Welcome to the WCN 2021 Interactive Program

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Displaying One Session

Free Communication
Session Time
09:30 - 11:00
Room
Free Communication C
Chair(s)
  • Francesco Patti (Italy)
Free Communication

INTERLEUKIN-17 AXIS IN THE MODULATION OF CORTICAL AND SUBCORTICAL SYNAPTIC PLASTICITY ACROSS DISEASE STAGES IN EXPERIMENTAL MULTIPLE SCLEROSIS

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
09:30 - 09:40
Presenter
  • Andrea Mancini (Italy)

Abstract

Background and Aims:

Interleukin-17A (IL-17) is known to be deeply involved in the immunopathogenesis of multiple sclerosis (MS), but recent reports suggest that it may also participate in synaptic modulation. The aim of our study was to explore the role exerted by IL-17 axis in the regulation of hippocampal and striatal synaptic plasticity in physiological conditions and across different stages of experimental MS.

Methods:

Electrophysiological recordings were performed in the hippocampus (CA1 area) and in the striatum of control mice, mice affected by experimental autoimmune encephalomyelitis (EAE) and mice lacking IL-17 or IL-17 receptor (IL-17R). IL-17 levels were assessed through ELISA assays and IL-17 and IL-17R expression patterns through immunohistochemical analysis.

Results:

Functional IL-17 axis is required for physiological hippocampal and striatal synaptic plasticity, since the absence of IL-17R and the exposure to high IL-17 levels were associated with altered LTP induction. Hippocampal long-term potentiation (LTP) was disrupted during pre-acute and acute EAE phases, in parallel with increased IL-17 hippocampal expression levels. The recovery phase of EAE was characterized by a restoration of hippocampal LTP and by a reduction of IL-17 production. Hippocampal-dependent cognitive tasks are preserved when EAE is induced in mice lacking IL-17. Immunohistochemical analysis suggested that microglial-produced IL-17 may directly act on IL-17Rs expressed by hippocampal neurons. The inhibition of IL-17R axis (p38MAPK) or the in vitro exposure to anti-IL-17 antibodies limited the IL-17-dependent disruption of hippocampal LTP.

Conclusions:

Targeting IL-17 axis may help counteract the loss of brain plastic properties contributing to disease progression and cognitive impairment during MS.

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Free Communication

LONG-TERM DISABILITY PROGRESSION IN CHILDHOOD AND ADOLESCENT ONSET MULTIPLE SCLEROSIS PATIENTS

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
09:40 - 09:50
Presenter
  • Ermelinda De Meo (Italy)

Abstract

Background and Aims:

Early onset pediatric multiple sclerosis (MS) is extremely rare, occurring in 0.2-0.6% of all MS cases. The aim of this study is to describe and compare disease course and prognosis of early and late (ie, disease onset before and after age 11 years) onset pediatric MS.

Methods:

Prospectively collected clinical information from Italian MS Register from 1993 pediatric MS patients, of whom 172 with early onset, was analyzed. Cox proportional hazards regression models adjusted for sex and disease-modifying treatments (DMT) exposure were used to assess the risk of reaching confirmed Expanded Disability Status Scale (EDSS) scores of 3, 4, and 6 in early vs late onset pediatric MS, along with prognostic factors.

Results:

A greater proportion of males, isolated brainstem involvement, and longer time to first relapse was observed in early vs late onset pediatric MS patients. Compared to late onset, early onset pediatric MS patients took longer time from disease onset to convert to a secondary progressive phenotype and to reach all 3 disability milestones, thus reaching them at the same age. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease and DMT exposure were independent predictors for long-term disability in early onset pediatric MS patients.

Conclusions:

The different natural history of early vs late onset pediatric MS underscores the existence of specific pathophysiological mechanisms as well as a greater capability to counteract damage in early onset pediatric MS patients.

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PREVALENCE OF 2-YEAR “NO EVIDENCE OF DISEASE ACTIVITY” (NEDA-3 AND NEDA-4) IN RELAPSING-REMITTING MULTIPLE SCLEROSIS. A REAL-WORLD STUDY.

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
09:50 - 10:00
Presenter
  • Veronica Bazzurri (Italy)

Abstract

Background and Aims:

No evidence of disease activity (NEDA) is becoming a gold standard in the evaluation of disease modifying therapies (DMT) in relapsing-remitting multiple sclerosis (RRMS). NEDA-3 status is defined as the absence of clinical relapses, disability progression, and new/enlarging/enhancing lesions on brain MRI. NEDA-4 meets all NEDA-3 criteria plus an annualized brain volume loss (a-BVL) <0.4%. Aim of this study was to investigate the prevalence of two-year NEDA-3, NEDA-4, six-month delayed NEDA-3 (6mdNEDA-3), and six-month delayed NEDA-4 (6mdNEDA-4) in a cohort of patients with RRMS referred to an Italian tertiary MS Centre. Six-month delayed measures were introduced to consider latency of action of drugs and the phenomenon of pseudoatrophy.

Methods:

Observational retrospective monocentric study. All the patients with RRMS starting DMT between 2015 and 2018, and with 2-year follow-up, were included. a-BVL was calculated by SIENA software.

Results:

We included 108 patients, 84 of whom treated with first line DMT and 24 with second line DMT. At 2-year follow-up, 50% of patients were 6mdNEDA-3, 35% NEDA-3, 28% 6mdNEDA-4, and 17% NEDA-4. Loss of NEDA-3 status was mainly driven by MRI activity (70%), followed by relapses (56%), and only minimally by disability progression (7%). NEDA-3 and 6mdNEDA-3 patients had had fewer relapses in the two years preceding DMT start vs nonNEDA (p=0.03 and p=0.001, respectively).

Conclusions:

In our cohort 2-year-NEDA status, especially including lack of brain atrophy, was hardly achieved. Further studies are needed to establish the prognostic value of NEDA-3, 6mdNEDA3, NEDA-4, and 6mdNEDA4 in long-term follow-up.

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Free Communication

COMPARATIVE EFFECTIVENESS OF EARLY INTENSIVE OR ESCALATION TREATMENT STRATEGIES ON LONG TERM DISABILITY TRAJECTORIES IN RELAPSING MULTIPLE SCLEROSIS PATIENTS

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
10:00 - 10:10
Presenter
  • Pietro Iaffaldano (Italy)

Abstract

Background and Aims:

How aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) is still a matter of debate.

To evaluate long-term disability trajectories in RRMS patients treated with two different therapeutic strategies: early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods:

RRMS patients with ≥5-year follow-up and ≥3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received, as first DMT natalizumab, fingolimod, alemtuzumab, ocrelizumab, cladribine, mitoxantrone,. ESC group patients received the high efficacy DMT after ≥1 year of injectables DMTs, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS)-matched for characteristics at the first DMT. A longitudinal model for repeated measures was applied to evaluate the disability trajectories. To estimate the effect of early versus late start of high-efficacy DMT the mean annual EDSS changes were compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results:

2,702 patients were included in our study cohort. After PS matching procedure 363 pairs were retained. The median (IQR) follow-up was 8.5 (6.5–11.7) years. The ESC strategy was associated with a faster EDSS increase over time in comparison to the EIT (p<0.02). The mean delta-EDSS differences between the two groups increased from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions:

Our findings indicate a higher effectiveness of EIT than ESC strategy in slowing disability worsening over time.

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Free Communication

GENETIC FACTORS IMPLICATED IN THE RESPONSE TO FINGOLIMOD TREATMENT IN MULTIPLE SCLEROSIS PATIENTS: RESULTS FROM A PHARMACOGENETIC META-ANALYSIS

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
10:10 - 10:20
Presenter
  • Laura Ferrè (Italy)

Abstract

Background and Aims:

Multiple Sclerosis (MS) is a complex disease with high heterogeneity in terms of clinical presentation and treatment response. Pharmacogenetics can help to develop a more personalized approach and to improve disease management. We report the results of a GWAS on fingolimod-treated relapsing-remitting MS patients.

Methods:

We included 4 cohorts of fingolimod-treated MS patients from San Raffaele Hospital, Milan, Italy (OSR1: 246 patients, OSR2: 98 patients), Brigham and Women’s Hospital, Boston, USA (USA: 136 patients) and the Centre Hospitalier Universitaire de Toulouse, France (CHUT: 81 patients). We classified treatment response according to the NEDA (no evidence of disease activity) criterion at 2 years and time to first relapse (TFR). We performed a GWAS separately on each cohort and meta-analyzed them using a fixed-effect model.

Results:

three genome-wide significant variants were associated with TFR: rs9397818A on chr6 increases the risk of an earlier relapse and has an eQTL effect in whole blood on TFB1M, key to mitochondrial gene expression, and TIAM2, implicated in endothelial function and cell migration; rs2071572A is a risk allele intronic to synaptotagminV, involved in exocytosis of secretory vesicles, with an eQTL effect in brain cortex; finally the risk allele rs6124768A maps to CD40 locus and increases its expression according to a public eQTL database. No significant variants were identified in the NEDA analysis.

Conclusions:

genetic variants possibly implicated in cell migration, neuronal functions and immune response were associated with response to fingolimod. Functional studies are ongoing.

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Free Communication

EFFECTIVENESS OF AUTOLOGOUS HAEMATOPOIETIC STEM CELL TRANSPLANTATION AND CONVENTIONAL IMMUNOSUPPRESSION IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS: A RETROSPECTIVE PROPENSITY-MATCHED CASE-CONTROL STUDY

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
10:20 - 10:30
Presenter
  • Alice Mariottini (Italy)

Abstract

Background and Aims:

Autologous haematopoietic stem cell transplantation (AHSCT) suppresses relapses but its effect on disability progression in secondary-progressive multiple sclerosis (SP-MS) seems moderate, and the benefit/risk ratio is still controversial. The effectiveness of AHSCT was therefore evaluated in SP-MS comparing it with conventional immunosuppression with cyclophosphamide (Cy).

Methods:

SP-MS patients treated with AHSCT or Cy were retrospectively included and propensity-score matched according to baseline clinical-demographic characteristics. AHSCT procedure: BEAM+ATG; Cy treatment: monthly i.v. infusions (0.75 gr/m2), over a 3 years-period. Time to event was estimated by Kaplan-Meier analysis and adjusted using Cox-regression model.

Results:

93 SP-MS were included: 31 AHSCT; 62 Cy. Disability progression free-survival at year 5 was 70% in the AHSCT group and 75% in the Cy group (not significant); survival free from EDSS worsening was similar in the two groups, being 43% and 47% in the AHSCT and Cy groups respectively (not significant). Annualized-relapse rate significantly dropped from pre-treatment in both groups (p<0.0001): from 0.56 (95%CI 0.3-0.7) to 0.00 (95%CI 0.0–0.0) in AHSCT and from 0.45 (95%CI 0.3-0.5) to 0.20 (95%CI 0.10–0.30) in Cy, but survival-free from relapses was significantly higher for AHSCT than for Cy cases (100% vs 52% respectively at 3 years, p<0.0001).

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Conclusions:

In SP-MS effectiveness of AHSCT on disability was similar to that of Cy, whereas it was remarkably superior as for relapses suppression. These data suggest that the risk/benefit ratio of AHSCT needs further evaluation in SP-MS and confirm that disability progression becomes independent from relapses in advanced MS, as probably based more on neurodegeneration than on inflammation.

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Free Communication

CSF TAU PROTEIN CORRELATES WITH COGNITIVE IMPAIRMENT IN MULTIPLE SCLEROSIS PATIENTS AT DIAGNOSIS

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
10:30 - 10:40
Presenter
  • Eleonora Virgilio (Italy)

Abstract

Background and Aims:

Cognitive impairment (CI) is a frequent and disabling symptom in Multiple Sclerosis (MS). Axonal damage may contribute to CI development from early stages. Nevertheless, no biomarkers are at the moment available to track CI in MS patients. We aimed to explore the correlation of cerebrospinal fluid (CSF) axonal biomarkers, in particular: light-chain neurofilaments (NFL), Tau, and Beta-amyloid protein (Abeta) in MS patients with CI at the diagnosis.

Methods:

We enrolled 60 newly-diagnosed MS patients and cognition was evaluated using Brief International Cognitive Assessment for MS (BICAMS) battery, which includes the Symbol Digit Modalities Test (SDMT) for the assessment of information processing speed (IPS). NFL, Abeta, and Tau levels were determined with commercial ELISA.

Results:

Of our patients (40 female, mean age of 40 years old), 22 had CI defined as a T-score below 35 (equivalent to z-score below -1.5) in at least one of the three tests of BICAMS. Patients with CI showed greater neurodegeneration; in particular subjects with slowed IPS exhibited higher mean CSF Tau protein (176.8 ± 54.4 pg/ml versus 137.1 ± 60.3 pg/ml p:0.01) and SDMT T-score and Tau were significantly correlated (r:-0.31 p:0.01).

Conclusions:

CI has an important burden on the quality of life of MS patients and should be looked for even at diagnosis. BICAMS easily detects CI in newly-diagnosed MS patients. Axonal damage biomarkers seem to reflect cognition in early stages. Few data are reported in literature, and to our knowledge, our study is the first indicating a possible role of Tau protein in that process.

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Free Communication

ASSESSMENT AND MANAGEMENT OF INFECTIOUS RISK IN MULTIPLE SCLEROSIS PATIENTS TREATED WITH DISEASE-MODIFYING THERAPIES

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
10:40 - 10:50
Presenter
  • Maria Antonella Zingaropoli (Italy)

Abstract

Background and Aims:

We aim to define the infectious risk in DMT-treated MS patients with approaches tailored to individual patients.

Methods:

At the Neuroinfectious Unit of Policlinico Umberto I Hospital, Sapienza University of Rome, MS patients were evaluated for infectious risk before starting, switching or during DMT-treatment. The evaluation consisted in two levels: a first level common to each patient and a second-one specific for those positive patients at the first level.

Results:

From February 1, 2018 to April 1, 2021, 174 MS patients were enrolled. The first level identified 18 patients with anti-HBc+, 4 patients with anti-HCV+, 19 patients with QuantiFERON®-TB Gold In-Tube (QFT)+. A specific second level was performed. No anti-HBc+ patients showed a detectable HBV-DNA. These patients were defined as past HBV infected and started DMT-treatment. No anti-HCV+ patients showed HCV-RNA detectable, thus patients started DMT-treatment. Among QTB+ patients the second level infectious risk assessment identified 17 latent TB infection (LTBI) and 2 active TB infection. After one month of LTBI prophylaxis or TB treatment, respectively, patients started DMT. During DMT-treatment one ocrelizumab-treated anti-HBc+ patient revealed HBV reactivation, one IFN-β-treated, three natalizumab-, two ocrelizumab-treated patients showed a reactivation of HSV-1, one cladribine-treated patient showed a VZV reactivation. No TB reactivation was observed. All the latent infection reactivations have been successfully treated.

Conclusions:

Extensive screening of infectious disease should be recommended in MS patient candidate for DMTs to mitigate the infectious risk. During DMT-treatment, a regular assessment of infectious risk allows to avoid discontinuing MS therapy and guarantee the safety of the patient.

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Free Communication

LIVE Q&A

Session Type
Free Communication
Date
05.10.2021, Tuesday
Session Time
09:30 - 11:00
Room
Free Communication C
Lecture Time
10:50 - 11:00