the department of neurology at University Hopsital Basel (Switzerland).
Among patients with MS, blood NfL levels predict disability, brain volume loss, and spinal cord atrophy. In addition, studies have found that blood NfL decreases in response to disease-modifying therapy (DMT) and that second-line DMTs may decrease blood NfL more than first-line DMTs do.
The establishment of normative databases and reference biomarkers may allow neurologists to use NfL in their care of individual patients, Dr. Leppert predicted at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “I am very positive that we will make a breakthrough in the next 2 or 3 years for an individual use of neurofilaments,” he said.
Response to DMT
An analysis of blood NfL levels from patients with MS and from healthy controls in two phase 3 trials of fingolimod, FREEDOMS and TRANSFORMS, provides insights into NfL’s response to DMT (Neurology. 2019 Mar 5;92[10]:e1007-15). In FREEDOMS, which compared fingolimod with placebo, “fingolimod leads to a rapid decrease of neurofilament levels, close to normality, while placebo patients continue to have high levels,” said Dr. Leppert, a coauthor of the study.
TRANSFORMS compared interferon-beta and fingolimod. “The clinical experience that fingolimod is a more potent compound than interferon is actually reflected here by the NfL results,” Dr. Leppert said. “Both compounds lead to a decrease of neurofilaments – so, a decrease of neuronal damage – but one drug is more potent than the other one.”
Similarly, data from the observational EPIC study indicate that patients who do not receive DMT have a consistent increase in NfL levels, whereas those who receive platform therapies have a slight decrease in NfL and those who receive second-line therapies have a greater decrease, Dr. Leppert said.
Decades of research
For about 20 years, researchers have studied neurofilaments in cerebrospinal fluid (CSF) as a potential biomarker for MS and other diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and head trauma.
“What prevented the emergence of NfL to clinical practice was the inability to measure it in blood because levels are 50-100 times lower [in blood] than in CSF,” Dr. Leppert said.
The development of single molecule array (SIMOA) technology enabled researchers to show a proper correlation between levels of NfL in CSF and those in blood, Dr. Leppert said. “That is now allowing repetitive testing in an accessible fluid compartment, meaning serum or plasma,” he said.
Compared with brain MRI, NfL may provide novel insights into MS disease activity. “MRI is measuring a structural deficit of the past,” Dr. Leppert said. “NfL is measuring online, real time what axonal damage is occurring.”
Correlation with outcomes
At the group level, patients with MS have higher levels of NfL, compared with controls, and levels are higher in patients with progressive forms of MS versus relapsing forms. “Levels increase dramatically in the wake of relapse,” he said.
Barro et al. found that patients with higher serum levels of NfL are more likely to experience Expanded Disability Status Scale (EDSS) worsening (Brain. 2018 Aug 1;141[8]:2382-91). Furthermore, MRI lesions are independently associated with serum NfL, and patients with higher levels of serum NfL have significantly greater average loss in brain volume and spinal cord volume over 5 years.
A treatment algorithm
NfL someday could be incorporated into MS treatment algorithms, Dr. Leppert suggested. For instance, if a patient has high levels of disease activity based on MRI or clinical grounds, then prescribe a high-efficacy therapy. If not, measure NfL. “If the levels are low, then you can be assured to use platform therapies or continue what the patient has. But if NfL levels are high, then you should choose high efficacious therapies or switch to high-efficacious therapies in the long run,” he said.
Limitations and next steps
Although NfL is a specific marker of neuronal damage, it is not specific for the cause of the damage. Further studies are needed to better understand NfL metabolism and confounding factors such as age. Reference biomarkers likely will be needed “to conceptualize whether the signal of NfL is due to acute disease or chronic disease,” Dr. Leppert said.
“We need to optimize the assay and come to a worldwide agreement on the platform. We need to have prospective studies, mainly to achieve regulatory acceptance. And we need to have a normative database” to determine which NfL values are pathologic at a particular age, he said.
Despite the biomarker’s potential, blood NfL levels will not replace clinical expertise. “Biomarkers cannot be of value without a clinical backing and a clinical evaluation,” Dr. Leppert said. “The idea that this will replace us or any other person who makes a clinical judgment is a big error. NfL will prevail as a biomarker. ... But interpretation of the clinical background is germane.”
Dr. Leppert has been an employee of pharmaceutical companies, most recently Novartis.
DALLAS – Neurologists soon may use a blood biomarker of axonal damage to monitor patients with multiple sclerosis (MS) and guide treatment decisions, according to a lecture delivered at ACTRIMS Forum 2019.
said David Leppert, MD, senior research associate in the department of neurology at University Hopsital Basel (Switzerland).
Among patients with MS, blood NfL levels predict disability, brain volume loss, and spinal cord atrophy. In addition, studies have found that blood NfL decreases in response to disease-modifying therapy (DMT) and that second-line DMTs may decrease blood NfL more than first-line DMTs do.
The establishment of normative databases and reference biomarkers may allow neurologists to use NfL in their care of individual patients, Dr. Leppert predicted at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “I am very positive that we will make a breakthrough in the next 2 or 3 years for an individual use of neurofilaments,” he said.
Response to DMT
An analysis of blood NfL levels from patients with MS and from healthy controls in two phase 3 trials of fingolimod, FREEDOMS and TRANSFORMS, provides insights into NfL’s response to DMT (Neurology. 2019 Mar 5;92[10]:e1007-15). In FREEDOMS, which compared fingolimod with placebo, “fingolimod leads to a rapid decrease of neurofilament levels, close to normality, while placebo patients continue to have high levels,” said Dr. Leppert, a coauthor of the study.
TRANSFORMS compared interferon-beta and fingolimod. “The clinical experience that fingolimod is a more potent compound than interferon is actually reflected here by the NfL results,” Dr. Leppert said. “Both compounds lead to a decrease of neurofilaments – so, a decrease of neuronal damage – but one drug is more potent than the other one.”
Similarly, data from the observational EPIC study indicate that patients who do not receive DMT have a consistent increase in NfL levels, whereas those who receive platform therapies have a slight decrease in NfL and those who receive second-line therapies have a greater decrease, Dr. Leppert said.
Decades of research
For about 20 years, researchers have studied neurofilaments in cerebrospinal fluid (CSF) as a potential biomarker for MS and other diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and head trauma.
“What prevented the emergence of NfL to clinical practice was the inability to measure it in blood because levels are 50-100 times lower [in blood] than in CSF,” Dr. Leppert said.
The development of single molecule array (SIMOA) technology enabled researchers to show a proper correlation between levels of NfL in CSF and those in blood, Dr. Leppert said. “That is now allowing repetitive testing in an accessible fluid compartment, meaning serum or plasma,” he said.
Compared with brain MRI, NfL may provide novel insights into MS disease activity. “MRI is measuring a structural deficit of the past,” Dr. Leppert said. “NfL is measuring online, real time what axonal damage is occurring.”
Correlation with outcomes
At the group level, patients with MS have higher levels of NfL, compared with controls, and levels are higher in patients with progressive forms of MS versus relapsing forms. “Levels increase dramatically in the wake of relapse,” he said.
Barro et al. found that patients with higher serum levels of NfL are more likely to experience Expanded Disability Status Scale (EDSS) worsening (Brain. 2018 Aug 1;141[8]:2382-91). Furthermore, MRI lesions are independently associated with serum NfL, and patients with higher levels of serum NfL have significantly greater average loss in brain volume and spinal cord volume over 5 years.
A treatment algorithm
NfL someday could be incorporated into MS treatment algorithms, Dr. Leppert suggested. For instance, if a patient has high levels of disease activity based on MRI or clinical grounds, then prescribe a high-efficacy therapy. If not, measure NfL. “If the levels are low, then you can be assured to use platform therapies or continue what the patient has. But if NfL levels are high, then you should choose high efficacious therapies or switch to high-efficacious therapies in the long run,” he said.
Limitations and next steps
Although NfL is a specific marker of neuronal damage, it is not specific for the cause of the damage. Further studies are needed to better understand NfL metabolism and confounding factors such as age. Reference biomarkers likely will be needed “to conceptualize whether the signal of NfL is due to acute disease or chronic disease,” Dr. Leppert said.
“We need to optimize the assay and come to a worldwide agreement on the platform. We need to have prospective studies, mainly to achieve regulatory acceptance. And we need to have a normative database” to determine which NfL values are pathologic at a particular age, he said.
Despite the biomarker’s potential, blood NfL levels will not replace clinical expertise. “Biomarkers cannot be of value without a clinical backing and a clinical evaluation,” Dr. Leppert said. “The idea that this will replace us or any other person who makes a clinical judgment is a big error. NfL will prevail as a biomarker. ... But interpretation of the clinical background is germane.”
Dr. Leppert has been an employee of pharmaceutical companies, most recently Novartis.
DALLAS – Neurologists soon may use a blood biomarker of axonal damage to monitor patients with multiple sclerosis (MS) and guide treatment decisions, according to a lecture delivered at ACTRIMS Forum 2019.
said David Leppert, MD, senior research associate in the department of neurology at University Hopsital Basel (Switzerland).
Among patients with MS, blood NfL levels predict disability, brain volume loss, and spinal cord atrophy. In addition, studies have found that blood NfL decreases in response to disease-modifying therapy (DMT) and that second-line DMTs may decrease blood NfL more than first-line DMTs do.
The establishment of normative databases and reference biomarkers may allow neurologists to use NfL in their care of individual patients, Dr. Leppert predicted at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “I am very positive that we will make a breakthrough in the next 2 or 3 years for an individual use of neurofilaments,” he said.
Response to DMT
An analysis of blood NfL levels from patients with MS and from healthy controls in two phase 3 trials of fingolimod, FREEDOMS and TRANSFORMS, provides insights into NfL’s response to DMT (Neurology. 2019 Mar 5;92[10]:e1007-15). In FREEDOMS, which compared fingolimod with placebo, “fingolimod leads to a rapid decrease of neurofilament levels, close to normality, while placebo patients continue to have high levels,” said Dr. Leppert, a coauthor of the study.
TRANSFORMS compared interferon-beta and fingolimod. “The clinical experience that fingolimod is a more potent compound than interferon is actually reflected here by the NfL results,” Dr. Leppert said. “Both compounds lead to a decrease of neurofilaments – so, a decrease of neuronal damage – but one drug is more potent than the other one.”
Similarly, data from the observational EPIC study indicate that patients who do not receive DMT have a consistent increase in NfL levels, whereas those who receive platform therapies have a slight decrease in NfL and those who receive second-line therapies have a greater decrease, Dr. Leppert said.
Decades of research
For about 20 years, researchers have studied neurofilaments in cerebrospinal fluid (CSF) as a potential biomarker for MS and other diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and head trauma.
“What prevented the emergence of NfL to clinical practice was the inability to measure it in blood because levels are 50-100 times lower [in blood] than in CSF,” Dr. Leppert said.
The development of single molecule array (SIMOA) technology enabled researchers to show a proper correlation between levels of NfL in CSF and those in blood, Dr. Leppert said. “That is now allowing repetitive testing in an accessible fluid compartment, meaning serum or plasma,” he said.
Compared with brain MRI, NfL may provide novel insights into MS disease activity. “MRI is measuring a structural deficit of the past,” Dr. Leppert said. “NfL is measuring online, real time what axonal damage is occurring.”
Correlation with outcomes
At the group level, patients with MS have higher levels of NfL, compared with controls, and levels are higher in patients with progressive forms of MS versus relapsing forms. “Levels increase dramatically in the wake of relapse,” he said.
Barro et al. found that patients with higher serum levels of NfL are more likely to experience Expanded Disability Status Scale (EDSS) worsening (Brain. 2018 Aug 1;141[8]:2382-91). Furthermore, MRI lesions are independently associated with serum NfL, and patients with higher levels of serum NfL have significantly greater average loss in brain volume and spinal cord volume over 5 years.
A treatment algorithm
NfL someday could be incorporated into MS treatment algorithms, Dr. Leppert suggested. For instance, if a patient has high levels of disease activity based on MRI or clinical grounds, then prescribe a high-efficacy therapy. If not, measure NfL. “If the levels are low, then you can be assured to use platform therapies or continue what the patient has. But if NfL levels are high, then you should choose high efficacious therapies or switch to high-efficacious therapies in the long run,” he said.
Limitations and next steps
Although NfL is a specific marker of neuronal damage, it is not specific for the cause of the damage. Further studies are needed to better understand NfL metabolism and confounding factors such as age. Reference biomarkers likely will be needed “to conceptualize whether the signal of NfL is due to acute disease or chronic disease,” Dr. Leppert said.
“We need to optimize the assay and come to a worldwide agreement on the platform. We need to have prospective studies, mainly to achieve regulatory acceptance. And we need to have a normative database” to determine which NfL values are pathologic at a particular age, he said.
Despite the biomarker’s potential, blood NfL levels will not replace clinical expertise. “Biomarkers cannot be of value without a clinical backing and a clinical evaluation,” Dr. Leppert said. “The idea that this will replace us or any other person who makes a clinical judgment is a big error. NfL will prevail as a biomarker. ... But interpretation of the clinical background is germane.”
Dr. Leppert has been an employee of pharmaceutical companies, most recently Novartis.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019