Abstract

Metabolic syndrome constitutes a cluster of metabolic abnormalities including central obesity, hypertension, insulin resistance and atherogenic dyslipidemia, which are associated with an increased risk of cardiovascular disease. A growing body of evidence suggests that obesity, and components of the metabolic syndrome (MetS) influence the risk of multiple sclerosis (MS) or outcomes after MS onset. Specifically, obesity is associated with an increased risk of developing MS. Obesity and the components of MetS are associated with longer diagnostic delays from symptom onset to diagnosis, relapse rates, disability progression, brain atrophy and mortality. Obesity may also influence the effectiveness of disease-modifying therapy. These findings have important implications for disease management.

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).

Abstract

Metabolic syndrome constitutes a cluster of metabolic abnormalities including central obesity, hypertension, insulin resistance and atherogenic dyslipidemia, which are associated with an increased risk of cardiovascular disease. A growing body of evidence suggests that obesity, and components of the metabolic syndrome (MetS) influence the risk of multiple sclerosis (MS) or outcomes after MS onset. Specifically, obesity is associated with an increased risk of developing MS. Obesity and the components of MetS are associated with longer diagnostic delays from symptom onset to diagnosis, relapse rates, disability progression, brain atrophy and mortality. Obesity may also influence the effectiveness of disease-modifying therapy. These findings have important implications for disease management.

Abstract

Metabolic syndrome constitutes a cluster of metabolic abnormalities including central obesity, hypertension, insulin resistance and atherogenic dyslipidemia, which are associated with an increased risk of cardiovascular disease. A growing body of evidence suggests that obesity, and components of the metabolic syndrome (MetS) influence the risk of multiple sclerosis (MS) or outcomes after MS onset. Specifically, obesity is associated with an increased risk of developing MS. Obesity and the components of MetS are associated with longer diagnostic delays from symptom onset to diagnosis, relapse rates, disability progression, brain atrophy and mortality. Obesity may also influence the effectiveness of disease-modifying therapy. These findings have important implications for disease management.

Background

In clinical trials, the probability of confirmed disability worsening (CDW) is significantly lower with intramuscular (IM) interferon beta-1a (IFNβ1a) and peginterferon beta-1a (PEG) treatment than with placebo in patients with relapsing forms of multiple sclerosis (RMS). Registry data provides information on disability outcomes with long-term treatment.

Objectives

To examine the long-term effects of IM IFNβ1a and PEG on real-world effectiveness in participants with RMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry.

Methods

This analysis included NARCOMS participants diagnosed with RMS who initiated IM IFNβ1a treatment between April 2004 and October 2019 (N=760) or PEG between October 2014 and October 2019 (N=116). Patient-reported outcomes were collected every 6 months. The primary endpoint was 6-month CDW, defined as a ≥1-point increase in Patient Determined Disease Steps (PDDS) score sustained for ≥6 months. Separate analyses were conducted in the IM IFNβ1a and PEG cohorts. A Kaplan-Meier analysis assessed the cumulative probability of CDW; participants were censored if they discontinued treatment or had no additional follow-up. Only participants who completed ≥2 surveys with treatment history and ≥3 surveys with PDDS history were included in the CDW analysis (IM IFNβ1a: N=760; PEG: n=81). Progression to secondary progressive multiple sclerosis (SPMS) was analysed in IM IFNβ1a participants who completed ≥50% of their surveys (n=630) and in PEG participants (n=102).

Results

At the first survey on treatment in IM IFNβ1a and PEG participants, the mean age was 49.7 and 53.0 years, respectively, the mean (standard deviation [SD]) disease duration was 11.1 (8.6) and 15.8 (7.9) years, respectively, and 8.4% and 91.2% had prior disease modifying therapy (DMT) use, respectively. The median PDDS score at the first survey was 2.0 for both populations, indicating moderate disability. The cumulative probability of remaining free of CDW was 77.6% and 43.6% at 2 and 11 years of IM IFNβ1a treatment, respectively, and 84.4% at 2 years of PEG treatment. The cumulative probability of participant-reported progression to SPMS was 1.2% and 12.0% at 2.5 and 11 years in IM IFNβ1a participants, respectively, and 3.3% at 2.5 years in PEG participants.

Conclusions

These results support clinical trial data showing the effectiveness of IM IFNβ1a and PEG in preventing CDW and demonstrate their long-term effectiveness in RMS patients.

This study is funded by Biogen. Biogen funded the analyses and writing support for this abstract. Writing support was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

Background

Studies examining the role of the microbiota in multiple sclerosis (MS) often focus on the gut bacteria; few have considered a potential role of gut mycobiota. Methods for evaluating gut mycobiota are lacking and require systematic evaluation of sequencing protocols, reference databases, and bioinformatics pipelines to properly investigate possible gut mycobiome influences on MS.

Objectives

We set out to evaluate the performance of different sequencing conditions and analytical approaches for characterizing the gut mycobiome in a cohort of healthy individuals and cases with monophasic acquired demyelinating syndrome (mono ADS) or pediatric-onset MS.

Methods

We first assessed a mock-community control pool of known, staggered quantities of 19 defined fungal organisms. We then assessed 201 stool samples obtained from our cohort of 52 healthy individuals, 49 individuals with mono ADS, and 46 participants with pediatric-onset MS. The fungal internal transcribed spacer (ITS) 2 region was sequenced using the Illumina® MiSeq platform. Varying concentrations of PhiX Control v3 Library spike-in were tested to address low-complexity amplicon sequencing. Generated sequences were characterized by the UNITE database—a curated collection of eukaryotic ITS sequences—in conjunction with three distinct fungal sequence analysis pipelines: LotuS, mothur, and PIPITS.

Results

Taxa identified in our mock-community differed across sequencing conditions but were similar between technical replicates. LotuS correctly classified 7 taxa at species-level, 7 taxa at genus-level, whereas 5 remained unclassified. Mothur correctly identified 5 species-level taxa, 11 genus-level taxa, whereas 3 remained unclassified. Lastly, PIPITS correctly identified only 3 species-level taxa, 12 genus-level, while 4 remained unclassified. We successfully generated sequence data for 112 of 147 (76%) individuals (70 females; 42 males). The mean age at stool sample collection was 17.3 (SD 5.1) years. Of the tested sequencing conditions, a spike-in of 50% PhiX produced the highest-quality reads.

Conclusions

The LotuS pipeline best identified fungal taxa in our mock-community, with optimal resolution to species level. Sequencing read quality was optimal when 50% PhiX was used for sequencing ITS2 amplicon libraries of stool samples. Establishment of this validated sequencing pipeline, confirmed using a mock-community with known fungal identities, will aid characterization of gut mycobiomes for our cohort of individuals with/without pediatric-onset MS.

Background

Adverse childhood experiences (ACE) encompass abuse, neglect and household dysfunction, such as parental divorce or mental illness, in early life. ACE may increase the risk of adverse physical and psychiatric health outcomes. A prior study showed an association between multiple sclerosis (MS) and ACE, but the impact of ACE on psychiatric comorbidity in MS and other immune-mediated inflammatory diseases (IMID) is not well-characterized.

Objectives

To determine whether ACE, specifically abuse and neglect, are associated with MS and other IMID, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). We further aimed to determine the relationship between ACE and psychiatric comorbidity in the IMID population and whether these relationships differed between MS and other IMID.

Methods

There were 925 adult participants in this study, across five cohorts (MS: 232, IBD: 216, RA: 130, anxiety and depression [ANX/DEP]: 244, healthy control: 103). A structured psychiatric interview was used to identify psychiatric disorders. The validated Childhood Trauma Questionnaire was used to evaluate five types of ACE: emotional abuse (EA), physical abuse, sexual abuse, emotional neglect and physical neglect. We evaluated associations between ACE, IMID and psychiatric comorbidity using multivariable binary and ordinal logistic regression models.

Results

Overall, 66.2% of the participants had ≥1 category of ACE. Prevalence of ACE was similar across IMID groups, but higher than in healthy controls (MS: 63.8%, IBD: 61.6%, RA: 62.3%, ANX/DEP: 83.2%, control: 45.6%). Only EA was associated with increased odds of having an IMID (adjusted odds ratio [aOR] 2.37; 1.15-4.89). Presence of any ACE was associated with psychiatric comorbidity in the IMID cohort (OR 2.24; 1.58-3.16), but this association did not differ among MS, IBD and RA. Furthermore, in those with IMID, total number of ACE (aOR 1.36; 1.17-1.59) and EA (aOR 2.64; 1.66-4.21) were independently associated with increased odds of psychiatric comorbidity.

Conclusions

A history of ACE is more common in MS and other IMID than in a healthy population. ACE is associated with psychiatric comorbidity in IMID populations. Given the high burden of psychiatric disorders in the MS population, clinicians should be aware of the possible contribution of ACE, and the potential need for trauma-informed care strategies in these patients.

Background

Depression is associated with an increased risk of macrovascular disease and mortality in the general population. Depression is also the most frequent comorbidity in people with multiple sclerosis (PWMS); however, it is unknown whether it might disproportionally affect the risk of vascular disease and all-cause mortality in PWMS as compared with the general population.

Objectives

Assess whether the association between depression, vascular disease, and mortality differs in PWMS as compared with the general population.

Methods

Population-based retrospective matched cohort study, which included PWMS diagnosed between 1-Jan 1987 and 30-Sep 2018 and registered with general practices in England, and up to 6 controls matched by age, sex, and general practice. We used Cox proportional hazard regression models to assess differences in the risk of any macrovascular disease (acute coronary syndrome, cerebrovascular,and peripheral arterial disease) and mortality. We included an interaction term between MS status and depression in the model. Covariates included sex, age, ethnicity, smoking status, diabetes, treatment with antidiabetic, anti-hypertensive, antilipid, anti-platelet, and anti-coagulant medications, deprivation index, number of primary care visits, and MS diagnosis year. Analyses were also stratified by sex. We present results as adjusted hazard ratios (HR), attributable proportion due to interaction (API), and 95% confidence intervals (95%CI).

Results

We matched 12,251 PWMS to 72,572 controls. 21% (2535) PWMS and 8.7% (6,278) controls had a depression diagnosis at index year. As compared with controls without depression, risk of any macrovascular disease was greater in controls with depression (HR 2.93, 95%CI 2.53-3.40), greater in PWMS without depression (HR 1.38, 95%CI 1.17-1.62), and greater in PWMS with depression (HR 3.53, 95%CI 2.83-4.40). Mortality risk was greater in controls with depression (HR 1.74, 95%CI 1.60-1.90), greater in PWMS without depression (HR 3.59, 95%CI 3.39-3.81), and 5-fold greater in PWMS with depression (HR 4.99, 95%CI 4.53-5.50). 13% of the combined effect of MS and depression on mortality was due to interaction (API 0.13, 95%CI 0.04-0.22). Differences were greater in men.

Conclusions

Depression is associated with increased risk of macrovascular disease and mortality in PWMS. The effect of depression and MS on mortality risk is synergistic overall and offers a clear treatment opportunity which is likely to be under-utilised.

Background

The efficacy of a disease-modifying drug (DMD) is typically established via brief clinical trials in highly selected groups. However, in clinical practice, DMDs are used for many years in a more diverse population of persons with multiple sclerosis (MS).

Objectives

The aim of the study was to describe the characteristics of a population with MS who are exposed to their first DMD in the real-world setting.

Methods

Using linked population-based health administrative data, we identified all individuals with MS aged ≥18 years who filled a prescription for a MS DMD in the province of British Columbia, Canada between 1996 and 2017. Individuals were followed from their first recorded demyelinating event to the earliest of death, emigration from the province, or study end (December 2017). We summarized cohort characteristics at their first filled DMD prescription (sex, age, socioeconomic status) and over the preceding year (comorbidity burden measured by the Charlson Comorbidity Index [CCI]).

Results

Overall, 4283 with MS filled a DMD prescription during the study period. Most were women (n=3132, 73%), with a mean (SD) age at the time of the first DMD prescription fill of 39.9 (9.9) years, and the socioeconomic status was distributed evenly across the income-based quintiles (neighborhood-level). Seventeen percent (n=741) had a CCI score ≥1. The most prevalent comorbidity was chronic pulmonary disease (n=235, 5%), followed by cerebrovascular disease (n=157, 4%) and diabetes (n=128, 3%). At the first DMD prescription fill, the proportion of women ranged from 63% (n=177/282) for dimethyl fumarate to 83% (n=15/18) for fingolimod. The mean (SD) age at first DMD prescription fill ranged from 37.2 (10.0) years for alemtuzumab to 43.0 (10.6) years for teriflunomide. Nearly 20% (n=724) were ≥50 years of age when they filled their first DMD prescription and 3% (n=108) were ≥60 years of age. From 1996-2012, the most common first DMD prescription filled was for either beta-interferon (n=2548/3190, 80%) or glatiramer acetate (n=612/3190, 19%). From 2013-2017, the most common first DMD prescription filled was for glatiramer acetate (n=379/1093, 35%), dimethyl fumarate (n=282/1093, 26%) or teriflunomide (n=182/1093, 17%).

Conclusions

Almost 1 in 5 persons with MS had at least some comorbidity at the time of initiation of their first DMD, while a minority were ≥60 years of age. As these individuals are often excluded from clinical trials, our data show an unmet need to understand the harms and benefits of DMD use in these understudied groups.

Background

Multiple sclerosis (MS) is associated with increased incidence and prevalence of some comorbidities including vascular disease and mood disorders. Although immigrants have lower incidence of MS than long-term residents in Ontario, Canada, comorbidity burden was associated with increased MS risk in immigrants.

Objectives

To compare prevalence of individual comorbidities in immigrants and long-term residents at MS diagnosis, and in matched control populations without MS.

Methods

We identified incident cases of MS aged 20-65 years using a validated case definition applied to health administrative data in Ontario, Canada from 1994-2017. Incident MS cases were categorized as immigrants or long-term residents. We identified two control populations of immigrants and long-term residents without MS matched 3:1 on sex, age and rurality status to MS cases. We identified comorbidities at MS diagnosis using validated administrative case definitions applied to the three years before MS diagnosis. We calculated prevalence ratios (PRs) of individual comorbidities for immigrants compared to long-term residents with MS and for both MS groups compared with their respective controls.

Results

There were 1,534 immigrants and 23,731 long-term residents with MS, as well as 4,585 immigrant and 71,193 long-term resident controls without MS. Common comorbidities in immigrants at MS diagnosis included mood or anxiety disorders (27.4%), hypertension (9.1%), and migraines (4.7%). Chronic obstructive pulmonary disease (COPD) (PR 1.68; 95%CI 1.17-2.40), diabetes (PR 2.57; 95%CI 1.86-3.55), ischemic heart disease (IHD) (PR 1.41; 95%CI 1.05-1.90), migraine (PR 2.12; 95%CI 1.73-2.60), epilepsy (PR 2.20; 95%CI 1.32-3.68), and mood/anxiety disorders (PR 1.97; 95%CI 1.78-2.17) were more common in immigrants with MS compared to immigrant controls. These comorbidities were also more common in long-term residents with MS than in long-term resident controls (p<0.05). Immigrants with MS had relatively higher prevalence of diabetes, migraine, and mood/anxiety disorders compared to long-term residents with MS.

Conclusions

Immigrants who develop MS have a high comorbidity burden and are more likely to be affected by comorbidities such as mood/anxiety disorders, migraine, diabetes, COPD, and IHD than other immigrants. Since comorbidities worsen long-term outcomes in MS, clinicians should pay close attention to identification and management of comorbidity in immigrants with MS.

Background

Previous studies have described extensive microstructural brain tissue abnormalities in pediatric MS patients. However, available techniques do not distinguish the extent to which such abnormalities are due to axonal loss or demyelination. Further, little is known about microstructural brain tissue changes in MOG-associated disorders (MOGad).

Objectives

To apply a combined analysis of magnetization transfer saturation (MT_sat) and multi-shell diffusion-weighted imaging (DWI) with computation of myelin and axonal volume fractions (MVF and AVF) and imaging g-ratio (the ratio between inner and outer diameter of the myelin sheath); to investigate the specific relationship between these metrics in the corpus callosum (CC) and within brain white matter lesions (WML) of pediatric MS and MOGad.

Methods

We acquired standardized 3T brain MRI in 26 healthy controls (HC) (58% females (F), mean age [years (y) (range)] 15y (9-19)); 16 MS (69% F, 17y (14-18), disease duration (DD) 3y (1-7), time from last relapse (TLR) 2y (0-6)); and 11 MOGad (72% F, 12y (8-18), DD 3y (0-6), TLR 1y (0-3), 8/11 relapsing). WML and CC were segmented according to establishes procedures. DWI processing was performed with FSL and DMIPy; MT_sat, MVF, AVF, and g-ratio were computed using the Jargon data management system. We used general linear models to model average MVF, AVF, and g-ratio in the CC and WML of each group, including the factors age, DD, and the interaction term group*DD. Models including sex were tested, and all exhibited lower AIC.

Results

Relative to HC, MS showed decreased CC MVF (-0.018/y, p=0.0304) and AVF (-0.0069/y; p=0.053) and corresponding increased CC g-ratio (0.0084/y, p=0.059) with increased DD. Relative to HC, MOGad showed decreased CC MVF (-0.017/y, p=0.0304) and AVF (-0.0081/y, p=0.014) with increased DD, without significant CC g-ratio changes. Both MS and MOGad showed decreased average WML MVF compared to HC WM (-0.19, p<10^-8; and -0.2, p<10^-8). MOGad also showed decreased average WML AVF (-0.067, p=0.0048) compared to HC. Average WML g-ratio was higher in MS than MOGad (0.17, p=0.0102), but not significantly different from HC in either group. WML MVF, AVF, and g-ratio did not change significantly with DD in MS or MOGad compared to HC.

Conclusions

Both pediatric MS and MOGad exhibited MRI correlates of axonal loss and demyelination in the CC and WML. Our measures of axonal loss in MOGad reinforces recent work warning of potentially long-term impacts on the brain from non-MS demyelinating pathologies.

Background

Multiple sclerosis (MS) and MOG-associated disorders (MOGad) are characterized by hyperintense white matter (WM) lesions on T₂/FLAIR MRI. Conventional imaging is sensitive but does not inform on the specific pathological substrate. Magnetization transfer saturation provides a good myelin measure, and multishell diffusion is sensitive to the axon + myelin assembly. Together, these can be modelled to estimate myelin volume fraction (MVF), axonal volume fraction (AVF) and imaging g-ratio.

Objectives

To quantify gradients of damage to axons and myelin in lesions and surrouding normal appearing white matter, in pediatric MS and MOGad.

Methods

15 MS [67% females (F), mean (range) age [years (y)]: 17y (14-18), disease duration (DD) 3y (0-6), time from last relapse (TLR) 2y (0-6)] and 7 MOGad [86% F, 13y (8-18), DD 3y (0-6), TLR 1y (0-3), 6/7 relapsing] participants received 3T brain MRI. MVF, AVF and g-ratio were computed according to established procedures. T₂ lesions were segmented according to standardized pipelines and WM masks by multi-atlas segmentation. Euclidean distance transforms labelled voxels in normal-appearing WM with the distance to the nearest lesion voxel, and voxels inside lesions with the distance to the nearest non-lesional WM voxel. Mean MVF, AVF and g-ratio were computed on each isodistant surface. Data were modeled using linear mixed models with distance, diagnosis, and their interaction. Knots were used at 0 and 2mm distance.

Results

MVF decreased towards the center of lesions (MOGad: -0.03/mm; MS: -0.05/mm; p values (ps)<0.002; difference n.s.) as did AVF (MOGad: -0.03/mm; MS: -0.01/mm; ps<0.0002; difference p=0.02); this graded damage extended to 2mm outside lesions. Beyond this, AVF continued to increase (MOGad: 0.001/mm; MS: 0.0003/mm; ps<10^-6; difference p<10^-6). Inside lesions, g-ratio increased towards the center in MS (0.03/mm, p<10^-6) and decreased in MOGad (p=0.15; MOGad-MS difference p<10^-4). G-ratio rose with distance outside lesions (MOGad: 0.001/mm; MS: 0.0004/mm; ps<10^-4; difference p<10^-5). AVF and g-ratio were similar between groups (within 2%) at 20mm from lesions; MVF was higher in MS (14%, p=0.08).

Conclusions

MS and MOGad showed myelin and axonal loss of decreasing severity with distance from lesion center, and this damage extended outside visible lesions. However, MOGad exhibited more severe axonal loss within and near lesions. The corresponding decreasing g-ratio relative to MS may indicate preferential loss of small axons in MS, or relatively better remyelination in MOGad.

Background

The gut microbiota may influence multiple sclerosis (MS) onset. Pediatric MS offers the opportunity to examine pathological processes close to risk acquisition.

Objectives

To examine the gut microbiota from stool samples of persons with pediatric onset MS, or monophasic acquired demyelinating syndromes (ADS) and unaffected controls in a case-control study.

Methods

Persons ≤21 years old with symptom onset <18 years of age with either MS (McDonald criteria) or ADS were eligible, as were unaffected controls with no known neurological or immune-mediated condition (migraine, asthma/allergies were permissible) were enrolled via the Canadian Pediatric Demyelinating Disease Network. Stools were collected between Nov/2015–Mar/2018, shipped on ice, and stored at -80°C. The 16S ribosomal RNA gene (V4 region) was amplified from extracted DNA and sequenced via the Illumina MiSeq platform. Amplicon sequence variants were used to compare the gut microbiota by disease status (MS/ADS/controls). The MS cases were also compared by disease-modifying drug (DMD) status (exposed/naïve). Negative binomial regression was used for genus-level analyses, with rate ratios adjusted (aRR) for age and sex.

Results

Of the 32/41/36 included MS/ADS/control participants, 24/23/21 were girls, averaging age 16.5/13.8/15.1 years at stool sample, respectively. The MS/ADS cases were 14.0/6.9 years at symptom onset. The 3 groups (MS/ADS/controls) were relatively similar for: body mass index (median: 22.8/19.7/19.9), presence of constipation (number of participants with a Bristol Stool Scale score of 1 or 2=8/9/7) and diet (% caloric intake for fat (median)=34/35/34 and for fibre (median)=9/10/11 g/day). Nine MS cases (28%) were DMD naïve. Gut microbiota diversity (alpha and beta) did not differ by disease (MS/ADS/controls), or DMD status (all p>0.1), while taxa-level findings did. For example, relative abundance of the Proteobacteria, Sutterella was depleted for MS cases vs controls and MS vs ADS cases (aRR:0.13;95%CI:0.03–0.59 and 0.21;95%CI:0.05–0.98), but did not differ for the ADS cases vs controls or by DMD status for the MS cases (all p>0.1). Several of the butyrate-producing genera within the Clostridia class (Firmicutes phylum) —Ruminococcaceae UCG−003, Lachnospiraceae UCG−008 and UCG−004—exhibited similar patterns.

Conclusions

Gut microbiota diversity was similar for individuals with pediatric MS relative to either monophasic ADS or unaffected controls. However, at the taxa-level, differences were observed which differentiated the MS cases from the monophasic ADS cases and controls.

Background

Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (PwMS). Currently, no treatments exist that substantially modify the course of clinical progression in MS, one of the greatest unmet needs in clinical practice. Characterizing the determinants of clinical progression is essential for the development of novel therapeutic agents and treatment approaches that target progression in PwMS.

Objectives

The overarching aim of CanProCo is to evaluate a wide spectrum of factors associated with the onset and rate of disease progression in MS, and to describe how these factors interact with one another to influence progression.

Methods

CanProCo is a prospective, observational cohort study aiming to recruit 1000 individuals with radiologically-isolated syndrome (RIS), relapsing-remitting MS (RRMS), and primary-progressive MS (PPMS) within 10-15 years of disease onset, and 50 healthy controls (HCs) from five large academic MS centers in Canada. Participants undergo detailed clinical evaluations annually. A subset of participants enrolled within 5-10 years of disease onset (n=500) also have blood, cerebrospinal fluid, and MRIs collected facilitating study of biological measures (e.g. single-cell RNA-sequencing[scRNASeq]), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and environmental factors as determinants contributing to the differential progression in MS.

Results

Recruitment commenced in April/May 2019 and n=536 patients have been recruited to date (RRMS=457, PPMS=35, RIS=25, HC=19). Baseline age, sex distribution, and Expanded Disability Status Scale (EDSS) scores (median, range) of each subgroup are: RRMS=38 years, 73% female, EDSS=1.5 (0-6.0); PPMS=52 years, 40% female, EDSS=4.0 (1.5-6.5); RIS=41 years, 68% female, EDSS=0 (0-3.0); HC=37 years, 63% female. Recruitment has surpassed the 50% target but has been paused due to the COVID-19 pandemic. scRNASeq on frozen blood samples has been validated.

Conclusions

Halting the progression of MS is a fundamental clinical need to improve the lives of PwMS. Achieving this requires leveraging transdisciplinary approaches to better characterize mechanisms underlying clinical progression. CanProCo is the first prospective cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Background

Ocrelizumab (OCR) was approved for relapsing and primary progressive forms of multiple sclerosis (MS) in 2017. Patient-reported outcome data among patients initiating OCR in clinical practice is limited.

Objectives

To evaluate the characteristics, experience and outcomes of participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who initiated OCR.

Methods

NARCOMS is a voluntary registry enrolling persons with MS who update their information using semi-annual surveys. This analysis included participants initiating OCR between April 2017 and April 2019, including a subset of participants who completed 1-year follow-ups. Outcomes included Patient Determined Disease Steps (PDDS), relapses, health care utilization and employment (i.e. employed/unemployed status, absenteeism). Changes from baseline for the subgroup who completed 1-year surveys were evaluated using the nonparametric Wilcoxon-Signed Rank or McNemar’s tests.

Results

During the study period 829 participants initiated OCR. They had a mean [SD] age of 56.6 [10.6] years and time since diagnosis of 18.7 [9.9] years. Most participants were female (75.3%). The most common clinical course was relapsing-remitting (45.4%) followed by secondary progressive (32.1%) and primary progressive (22.6%). The median (interquartile range [IQR]) PDDS was 5.0 [3.0–6.0]. Similar baseline characteristics were observed in the subgroup of 435 participants who had ≥1 year of follow-up (median [IQR] follow-up, 1.5 [1.0–2.0] years). In this subgroup, participants were less likely to report a steroid-treated relapse at 1 year (7.7%) compared with baseline (1-year lookback, 4.7%; p=0.04), although no differences were observed with respect to emergency room or hospital admissions. More than half of participants reported either improvement (40.7%) or no change (15.3%) on the PDDS; 44% reported worsening. Among employed participants at baseline (n=139), 8% reported leaving the workforce during follow-up; among those who remained employed, fewer reported missing work in the follow-up year (33.9%) compared with baseline (1-year lookback; 46.5%; p=0.003).

Conclusions

Participants initiating ocrelizumab in the NARCOMS registry are representative of a prevalent MS population, consistent with the full registry population. Patients with longitudinal follow-up on ocrelizumab reported fewer relapses and lower work absenteeism, with no differences in health resource utilization compared to baseline.