Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
Neurology

Author Of 2 Presentations

Pediatric MS Oral Presentation

FC02.04 - Teriflunomide efficacy and safety in pediatric patients with relapsing forms of MS: Interim analysis of open-label TERIKIDS trial extension

Speakers
Presentation Number
FC02.04
Presentation Topic
Pediatric MS
Lecture Time
13:36 - 13:48

Abstract

Background

Treatment options for pediatric patients with relapsing forms of multiple sclerosis (RMS) are limited. Teriflunomide, approved for adults with RMS in >80 countries, was investigated in pediatric RMS in TERIKIDS (NCT02201108), a 2-year, multicenter, multinational, randomized, double-blind (DB), placebo-controlled, parallel-group phase 3 study.

Objectives

To report the interim results in pediatric patients from the open-label (OL) period of the TERIKIDS study as of 27 November 2019.

Methods

Patients who either completed 96-week DB treatment or qualified for early switch from DB treatment to OL teriflunomide could continue in the OL period until 192 weeks after initial randomization. All patients in the OL period received teriflunomide at a dose based on body weight, equivalent to 14 mg in adults.

Results

In the DB period, teriflunomide reduced risk of relapse (−34%); however, the difference was not statistically significant versus placebo (P=0.29) so TERIKIDS did not meet its primary endpoint. Teriflunomide significantly reduced risk of relapse or high MRI activity (−43%; P=0.041; prespecified sensitivity analysis), number of new/enlarging T2 lesions (−55%; P=0.0006), and number of gadolinium-enhancing lesions (−75%; P<0.0001) relative to placebo. At the cut-off date, 100 (91.7%) patients from the teriflunomide and 52 (91.2%) from the placebo group enrolled in the OL period; 34 patients discontinued, 30 completed, and 88 were ongoing. From DB randomization to week 192, risk of relapse was numerically lower with continuous teriflunomide versus placebo/teriflunomide (hazard ratio [95% CI]: 0.61 [0.38 to 0.98]; P=0.098), as was risk of disability progression sustained for 24 weeks (hazard ratio [95% CI]: 0.552 [0.245 to 1.242]). Number of new/enlarging T2 lesions per MRI scan was reduced with continuous teriflunomide versus placebo/teriflunomide (6.3 vs 13.0; P=0.0006). Incidence of adverse events during the OL period was lower with continuous teriflunomide versus placebo/teriflunomide (68.0% vs 82.7%). Adverse events led to treatment discontinuation during the OL period in 8 patients (increased alanine aminotransferase [n=5], peripheral neuropathy [n=1], pancreatitis [n=2]).

Conclusions

Interim analysis showed that continuous teriflunomide numerically lowered the risk of clinical relapses and 24-week sustained disability progression in pediatric patients compared with delayed initiation of teriflunomide after placebo. Teriflunomide was well tolerated and had a manageable safety profile.

STUDY SUPPORT: Sanofi.

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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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Presenter Of 1 Presentation

Pediatric MS Oral Presentation

FC02.04 - Teriflunomide efficacy and safety in pediatric patients with relapsing forms of MS: Interim analysis of open-label TERIKIDS trial extension

Speakers
Presentation Number
FC02.04
Presentation Topic
Pediatric MS
Lecture Time
13:36 - 13:48

Abstract

Background

Treatment options for pediatric patients with relapsing forms of multiple sclerosis (RMS) are limited. Teriflunomide, approved for adults with RMS in >80 countries, was investigated in pediatric RMS in TERIKIDS (NCT02201108), a 2-year, multicenter, multinational, randomized, double-blind (DB), placebo-controlled, parallel-group phase 3 study.

Objectives

To report the interim results in pediatric patients from the open-label (OL) period of the TERIKIDS study as of 27 November 2019.

Methods

Patients who either completed 96-week DB treatment or qualified for early switch from DB treatment to OL teriflunomide could continue in the OL period until 192 weeks after initial randomization. All patients in the OL period received teriflunomide at a dose based on body weight, equivalent to 14 mg in adults.

Results

In the DB period, teriflunomide reduced risk of relapse (−34%); however, the difference was not statistically significant versus placebo (P=0.29) so TERIKIDS did not meet its primary endpoint. Teriflunomide significantly reduced risk of relapse or high MRI activity (−43%; P=0.041; prespecified sensitivity analysis), number of new/enlarging T2 lesions (−55%; P=0.0006), and number of gadolinium-enhancing lesions (−75%; P<0.0001) relative to placebo. At the cut-off date, 100 (91.7%) patients from the teriflunomide and 52 (91.2%) from the placebo group enrolled in the OL period; 34 patients discontinued, 30 completed, and 88 were ongoing. From DB randomization to week 192, risk of relapse was numerically lower with continuous teriflunomide versus placebo/teriflunomide (hazard ratio [95% CI]: 0.61 [0.38 to 0.98]; P=0.098), as was risk of disability progression sustained for 24 weeks (hazard ratio [95% CI]: 0.552 [0.245 to 1.242]). Number of new/enlarging T2 lesions per MRI scan was reduced with continuous teriflunomide versus placebo/teriflunomide (6.3 vs 13.0; P=0.0006). Incidence of adverse events during the OL period was lower with continuous teriflunomide versus placebo/teriflunomide (68.0% vs 82.7%). Adverse events led to treatment discontinuation during the OL period in 8 patients (increased alanine aminotransferase [n=5], peripheral neuropathy [n=1], pancreatitis [n=2]).

Conclusions

Interim analysis showed that continuous teriflunomide numerically lowered the risk of clinical relapses and 24-week sustained disability progression in pediatric patients compared with delayed initiation of teriflunomide after placebo. Teriflunomide was well tolerated and had a manageable safety profile.

STUDY SUPPORT: Sanofi.

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Moderator Of 1 Session

Parallel Session Sat, Sep 12, 2020
Moderators
Session Type
Parallel Session
Date
Sat, Sep 12, 2020
Time (ET)
09:15 - 10:45

Author Of 11 Presentations

COVID-19 Late Breaking Abstracts

LB1231 - Demographic and Clinical Profile of Pediatric patients with Multiple Sclerosis infected with SARS-Cov2 (ID 2111)

Abstract

Background

COVID-19, the disease caused by SARS CoV2, causes severe respiratory disease, and rarely multisystem inflammatory syndrome, in some pediatric patients. Little is known about the disease course among patients with pediatric-onset multiple sclerosis.

Objectives

To describe the demographic and clinical characteristics of a subgroup of pediatric-onset multiple sclerosis (POMS) patients infected with SARS CoV2.

Methods

The Network of Pediatric Multiple Sclerosis Centers (NPMSC), a consortium of 10 US pediatric multiple sclerosis (MS) centers contributes clinical information about POMS patients and demyelinating disorders to a centralized database, the Pediatric Demyelinating Disease Database (PeMSDD), to facilitate research for this rare disorder. In addition to collecting clinical data on clinical course, comorbidities, disease modifying therapy use, and functional status, the NPMSC developed a screening questionnaire to administer to patients during standard of care visits to further evaluate their COVID- 19 status. Additionally POMS patients with confirmed or highly suspected COVID-19, will be assessed for risk factors including smoking use, recent glucocorticoid use, comorbidities; clinical presentation, including symptoms, radiological and laboratory data; COVID-19 treatments and outcomes. POMS patients will also complete the COViMS (COVID-19 Infections in MS & Related Diseases) database, a joint effort of the US National MS Society and the Consortium of MS Centers to capture information on outcomes of people with MS and other central nervous system (CNS) demyelinating diseases (Neuromyelitis Optica Spectrum Disease, or MOG antibody disease) who have developed COVID-19. Together with data collected from the PeMSDD, we will present comprehensive data on the POMS patient experience with COVID-19 and compare it to POMS patients without known or suspected COVID-19.

Results

Data collection continues. Results available by the meeting due date will describe the demographics, risk factors, treatments and outcomes of POMS with COVID-19.

Conclusions

Conclusions will be drawn pending results of data analysis. We anticipate reporting on demographic data, risk factors, outcomes and any associations with disease modifying therapy.

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COVID-19 Late Breaking Abstracts

LB1262 - Low Prevalence of SARS-CoV-2 Antibodies in People with Multiple Sclerosis Residing in Massachusetts (ID 2159)

Abstract

Background

Seroepidemiology is an important tool to characterize the epidemiology and immunobiology of SARS-CoV-2. Most people with multiple sclerosis (MS) are treated with immunomodulators or immunosuppressants, so it is crucial to understand the immune response to the novel SARS-CoV-2 in people with MS.

Objectives

To investigate the prevalence and persistence of the SARS-CoV-2 antibody response in MS and how this relates to MS phenotype and treatment.

Methods

227 consecutive people with MS residing in MA and receiving care at Massachusetts General Hospital or Brigham and Women’s Hospital and 143 of their cohabitants were enrolled May 29-July 23, 2020. In addition, 8 people with MS receiving care elsewhere who tested positive for SARS-CoV-2 nasal swab PCR and 7 cohabitants of that group were enrolled to enrich the sample for select analyses. Each participant remotely submitted a dried blood card for in-house MGH SARS-CoV-2 IgG ELISA assay testing. The assay displays 99.7% sensitivity and 100% specificity >14 days from symptom onset. Participants completed a REDCap questionnaire covering demographics, MS history and treatments, comorbidities, and COVID-19 symptoms and exposure. Antibody prevalence in MS participants will be compared to that in their cohabitants using Pearson’s Chi-squared tests.

Results

The majority of MS participants were characterized as relapsing/remitting (76.8%) and were taking disease modifying therapies (72.6%) at the time of collection. SARS-CoV-2 antibodies were detected in 3.5% of people with MS residing in MA and 6.3% of their cohabitants (X2=1.54, p=0.22). For comparison, ~1.5% of the MA population had tested positive by PCR in this date range. Exposure and treatment data will be presented in 13 cases of antibody discordance between the person with MS and his/her cohabitant; the person with MS was antibody-negative in 10 cases and antibody-positive in 3 cases with discordance. In total there were 6 MS participants and no cohabitants who previously tested positive by nasal swab PCR but lacked antibodies at follow-up. Of the COVID-positive participants (by PCR or antibody), 54.5% (6 of 11) of MS and 88.9% (8 of 9) of cohabitants were asymptomatic (p=0.16).

Conclusions

Antibody prevalence was low overall in people with MS residing in MA. Discordance between MS participants and their cohabitants and lack of detectable antibodies in some people with MS with prior nasal swab PCR positivity suggest SARS-CoV-2 antibodies may be less persistent in people with MS.

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Gender Differences, Hormones and Sex Chromosomes Late Breaking Abstracts

LB1264 - Endocrine disrupting chemicals affect T cell phenotypes and show a role for environmental factors in MS pathophysiology. (ID 2162)

Speakers
Presentation Number
LB1264
Presentation Topic
Gender Differences, Hormones and Sex Chromosomes

Abstract

Background

Autoimmune diseases, including Multiple Sclerosis (MS), are more common in females, suggesting that immune-endocrine mechanisms are central for polarizing the immune response and maintaining tolerance. The accelerated use of chemicals in consumer products has called attention to a subset of additives used during manufacturing of goods and materials, termed endocrine disrupting chemicals (EDCs). These synthetic compounds are structural mimics of endogenous hormones and may therefore drive immune cells to enhanced or different outcomes. In recent decades, the increased application of EDCs across daily-use products has been coincident with an increase in the female to male MS susceptibility ratio. Involvement of T cells in MS is an active area of research, but the potential role of environmental factors in T cell differentiation has not been fully resolved and could inform on the sex-bias of MS disease.

Objectives

Our study thus sought to determine whether EDCs adversely modulate T cell phenotypes and to identify which immune populations are most at-risk for deregulation by environmental factors.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from female healthy controls (HC) and MS patients and in vitro exposure to EDCs, bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP), was maintained throughout T cell conditioned differentiation. Negative selection was carried out on remaining PBMCs to isolate CD4 T cells for additional regulatory T cell (Treg) differentiation. Exposure to EDCs was similarly maintained throughout Treg differentiation. On a set-endpoint, cells were harvested and analyzed by flow cytometry using a Treg or multi-parameter T cell panel. Dimensionality reduction clustering and high parameter discovery using t-distributed stochastic neighbor embedding were used to identify EDC induced changes in T cell phenotypes. Data was collected across two batches (n=8 per group) and validated across one batch (n=3 per group). Final results (n=16) will include batch effect normalization.

Results

EDCs altered the phenotype and activation state of T cells, particularly BPA and low dose DEHP (10 nM) which led to increased central memory T cells (TCM). The TCM population was also more activated across EDC treatments, relative to untreated controls. These observations held true of both CD4 and CD8 T cells. For Treg differentiation, we identified only modest effects for BPA only, on total Tregs (Foxp3+CD25+); EDC treatments had no effect on Treg expression of latency-associated peptide (LAP).

Conclusions

Phenotyping of EDC-regulated T cells helps to elucidate population subtypes that could pose a risk for MS progression and severity. Results also emphasize the role of environmental factors in MS pathophysiology and offer an explanation for the sex-bias of MS disease.

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Invited Presentations Invited Abstracts

MTE01.01 - Meet the Expert – CNS Disorders in Children (ID 2025)

Speakers
Authors
Presentation Number
MTE01.01
Presentation Topic
Invited Presentations
Biomarkers and Bioinformatics Poster Presentation

P0063 - Development of a Custom Multivariate Proteomic Serum Based Assay for Association with Radiographic and Clinical Endpoints in MS (ID 833)

Abstract

Background

Multiple Sclerosis (MS) is a complex and heterogeneous disease. Investigating the biological pathways and cell types involved in MS pathophysiology as represented by protein biomarker expression can help inform the development of tools to monitor disease activity, disease progression, identify early evidence of relapse, and monitor treatment response.

Objectives

To develop a blood based multiplex proteomic assay that associates with clinical and radiographic endpoints in patients with MS. These endpoints include the presence of gadolinium-enhanced (Gd+) lesions, Annualized Relapse Rate (ARR) and clinically defined relapse status (active versus stable).

Methods

Serum samples (n=690 in total) from multiple deeply-phenotyped cohorts (ACP, CLIMB and EPIC) were tested in immunoassays for the measurement of 1196 proteins using Proximity Extension Assays (PEA) from OlinkTM and for 215 proteins using xMAPTM immunoassays from Myriad RBM, Inc. (RBM). Associated radiographic and clinical endpoints at the time of the blood draw were correlated with the protein levels. Twenty-one proteins were selected for inclusion in a custom assay based on their performance in univariate and multivariate statistical models, and replication across independent cohorts. Biological pathway modeling and network analysis were performed to ensure comprehensive representation of MS neurophysiology. Area under the curve (AUC) was selected as the key metric for model performance evaluation.

Results

Multivariate statistical ensembles restricted to the expression levels of the biomarkers selected for the custom assay achieved AUC performance of 0.827 for classification of the presence of Gd+ lesions, 0.802 for classification of clinically defined relapse status, and 0.930 for the classification of patients with Low ARR (≤0.2 relapses) vs High ARR (≥1.0 relapses). A multivariate model utilizing shifts in biomarker expression in longitudinally paired samples achieved the highest observed performance of 0.950 for classification of Gd+ lesion presence. In each case, the multivariate models significantly outperformed (p-value <0.05) the AUC of the highest performing univariate biomarker.

Conclusions

Multivariate models restricted to the 21 selected proteins effectively classified several radiographic and clinical endpoints with stronger performance than any single biomarker. A 21-plex custom assay panel is being developed for further investigation and validation using additional cohorts.

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Clinical Outcome Measures Poster Presentation

P0067 - Disability improvement by Multiple Sclerosis Functional Composite in progressive MS patients and MRI features (ID 1729)

Speakers
Presentation Number
P0067
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Disability improvement is an important functional measure in progressive MS. The MRI features of disability improvement have not been explored.

Objectives

To assess quantitative brain and spinal cord MRI measures, including volumetric features, that correlate with improvement in the T25FW or 9HPT compared to multiple sclerosis (MS) patients with stable or worsening features.

Methods

A nested cohort from the SysteMS substudy of Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) Study was selected to match inclusion criteria for patients enrolling in a phase 2 trial of repeat dose intrathecal Mesenchymal Stem Cells-Neurotrophic Factor (MSC-NTF) cells in patients with progressive MS (NCT03799718). 3T MRIs at baseline and at follow-up timepoint (12-24 months later) underwent brain and lesion volumetric analysis by Icometrix, as well as mean upper cervical cord area (MUCCA) which generated 34 measures. These 34 MRI volumetric measures (ml) were compared in patients with improved versus patients with worsening or stable 9-hole peg test (9HPT) or timed-25-foot-walk (T25FW) scores. Results were not corrected for multiple comparisons due to the exploratory nature of this study.

Results

48 patients met inclusion criteria. 17 patients had improved 9HPT score, while 29 had worsened or had stable 9HPT score from baseline to 12-24 months later. Whole brain volume at baseline for these 3 cohorts (Improved 9HPT:1505±51 vs. stable-worse 9HPT:1471±62;p=0.069;t-test) and follow-up (Improved:1501.555±52.039 vs. stable-worse:1461.304±63.562);p=0.03;t-test) differed between the two groups, as did gray matter volume at follow-up (Improved 1505.059 ±50.961 vs. stable-worse 865.57±41.352); p=0.063:t-test). For T25FW, 18 patients had an improved score, while 27 were worsened or stable over the 12-month period. Deep white matter FLAIR/T2 lesion volume at baseline (Improved:0.43±0.507 vs. stable-worse:0.827±0.561;p=0.03;t-test) and follow-up (Improved:0.429±0.503 vs. stable-worse:0.864±0.603;p=0.02) differed between two T25FW groups. MUCCA was not associated with improvement measures.

Conclusions

Improved 9HPT measures over a 12-month period correlated with baseline brain volume, while T25FW improvements correlated with baseline deep white matter T2 lesion volume. These results will inform analysis of clinical outcomes in the ongoing phase 2 clinical trial of MSC-NTF cells in progressive MS.

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Prognostic Factors Poster Presentation

P0488 - Relapse recovery in MS: Effect of treatment and contribution to long-term disability (ID 1039)

Speakers
Presentation Number
P0488
Presentation Topic
Prognostic Factors

Abstract

Background

Although a small number of studies has shown that recovery from relapses in multiple sclerosis appears to contribute to long-term outcomes, relapse recovery has largely been ignored as a treatment endpoint and predictor of disability. We hypothesized that relapse recovery in the early stages of disease will impact longer term disability.

Objectives

The first aim of this study was to identify demographic and clinical predictors associated with incomplete recovery from relapses in the first 3 years from the first MS symptom. The second aim was to examine the relationship between incomplete recovery in first 3 years and 10-year disability outcomes.

Methods

Recovery from relapses in the first three years from the first symptom was retrospectively assessed in 360 patients with relapsing remitting multiple sclerosis enrolled in the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB study), a large longitudinal cohort. Complete or incomplete recovery from each relapse was determined based on the return of the Expanded Disability Status Scale (EDSS), Functional System Scale (FSS) and neurologic signs to baseline levels at least 6 months after symptom onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and to predict 10-year disability and MRI outcomes (brain parenchymal fraction and T2 lesion volume).

Results

Including their initial episode, the 360 included patients had a total of 736 relapses within the first three years from their first symptom. 44.6% of these relapses had an incomplete recovery at 6 months. Relapses in untreated patients had an incomplete recovery in 51.8% of cases, compared to 28.9% in patients who were being treated with a disease modifying drug (p<0.001). In the multivariable analysis, recovery from relapses in the first 3 years was better younger patients, who were on interferon treatment, had no bowel or bladder symptoms and had a longer interval since their first symptom. For every incomplete recovery in the first three years, the EDSS at 10 years increased by 0.6 points, and the timed 25-foot walk at 10 years increased by 0.5 seconds. Both disability outcomes were also higher with older age at first symptom and higher BMI. Brain atrophy, measured by the brain parenchymal fraction on MRI, was associated only with older age at first symptom, whereas T2-hyperintense lesion volume was only associated with smoking.

Conclusions

Early initiation of first-line disease-modifying treatments can improve relapse recovery, which in turn prevents long-term disability.

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Microbiome Poster Presentation

P0671 - Exploring the gut microbiome in multiple sclerosis via the international MS Microbiome Study (iMSMS) (ID 1532)

Abstract

Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

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Observational Studies Poster Presentation

P0918 - Teriflunomide safety and efficacy in advanced progressive multiple sclerosis (ID 1541)

Presentation Number
P0918
Presentation Topic
Observational Studies

Abstract

Background

Teriflunomide is an FDA approved medication for relapsing-remitting multiple sclerosis. The efficacy of teriflunomide in progressive multiple sclerosis is not well characterized.

Objectives

To explore the safety and efficacy profile of teriflunomide in patients diagnosed with progressive multiple sclerosis.

Methods

We conducted a single-center retrospective observational analysis of a progressive multiple sclerosis population, assessing safety and efficacy in patients treated at least one year with teriflunomide or glatiramer acetate. Sustained progression of expanded disability status scale (EDSS) and sustained worsening of timed 25-foot walk (T25FW) were compared using a cox proportional hazards model.

Results

Teriflunomide group (n=29) mean characteristics: age=58 years (SD±7.6), disease duration=16.7 years (SD±9.5), EDSS =5.9 (SD±1.3), follow-up=32.4 months (SD±13.6). Glatiramer acetate group (n=30) mean characteristics: age=52.4 years (SD±11.3), disease duration=15.1 years (SD±10.4), EDSS =5.7 (SD±1.6), follow-up=46.9 months (SD±43.9). Both treatments were well tolerated without serious side effects. After adjustment for age, sex, and baseline EDSS, sustained EDSS progression did not differ between groups (Hazard Ratio =1.17; 95% Confidence Interval: 0.45, 3.08; p=0.75). Sustained T25FW worsening after adjustment also did not differ (Hazard Ratio =0.56; 95% Confidence Interval: 0.2, 1.53; p=0.26).

Conclusions

In an advanced progressive multiple sclerosis population no substantial differences in tolerability, safety, sustained EDSS progression, or sustained T25FW worsening over time were observed between glatiramer acetate and teriflunomide treated groups.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1010 - Comparison of Models for Disability Accumulation on the Expanded Disability Status Scale in Multiple Sclerosis (ID 1665)

Speakers
Presentation Number
P1010
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

When assessing long-term trends in disability accumulation and economic models to compare treatments in multiple sclerosis (MS), disability accumulation on the Expanded Disability Status Scale (EDSS) is commonly assumed to depend only on the present state of the patient. Such models also often assume that the probability of disability accumulation is constant over the disease course.

Objectives

The objective of this study was to assess the assumptions of models used to describe disability accumulation within patients with MS.

Methods

Patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) who had ≥6 consecutive clinic visits, which occurred every 6 months, were included in this analysis. This yielded 7257 observations for 1039 patients. To assess whether a previous EDSS score only was sufficient for modeling disability accumulation, we compared 2 models for EDSS transitions with the EDSS scale grouped into 3 score levels (0–1.5, 2–3.5, ≥4) using a likelihood ratio test. The first transition model included only the present EDSS score, and the second model included the present and the previous EDSS scores. In addition, we fit a repeated measures proportional odds model with 1, 2, and 3 previous EDSS scores to assess if additional previous EDSS scores added to the model. To determine if the probability of disability accumulation changed with time, we assessed whether disease duration <15 years or ≥15 years was associated with a change in the transition matrix using a likelihood ratio test. Finally, we fit the repeated measures proportional odds model to assess if disease duration improved the model that included 3 previous EDSS scores.

Results

When the model with only the present EDSS score was compared with the model with 2 previous EDSS scores, the model including the 2 previous EDSS scores led to a better model fit (P<0.001). Further, all previous EDSS scores were associated with subsequent EDSS score in the repeated measures proportional odds model (1 previous EDSS, OR [95% CI]: 4.64 [4.31–4.99]; 2 previous EDSS, OR [95% CI]: 1.77 [1.65–1.90]; 3 previous EDSS, OR [95% CI]: 1.63 [1.53–1.73]). Incorporating disease duration also improved model fit using both approaches (P<0.001 for each method).

Conclusions

Additional EDSS history and disease duration may be important to incorporate into disability accumulation modeling for MS.

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Pediatric MS Poster Presentation

P1082 - Therapeutic Response in Pediatric Neuromyelitis Optics Spectrum Disorder (ID 1820)

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition which can led to significant disability. Approximately 4% of the NMOSD cases are pediatric onset. At present, there are limited studies that aim at guiding physicians in their treatment choices for NMOSD in children.

Objectives

To evaluate the effect of different disease modifying therapies (DMT) with respect to attack prevention in children with NMOSD.

Methods

Cohort study that included 12 clinical centers participating in the US Network of Pediatric MS Centers. Cases were validated for NMOSD diagnostic criteria and classified via serostatus as AQP4+, MOG+, or double-seronegative (DS). Clinical data, including demographics, attack details, type of initial DMT (rituximab, mycophenolate mofetil, azathioprine, IVIg) and neurological visit data were extracted from charts, centrally collected in a database, and analyzed. Treatment response in the three serostatus subgroups was evaluated. Effect of DMTs on annualized relapse rate (ARR) was assessed by negative binomial regression.

Results

111 pediatric patients with NMOSD were identified: 80 AQP4+, 10 MOG+, 14 double seronegative (DS), and 7 with unknown serostatus (94 females and 17 males; 48 white, 47 African American, 13 other races). Mean follow-up duration was 1.9 years (SD±2.2). About 6% of patients were treatment-naive. First-line DMTs varied by serostatus: in the AQP4+ subgroup 42% used rituximab, 16% mycophenolate mofetil, 16% azathioprine, and 8% IVIg. Among MOG+ patients, 13% received rituximab, 13% azathioprine, 13% mycophenolate, and 38% IVIg. Within the DS group, rituximab was used in 21% of cases, azathioprine in 7%, mycophenolate in 21%, and IVIg in 21%. In the unknown serogroup, 33% received rituximab, 17% azathioprine, 0% mycophenolate, and 33% IVIg. The ARR calculated in all the serogroups was 0.25 (95% CI 0.13-0.46) for rituximab, 0.73 (95% CI 0.27-2.00) for azathioprine, 0.40 (95% CI 0.18-0.89) for mycophenolate, and 0.56 (95% CI 0.26-1.20) for IVIg. In the AQP4+ subgroup, the patients started on rituximab showed an ARR of 0.25 (95% CI 0.13-0.48), those on azathioprine an ARR of 0.76 (95% CI 0.24-2.39), those on mycophenolate an ARR 0.43 (95% CI 0.17-1.07), and those on IVIg an ARR of 0.63 (95% CI 0.26-1.55).

Conclusions

This retrospective study showed that rituximab is associated with a lowered annual relapse rate in pediatric NMOSD and in particular in the AQP4+ subgroup.

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Presenter Of 3 Presentations

Invited Presentations Invited Abstracts

MTE01.01 - Meet the Expert – CNS Disorders in Children (ID 2025)

Speakers
Authors
Presentation Number
MTE01.01
Presentation Topic
Invited Presentations
Biomarkers and Bioinformatics Poster Presentation

P0063 - Development of a Custom Multivariate Proteomic Serum Based Assay for Association with Radiographic and Clinical Endpoints in MS (ID 833)

Abstract

Background

Multiple Sclerosis (MS) is a complex and heterogeneous disease. Investigating the biological pathways and cell types involved in MS pathophysiology as represented by protein biomarker expression can help inform the development of tools to monitor disease activity, disease progression, identify early evidence of relapse, and monitor treatment response.

Objectives

To develop a blood based multiplex proteomic assay that associates with clinical and radiographic endpoints in patients with MS. These endpoints include the presence of gadolinium-enhanced (Gd+) lesions, Annualized Relapse Rate (ARR) and clinically defined relapse status (active versus stable).

Methods

Serum samples (n=690 in total) from multiple deeply-phenotyped cohorts (ACP, CLIMB and EPIC) were tested in immunoassays for the measurement of 1196 proteins using Proximity Extension Assays (PEA) from OlinkTM and for 215 proteins using xMAPTM immunoassays from Myriad RBM, Inc. (RBM). Associated radiographic and clinical endpoints at the time of the blood draw were correlated with the protein levels. Twenty-one proteins were selected for inclusion in a custom assay based on their performance in univariate and multivariate statistical models, and replication across independent cohorts. Biological pathway modeling and network analysis were performed to ensure comprehensive representation of MS neurophysiology. Area under the curve (AUC) was selected as the key metric for model performance evaluation.

Results

Multivariate statistical ensembles restricted to the expression levels of the biomarkers selected for the custom assay achieved AUC performance of 0.827 for classification of the presence of Gd+ lesions, 0.802 for classification of clinically defined relapse status, and 0.930 for the classification of patients with Low ARR (≤0.2 relapses) vs High ARR (≥1.0 relapses). A multivariate model utilizing shifts in biomarker expression in longitudinally paired samples achieved the highest observed performance of 0.950 for classification of Gd+ lesion presence. In each case, the multivariate models significantly outperformed (p-value <0.05) the AUC of the highest performing univariate biomarker.

Conclusions

Multivariate models restricted to the 21 selected proteins effectively classified several radiographic and clinical endpoints with stronger performance than any single biomarker. A 21-plex custom assay panel is being developed for further investigation and validation using additional cohorts.

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Clinical Outcome Measures Poster Presentation

P0067 - Disability improvement by Multiple Sclerosis Functional Composite in progressive MS patients and MRI features (ID 1729)

Speakers
Presentation Number
P0067
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Disability improvement is an important functional measure in progressive MS. The MRI features of disability improvement have not been explored.

Objectives

To assess quantitative brain and spinal cord MRI measures, including volumetric features, that correlate with improvement in the T25FW or 9HPT compared to multiple sclerosis (MS) patients with stable or worsening features.

Methods

A nested cohort from the SysteMS substudy of Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) Study was selected to match inclusion criteria for patients enrolling in a phase 2 trial of repeat dose intrathecal Mesenchymal Stem Cells-Neurotrophic Factor (MSC-NTF) cells in patients with progressive MS (NCT03799718). 3T MRIs at baseline and at follow-up timepoint (12-24 months later) underwent brain and lesion volumetric analysis by Icometrix, as well as mean upper cervical cord area (MUCCA) which generated 34 measures. These 34 MRI volumetric measures (ml) were compared in patients with improved versus patients with worsening or stable 9-hole peg test (9HPT) or timed-25-foot-walk (T25FW) scores. Results were not corrected for multiple comparisons due to the exploratory nature of this study.

Results

48 patients met inclusion criteria. 17 patients had improved 9HPT score, while 29 had worsened or had stable 9HPT score from baseline to 12-24 months later. Whole brain volume at baseline for these 3 cohorts (Improved 9HPT:1505±51 vs. stable-worse 9HPT:1471±62;p=0.069;t-test) and follow-up (Improved:1501.555±52.039 vs. stable-worse:1461.304±63.562);p=0.03;t-test) differed between the two groups, as did gray matter volume at follow-up (Improved 1505.059 ±50.961 vs. stable-worse 865.57±41.352); p=0.063:t-test). For T25FW, 18 patients had an improved score, while 27 were worsened or stable over the 12-month period. Deep white matter FLAIR/T2 lesion volume at baseline (Improved:0.43±0.507 vs. stable-worse:0.827±0.561;p=0.03;t-test) and follow-up (Improved:0.429±0.503 vs. stable-worse:0.864±0.603;p=0.02) differed between two T25FW groups. MUCCA was not associated with improvement measures.

Conclusions

Improved 9HPT measures over a 12-month period correlated with baseline brain volume, while T25FW improvements correlated with baseline deep white matter T2 lesion volume. These results will inform analysis of clinical outcomes in the ongoing phase 2 clinical trial of MSC-NTF cells in progressive MS.

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Moderator Of 1 Session

Meet The Expert Fri, Sep 11, 2020
Moderators
Session Type
Meet The Expert
Date
Fri, Sep 11, 2020

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

MTE01.01 - Meet the Expert – CNS Disorders in Children (ID 2025)

Speakers
Authors
Presentation Number
MTE01.01
Presentation Topic
Invited Presentations