E. Waubant

UCSF

Emmanuelle L. Waubant, MD, PhD, received her medical degree at the University of Lille, France. She then trained in France as well as at the University of California, San Francisco (UCSF) in adult neurology, neuroimmunology and MS clinical research.  She is currently Professor of Neurology and Pediatrics at UCSF. She has served as the Race to Erase MS medical director since 2001. She also directs the Regional Pediatric MS Center at UCSF and is the secretary for the Americas Committee on Treatment and Research in MS. Dr. Waubant serves or has served on the clinical care, fellowship and research grant review, and research programs advisory committees of the National Multiple Sclerosis Society and on the advisory board of the Society’s Northern California Chapter. She is the Chair of the Clinical Trial Task Force of the International Pediatric MS Study Group and a member of the US Pediatric MS Network and International Pediatric MS Study Group Steering Committee. She also directs translational research projects and mentors junior investigators on various clinical, research and career development aspects in the field of MS and related diseases. In 2018, Dr. Waubant started an international consortium (international Women in MS) to foster community spirit among clinicians and scientists from all over the world, promote diversity in professional organizations and mentor junior women in the field of MS.

Dr. Waubant’s specific interests include the translation of promising agents from the bench to bedside to advance patients’ care, and risk factors for MS susceptibility and disease modification in pediatric and adult MS.

Author Of 6 Presentations

Microbiome Late Breaking Abstracts

LB01.05 - Network analysis identifies gut bacteria associated with multiple sclerosis relapse among pediatric-onset patients

Abstract

Background

Commensal gut microbes are known to affect host immune function and may be modifiable. Recent work suggests gut microbiota composition contributes to onset of MS; however, little is known about its contribution to MS disease activity.

Objectives

Estimate the association between gut microbiota and subsequent disease activity among individuals with pediatric-onset MS (pedMS) from the U.S. Network of Pediatric MS Centers.

Methods

Stool samples were collected from cases (MS symptom onset <18 years) and profiled using 16S rRNA sequencing of the V4 region. Amplicon sequence variants (ASVs) were identified using the Divisive Amplicon Denoising Algorithm-2 (DADA2). ASVs present in <20% of samples were removed. ASV clusters (modules) were identified using weighted genetic correlation network analysis (WGCNA) and sparCC transformation of ASV abundance. Cox proportional hazard recurrent event models were used to examine the relationship between individual ASVs and then ASV clusters, adjusted for age, sex, and disease modifying therapy (DMT) use.

Results

Of 53 pedMS cases, 72% were girls. At stool sample collection, the mean age was 15.5 years (SD: 2.7) and disease duration was 1.1 years (SD: 1.0). Less than half (45%) had one relapse and 30% had >1 relapse over the subsequent mean follow-up of 2.5 years (SD:1.3). Over this time, 91% used a DMT. Among 270 individual ASVs included in the analyses, 20 were nominally significant (p<0.05), e.g. the presence of Blautia stercoris was associated with higher relapse risk (hazard ratio [HR]=2.50; 95% confidence interval [CI]=1.43, 4.37). WGCNA identified 6 ASV modules. Higher values of one module’s eigengene was significantly (false discovery rate q<0.2) associated with higher relapse risk (HR=1.23, 95% CI=1.02, 1.50). Four ASVs nominally associated with higher relapse risk were in this module. These included Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

Conclusions

We found that a high relative abundance of a gut microbiota species within the Blautia genus, and its interconnected variants, was associated with a higher relapse risk in pedMS cases. While our study represents the largest of its kind in MS, findings need to be replicated. However, Blautia stercoris has been linked to disease activity in other immune-mediated diseases such as systemic lupus erythematosus.

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Pediatric MS Oral Presentation

PS04.04 - Evidence for an interaction between ozone pollution and HLA-DRB1*15 alleles in pediatric multiple sclerosis

Abstract

Background

We previously reported a relationship between air pollutants and increased risk of pediatric MS (ped-MS). Environmental risk factor research in ped-MS offers the advantage of shorter duration between exposure and disease onset. Ozone, an air pollutant, is a major global health hazard thought to have a role in MS pathoetiology. Identifying gene-environment interactions advances the understanding of biological processes at play in MS susceptibility.

Objectives

We sought to examine the interaction between ozone pollution and DRB1*15 status as the main genetic variant associated with MS susceptibility.

Methods

Cases and controls enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers were analysed. County-level modeled ozone data were acquired from the CDC’s Environmental Tracking Network air pollution database. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS were assessed by logistic regression. Interaction between tertiles of ozone level and presence of DRB1*15 alleles on odds of ped-MS was evaluated. Models were adjusted for sex, race, ethnicity, age, second-hand smoke exposure, and mother’s education. Additive interaction was estimated using relative risk due to interaction (RERI) and attributable proportion of disease were calculated.

Results

355 ped-MS cases and 565 controls contributed to the analyses. Ozone levels were associated with MS with an odds ratio (OR) of 2.35 (95%CI 1.57–3.51) and 2.21 (95%CI 1.48–3.32) in the upper two tertiles, respectively, compared with the lowest tertile. DRB1 status was also independently associated with MS (OR 1.99; 95%CI 1.43–2.78). There was a significant additive interaction between ozone and DRB1, with a RERI of 2.74 (95%CI 0.50–4.98) and 2.43 (95%CI 0.36–4.5) in the upper two tertiles, respectively. Approximately 60% of the ped-MS risk in those with HLA-DRB1*15 haplotype and high ozone exposure was attributable to the interaction between these risk factors.

Conclusions

Our data revealed additive interaction between higher exposure to ozone and DRB1 alleles on ped-MS susceptibility. Further evaluation of additional genetic variants that might play a role in ozone-induced ped-MS is underway to provide mechanistic insight.

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Biomarkers and Bioinformatics Oral Presentation

PS09.05 - Value of serum neurofilament light chain levels as a biomarker of suboptimal treatment response in MS clinical practice

Abstract

Background

Serum neurofilament light chain (sNfL) reflects neuro-axonal damage and may qualify as a biomarker of suboptimal response to disease modifying therapy (DMT).

Objectives

To investigate the predictive value of sNfL in clinically isolated syndrome (CIS) and relapsing-remitting (RR) MS patients with established DMT for future MS disease activity in the Swiss MS Cohort Study.

Methods

All patients were on DMT for at least 3 months. sNfL was measured 6 or 12-monthly with the NF-light®assay. The association between sNfL and age was modeled using a generalized additive model for location scale and shape. Z-scores (sNfLz) were derived thereof, reflecting the deviation of a patient sNfL value from the mean value of same age healthy controls (n=8865 samples). We used univariable mixed logistic regression models to investigate the association between sNfLz and the occurrence of clinical events (relapses, EDSS worsening [≥1.5 steps if EDSS 0; ≥1.0 if 1.0-5.5 or ≥0.5 if >5.5] in the following year in all patients, and in those fulfilling NEDA-3 criteria (no relapses, EDSS worsening, contrast enhancing or new/enlarging T2 lesions in brain MRI, based on previous year). We combined sNfLz with clinical and MRI measures of MS disease activity in the previous year (EDA-3) in a multivariable mixed logistic regression model for predicting clinical events in the following year.

Results

sNfL was measured in 1062 patients with 5192 longitudinal samples (median age 39.7 yrs; EDSS 2.0; 4.1% CIS, 95.9% RRMS; median follow-up 5 yrs). sNfLz predicted clinical events in the following year (OR 1.21 [95%CI 1.11-1.36], p<0.001, n=4624). This effect increased in magnitude with increasing sNfLz (sNfLz >1: OR 1.41 [95%CI 1.15-1.73], p=0.001; >1.5: OR 1.80 [95%CI 1.43-2.28], p<0.001; >2: OR 2.33 [95%CI 1.74-3.14], p<0.001). Similar results were found for the prediction of future new/enlarging T2 lesions and brain volume loss. In the multivariable model, new/enlarging T2 lesions (OR 1.88 [95%CI 1.13-3.12], p=0.016) and sNfLz>1.5 (OR 2.18 [95%CI 1.21-3.90], p=0.009) predicted future clinical events (n=853), while previous EDSS worsening, previous relapses and current contrast enhancement did not. In NEDA-3 patients, change of sNfLz (per standard deviation) was associated with a 37% increased risk of clinical events in the subsequent year (OR 1.37 [95%CI 1.04-1.78], p=0.025, n=587).

Conclusions

Our data support the value of sNfL levels, beyond the NEDA3 concept, for treatment monitoring in MS clinical practice.

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Invited Presentations Invited Abstracts

PS10.01 - The Microbiome in Adult and Pediatric MS

Speakers
Authors
Presentation Number
PS10.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Abstract

Abstract

Following upon the discoveries that specific bacteria in the gut may modulate the onset of experimental autoimmune encephalomyelitis, an animal model for MS, the human gut microbiome has been investigated in the human disease. Data in MS have been mostly generated from small to moderate size studies using stool samples from patients with relatively long disease duration and often receiving disease-modifying therapies that can affect microbial communities. A consistent finding across these studies is that the alpha and beta diversity of gut microbial communities appears overall similar in MS patients and controls, i.e. the overall bacterial composition is not dramatically different. In contrast, increased or decreased abundance of specific microbes has been reported in cases compared to controls, with some current research emphasis on bacterial cluster differences. While a few of these differences are consistent across studies, many are not, possibly due to variability in geographical region of origin, diet, comorbidities, use of MS drugs and age of the patients. Immune changes in relation to gut microbial alterations have been reported in MS compared to controls. Very few publications have addressed so far the association between the gut microbiome characteristics and the risk of relapse or disability progression. A critical focus of current research is to unravel the changes in metabolic function resulting from alterations in microbial communities (i.e. the dysregulation of specific metabolic pathways due to variations in the presence or abundance of specific bacteria). Ongoing pilot trials of probiotic supplementation or microbiome transplant will determine the feasibility of these interventions and allow the design of future studies to attempt disease modification.

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Microbiome Oral Presentation

PS10.03 - Functional survey of the pediatric multiple sclerosis microbiome        

Speakers
Presentation Number
PS10.03
Presentation Topic
Microbiome
Lecture Time
09:45 - 09:57

Abstract

Background

Metagenomic sequencing reveals the functional potential of the gut microbiome, and may explain how the gut microbiome influences pediatric-onset multiple sclerosis (MS) risk.

Objectives

To examine the gut microbiome functional potential by metagenomic analysis of stool samples from pediatric MS cases and controls using a case-control design.

Methods

Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network who provided a stool sample and were not exposed to antibiotics or corticosteroids 30 days prior were included for study. All MS cases met McDonald criteria, had symptom onset <18 years of age and had either no prior disease-modifying drug (DMD) exposure or were exposed to beta-interferon or glatiramer acetate only. Twenty MS cases were matched to 20 non-affected controls by sex, age (± 3 years), stool consistency (Bristol Stool Scale, BSS) and, when possible, by race. Shotgun metagenomic reads were generated using the Illumina NextSeq platform and assembled using MEGAHIT. Metabolic pathway analysis was used to compare the gut microbiome between cases and controls, as well as cases by DMD status (DMD naïve vs DMD exposed MS cases vs controls). Gene ontology classifications were used to assess α-diversity and differential abundance analyses (based on the negative binomial distribution) reported as age-adjusted log-fold change (LFC) in relative abundance, 95% confidence intervals (CI), and false discovery rate adjusted p-values.

Results

The MS cases were aged 13.6 mean years at symptom onset. On average, MS cases and controls were 16.1 and 15.4 years old at the time of stool collection and 80% of each group were girls. MS cases and controls were similar for body mass index (median: 22.8 and 21.0, respectively), stool consistency (BSS types 1-2: n=4, types 3-5: n=16, for both MS and controls) and race (Caucasian: 11 and 9, respectively). Eight MS cases were DMD naïve. Richness of gene ontology classifications did not differ by disease status or DMD status (all p>0.4). However, differential analysis of metabolic pathways indicated that the relative abundance of tryptophan degradation (via the kynurenine pathway; LFC 13; 95%CI: 8–19; p<0.0005) and cresol degradation (LFC 19; 95%CI: 13–25; p<0.0001) pathways were enriched for MS cases vs controls. Differences by DMD status were also observed, e.g., choline biosynthesis was enriched in DMD exposed vs naïve MS cases (LFC 21; 95%CI: 12–29; p<0.0001).

Conclusions

We observed differences in the functional potential of the gut microbiome of young individuals with MS relative to controls at various metabolic pathways, including enrichment of pathways related to tryptophan and metabolism of industrial chemicals. DMD exposure affected findings, with enrichment of pathways involved in promoting CNS remyelination (e.g., choline).

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Clinical Trials Oral Presentation

PS13.02 - Randomized Trial of Amantadine, Modafinil and, Methylphenidate for Multiple Sclerosis Fatigue

Speakers
Presentation Number
PS13.02
Presentation Topic
Clinical Trials
Lecture Time
13:15 - 13:27

Abstract

Background

Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis (MS); however, the evidence supporting their efficacy is sparse and conflicting.

Objectives

Our goal was to compare the efficacy of these three medications against each other and placebo in patients with MS-related fatigue.

Methods

In this randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, patients with MS fatigue received twice-daily oral amantadine, modafinil, methylphenidate, or placebo, each given for up to six weeks. The primary outcome measure was the Modified Fatigue Impact Scale (MFIS) measured while taking the highest tolerated dose. Secondary outcomes included measures of sleepiness, adverse events, and the maximal tolerated dose of each medication.

Results

A total of 141 patients were enrolled and randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the intent-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51.3 at baseline, 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P=0.20 for the overall medication effect). As compared to placebo (30.6%), higher proportions of participants reported adverse events while taking amantadine (38.6%), modafinil (40.0%), and methylphenidate (39.5%).

Conclusions

Amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS-related fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, and methylphenidate for the treatment of fatigue in MS. (ClinicalTrials.gov number, NCT03185065.)

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Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

PS10.01 - The Microbiome in Adult and Pediatric MS

Speakers
Authors
Presentation Number
PS10.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Abstract

Abstract

Following upon the discoveries that specific bacteria in the gut may modulate the onset of experimental autoimmune encephalomyelitis, an animal model for MS, the human gut microbiome has been investigated in the human disease. Data in MS have been mostly generated from small to moderate size studies using stool samples from patients with relatively long disease duration and often receiving disease-modifying therapies that can affect microbial communities. A consistent finding across these studies is that the alpha and beta diversity of gut microbial communities appears overall similar in MS patients and controls, i.e. the overall bacterial composition is not dramatically different. In contrast, increased or decreased abundance of specific microbes has been reported in cases compared to controls, with some current research emphasis on bacterial cluster differences. While a few of these differences are consistent across studies, many are not, possibly due to variability in geographical region of origin, diet, comorbidities, use of MS drugs and age of the patients. Immune changes in relation to gut microbial alterations have been reported in MS compared to controls. Very few publications have addressed so far the association between the gut microbiome characteristics and the risk of relapse or disability progression. A critical focus of current research is to unravel the changes in metabolic function resulting from alterations in microbial communities (i.e. the dysregulation of specific metabolic pathways due to variations in the presence or abundance of specific bacteria). Ongoing pilot trials of probiotic supplementation or microbiome transplant will determine the feasibility of these interventions and allow the design of future studies to attempt disease modification.

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Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

PS10.01 - The Microbiome in Adult and Pediatric MS

Speakers
Authors
Presentation Number
PS10.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Abstract

Abstract

Following upon the discoveries that specific bacteria in the gut may modulate the onset of experimental autoimmune encephalomyelitis, an animal model for MS, the human gut microbiome has been investigated in the human disease. Data in MS have been mostly generated from small to moderate size studies using stool samples from patients with relatively long disease duration and often receiving disease-modifying therapies that can affect microbial communities. A consistent finding across these studies is that the alpha and beta diversity of gut microbial communities appears overall similar in MS patients and controls, i.e. the overall bacterial composition is not dramatically different. In contrast, increased or decreased abundance of specific microbes has been reported in cases compared to controls, with some current research emphasis on bacterial cluster differences. While a few of these differences are consistent across studies, many are not, possibly due to variability in geographical region of origin, diet, comorbidities, use of MS drugs and age of the patients. Immune changes in relation to gut microbial alterations have been reported in MS compared to controls. Very few publications have addressed so far the association between the gut microbiome characteristics and the risk of relapse or disability progression. A critical focus of current research is to unravel the changes in metabolic function resulting from alterations in microbial communities (i.e. the dysregulation of specific metabolic pathways due to variations in the presence or abundance of specific bacteria). Ongoing pilot trials of probiotic supplementation or microbiome transplant will determine the feasibility of these interventions and allow the design of future studies to attempt disease modification.

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