University of Montreal
Neuroscience

Author Of 9 Presentations

Pathogenesis – the Blood-Brain Barrier Late Breaking Abstracts

LB1270 - DICAM : A new cell adhesion molecule involved in myeloid cells infiltration in Multiple Sclerosis (ID 2168)

Speakers
Presentation Number
LB1270
Presentation Topic
Pathogenesis – the Blood-Brain Barrier

Abstract

Background

Disruption of the blood-brain barrier (BBB) and migration of leukocytes from the periphery to the central nervous system (CNS) are early events in lesion formation during multiple sclerosis (MS). Among CNS-infiltrated leukocytes, macrophages and dendritic cells are important contributors to inflammation and tissue damage. They readily cross the BBB to infiltrate the CNS and express pro-inflammatory cytokines. Using proteomic and RNA sequencing techniques, we have identified Dual Ig domain containing Cell Adhesion Molecule (DICAM) as a new adhesion molecule expressed by human TH17 lymphocytes and BBB endothelial cells (ECs). The expression and function of DICAM in MS pathogenesis remain unexplored.

Objectives

The current study aims to evaluate DICAM’s role in monocytes/macrophages and dendritic cells migration to the central nervous system.

Methods

To explore the DICAM expression profile, we performed flow cytometry and qPCR on human BBB-ECs and immune cells subsets isolated from healthy control peripheral blood. Confocal microscopy, flow cytometry and qPCR have been performed to explore DICAM expression in MS lesions and on peripheral immune cells in situ and ex vivo. To further investigate the expression of DICAM by myeloid cells in patients with MS, we performed flow cytometry analysis of peripheral blood mononuclear cells from males and females patients with relapsing remitting MS (n= 19), secondary progressive MS (n= 19) and primary progressive MS (n= 21) aged and sex-matched with controls individuals (n= 39) samples. The role of DICAM in monocytes adhesion to the BBB-ECs was assessed in vitro by blocking DICAM in a flow adhesion assay on a monolayer of human BBB-ECs. Different animal models of MS (EAE) were also used to explore DICAM function in vivo.

Results

We first demonstrated that DICAM and its ligand αvβ3 are upregulated on the BBB within inflammatory lesions in the brains of MS patients. In peripheral blood preliminary results indicates that DICAM expression by myeloid DCs and classical monocytes is associated with RRMS and SPMS forms of the disease. Moreover, blockade of DICAM restricts the adhesion of monocytes on human BBB-ECs and decreases disease severity in several EAE models.

Conclusions

This study aims to characterize the interaction mediated by DICAM between infiltrating leukocytes and the BBB. This adhesion molecule might be involved in MS pathogenesis and therefore, could become a new therapeutic target for MS treatment.

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Biostatistical Methods Poster Presentation

P0018 - Variability of the response to immunotherapy among sub-groups of patients with multiple sclerosis (ID 1239)

Abstract

Background

Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited.

Objectives

To assess whether patients’ response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype.

Methods

Using the international MSBase registry, we selected patients with MS followed for ≥1 year, with ≥3 visits, ≥1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity.

Results

Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively].

Conclusions

DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. In general, the effectiveness of DMTs was most pronounced in subgroups with shorter MS duration, lower EDSS, lower relapse rate and relapsing MS phenotype.

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Clinical Outcome Measures Poster Presentation

P0106 - Long-term single-centre experience with natalizumab. (ID 365)

Speakers
Presentation Number
P0106
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (NZB) is a disease-modifying treatment (DMT) used in persons with MS (PwMS) with an active relapsing course, either as a first-line, or after previous treatments.

The principal biological effect of NZB is thought to be the blockade of the molecular interaction between α4β1-integrin (also known as very late antigen-4) expressed by mononuclear inflammatory cells, and vascular cell adhesion molecule-1 (CAM-1) expressed by cerebral vascular endothelial cells.

NZB is a potent DMT which must be monitored with caution, its use being hampered by the risk of opportunistic infections, mostly progressive multifocal leukoencephalopathy (PML).

Objectives

To document the efficacy and safety of NZB for the treatment of RRMS in a population of persons with MS (PwMS) followed in a regular MS Clinic setting.

Methods

We report our single-centre experience over a period of 13 years: from JAN 2007 through the end of May 2020.

All PwMS treated with NZB were included, regardless of the treatment duration.

The retainment of patients in our MS Clinic is 95%.

We use the iMed database, an international MS registry. .

Results

We report on 230 PwMS, 159 women, 71 men treated with NZB since 2007, up to 30 April 2020.

We had no PML case. We had 2 PML 'clinical alerts', but CSF search for JC virus (JCV) was negative.

There was no rebound of activity, nor IRIS, after NZB cessation, as we usually quickly switch to an alternative DMT.

Median age at MS onset: 26.3 years. Median age at NZB initiation: 35 years. Median disease duration before treatment: 8.07 years.

First line use: 94. Previous BRACE DMT: 136.

Risk factors: previous immuno-suppression: 7; NZB duration > 24 months: 112; JCV index > 1: 81.

Median treatment duration: 23 months; still active: 71 including 7 after > 6 years.

ARR at NZB onset: 1.5; during NZB: 0.27; current: 0.89.

Median EDSS at NZB start: 3.0. Current median EDSS: 2.8. EDSS stable: 65, worsened: 58; improved: 60.

MRI: stable: 133 (58%) ; improved: 5 (2%); worsened: 35 (25%).

Conversion to SPMS: 48 (20%) 29 W, 19 M.

Reasons for NZB cessation: planned: 27; pregnancy: 3; loss of efficacy: 39; increased JCV index: 62. No blood toxicity (CBC, ALT).

We had 9 pregnancies: 4 planned interruptions; 5 full term, with normal babies.

Treatment after NZB cessation: 48 fingolimod, glatiramer: 17; ocrelizumab: 16; others: 29; none: 32 (no rebound observed).

One patient had COVID 1 year after NZB: complete recovery; needed only nasal O2 during 3 day hospital admission.

Conclusions

NZB, when used with caution, is an effective and safe MS DMT during the RRMS phase, even after extended disease and treatment durations.

NZB is most effective to reduce relapse frequency, less effective against progression, as 20% of PwMS transited to the secondary progressive phase.

Gender, disease duration, and age do not influence outcomes.

We encountered no significant toxicity, in particular no PML.

Clinical, JCV index measures, and MRI monitoring are paramount to maintain safety.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0382 - Reduction in CUA MRI lesions in the first 6 months of cladribine tablets treatment for highly active relapsing multiple sclerosis: MAGNIFY-MS study (ID 982)

Speakers
Presentation Number
P0382
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.

Objectives

To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.

Methods

MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.

Results

The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).

Conclusions

MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.

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Observational Studies Poster Presentation

P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)

Abstract

Background

Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.

Objectives

We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).

Methods

Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).

Results

5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).

Conclusions

Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS

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Observational Studies Poster Presentation

P0907 - Real-world experience with Cladribine Tablets in the MSBase Registry (ID 1587)

Abstract

Background

Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited.

Objectives

We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with ≥6 months follow-up data from cladribine initiation.

Methods

We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS).

Results

As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow-up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%).

Conclusions

This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setting. First-line use was uncommon. ARR was low, consistent with clinical trial data, and early discontinuations were very rare.

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Observational Studies Poster Presentation

P0909 - Real-world experience with Ocrelizumab in the MSBase Registry (ID 1559)

Abstract

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses.

Objectives

In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with ≥6 months follow-up data from OCR initiation.

Methods

Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with ≥6 months follow-up data from OCR initiation.

Results

As of 4th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT’s in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had ≥6 months follow-up during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06-0.10), compared to an ARR of 0.85 in the 24 months pre-OCR start. In the overall cohort, treatment persistence at 12 and 24 months was 98.4% (95% CI: 97.3-9.1%) and 92.5% (95%CI 89-95%), respectively.

Conclusions

This study characterizes an international population of patients with RRMS, PPMS, and SPMS newly treated with OCR in a real-world clinical setting. First-line use was uncommon in RRMS and SPMS. During OCR treatment, ARR was below 0.1, and OCR discontinuations were very rare.

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Observational Studies Poster Presentation

P0919 - The Canadian Prospective Cohort (CanProCo) Study to Understand Progression in Multiple Sclerosis: Rationale and Baseline Characteristics  (ID 1236)

Speakers
Presentation Number
P0919
Presentation Topic
Observational Studies

Abstract

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.

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Gender Differences, Hormones and Sex Chromosomes Poster Presentation

P1142 - “The contribution of sex hormones to disease incidence and phenotype in the spontaneous TCR1640 mouse model.” (ID 1487)

Speakers
Presentation Number
P1142
Presentation Topic
Gender Differences, Hormones and Sex Chromosomes

Abstract

Background

TCR1640 transgenic mice, a model of spontaneous experimental autoimmune encephalomyelitis (EAE), are a powerful tool to study the sexual dimorphism seen in MS patients. Being at higher risk of developing EAE, TCR1640 females develop a relapsing-remitting (RR) disease course while male TCR1640 develop mostly a primary progressive (PP) form. Clinical observations in MS patients and other EAE models suggest a potentially protective role of sex hormones but their contribution to disease development remains to be elucidated.

Objectives

We aim to characterize the role of sex hormones, in both sexes, on multiple aspects of the MS course including disease incidence, phenotype and severity in a unique and relevant mouse model.

Methods

Gonadectomies have been performed on TCR1640 mice between 21-28 days postnatal, before onset of puberty (n= 22 males, n= 25 females). These mice, as well as sham control mice (n= 17 males, n= 21 females), were scored daily for signs of paralysis and ataxia and were followed up for >150 days.

Results

For both male and female TCR1640 mice, gonadectomy seems to affect disease incidence. Absence of sex hormones in males display a major protective role on the disease 75 days after surgery whereas the protective effect of female sex hormones becomes apparent ~90 days after surgery. Not only there are fewer male and females sham mice that do fall ill in theses period, but mice that do fall ill do so with delayed onset compared to their gonadectomized littermates. Preliminary results show that gonadectomy does not seem to affect disease phenotype for either sex. More advanced bioinformatical analysis will now be used to define different phenotype clusters based on EAE score evolution, allowing us to zoom in on the potential influence of sex hormones on each of these different phenotypes.

Conclusions

We have demonstrated that both male and female sex hormones have a potential protective role in the TCR1640 model, appearing to decrease disease incidence as well as delaying disease onset. Sex hormones however do not seem to control disease phenotype, strongly suggesting that the sexual dichotomy seen in clinical disease course is dictated by sex chromosomes rather than sex hormones.

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