Free Communications Sun, Sep 13, 2020
Moderators
  • K. Selmaj
  • F. Zipp
Session Type
Free Communications
Date
Sun, Sep 13, 2020
Time (ET)
13:00 - 14:15
Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

FC01.01 - Long-term efficacy and safety of eculizumab monotherapy in AQP4+ neuromyelitis optica spectrum disorder

Speakers
  • S. Pittock
Authors
  • S. Pittock
  • K. Fujihara
  • J. Palace
  • A. Berthele
  • H. Kim
  • C. Oreja-Guevara
  • I. Nakashima
  • M. Levy
  • A. Pace
  • M. Yountz
  • L. Miller
  • R. Armstrong
  • D. Wingerchuk
Presentation Number
FC01.01
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
13:00 - 13:12

Abstract

Background

In the randomized, double-blind, placebo-controlled, phase 3 PREVENT trial (NCT01892345), eculizumab was well tolerated and significantly reduced relapse risk vs placebo in patients with aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). The treatment effect observed in a prespecified subgroup of patients who received eculizumab monotherapy vs placebo alone (i.e. without concomitant immunosuppressive therapy [IST]) was consistent with the overall population.

Objectives

To examine the long-term efficacy and safety of eculizumab monotherapy in patients with AQP4+ NMOSD during PREVENT and/or its ongoing open-label extension (OLE; NCT02003144).

Methods

During PREVENT and its OLE, adults with AQP4+ NMOSD received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (PREVENT only) with/without concomitant IST. Relapses, hospitalizations, IST changes and adverse events (AEs) with eculizumab monotherapy (PREVENT and its OLE; interim data cut-off, July 31, 2019) or with placebo alone (PREVENT) were descriptively analyzed post hoc.

Results

During PREVENT and/or its OLE, 33 patients received eculizumab monotherapy for a total of 85.3 patient-years (PY). Adjudicated relapses occurred in 1/33 patients (annualized relapse rate [ARR], 0.012; 95% confidence interval [CI]: 0.002–0.082), vs 7/13 with placebo alone in PREVENT. At 192 weeks, 96.2% of patients who received eculizumab monotherapy were relapse-free (95% CI: 0.757–0.994) vs 93.8% of patients who received eculizumab with concomitant IST (95% CI: 0.867–0.972). No patients receiving eculizumab monotherapy required hospitalization for a relapse and none started an IST. The treatment-related AE rate with eculizumab monotherapy in PREVENT and its OLE was similar to that with placebo alone in PREVENT (181.0 and 186.0 events/100 PY, respectively), the infection rate was similar between these groups (174.1 vs 186.0 events/100 PY), and the treatment-related serious AE rate was lower with eculizumab monotherapy than with placebo alone (5.7 vs 23.3 events/100 PY). No meningococcal infections or deaths occurred among these patients.

Conclusions

A very high proportion of patients who had experienced 1–2 relapses in the pre-study year remained relapse-free through 192 weeks of eculizumab monotherapy. Long-term eculizumab monotherapy was well tolerated. These data support the long-term effectiveness of eculizumab monotherapy in reducing relapse risk in AQP4+ NMOSD.

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Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

FC01.02 - Efficacy and safety of eculizumab in patients with neuromyelitis optica spectrum disorder previously treated with rituximab: findings from PREVENT

Speakers
  • M. Levy
Authors
  • M. Levy
  • A. Berthele
  • H. Kim
  • K. Fujihara
  • I. Nakashima
  • C. Oreja-Guevara
  • J. Palace
  • S. Pittock
  • M. Terzi
  • N. Totolyan
  • S. Viswanathan
  • K. Wang
  • A. Pace
  • M. Yountz
  • D. Lawson
  • E. Laudon-Meyer
  • D. Wingerchuk
Presentation Number
FC01.02
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
13:12 - 13:24

Abstract

Background

In PREVENT, eculizumab was associated with a significant reduction in relapse risk versus placebo and was well tolerated. In total, 46 patients (26/96 in the eculizumab arm, 20/47 in the placebo arm) were previously treated with the monoclonal antibody rituximab.

Objectives

To describe the efficacy and safety of eculizumab in patients in the PREVENT trial (NCT01892345) who had previously received rituximab.

Methods

Adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo with/without concomitant immunosuppressive treatment (except rituximab/mitoxantrone). A post hoc descriptive analysis was performed using data from patients with any prior rituximab treatment (within the previous year only for review of adverse events [AEs]) recorded more than 3 months before randomization.

Results

Baseline characteristics of the prior-rituximab subgroup were similar to those of the total PREVENT population; however, the subgroup included a lower proportion of Asian patients (10.9% vs 36.4% in total PREVENT) and greater representation from the Americas (58.7% vs 30.8%). In the subgroup, median times from last dose of rituximab to meningococcal vaccination and to first dose of study treatment were 31.7 and 38.7 weeks, respectively. Adjudicated relapses occurred in 1/26 patients (3.8%) and 7/20 patients (35.0%) in the eculizumab and placebo arms (hazard ratio: 0.093; 95% confidence interval: 0.011–0.755; p = 0.0055), respectively. Rates of AEs for eculizumab and placebo were 1025.8 and 1029.1 events/100 patient-years (100% of patients), respectively, and rates of serious AEs were 46.9 and 66.0 events/100 patient-years (38.9% and 47.1% of patients), respectively. Serious infections/infestations were recorded in 2/18 patients (11.1%) and 2/17 patients (11.8%) in the eculizumab and placebo arms, respectively.

Conclusions

In patients in PREVENT who had previously received rituximab, the risk of adjudicated relapse was significantly lower with eculizumab than with placebo. Rates of serious infections were similarly low with eculizumab and placebo.

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Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

FC01.03 - Effect of satralizumab on relapse severity in neuromyelitis optica spectrum disorder (NMOSD): results from the Phase III SAkura studies

Speakers
  • I. Kleiter
Authors
  • J. Palace
  • I. Kleiter
  • A. Traboulsee
  • T. Yamamura
  • F. Patti
  • D. Stokmaier
  • G. Klingelschmitt
  • T. Kuenzel
  • H. Von Büdingen
  • J. Bennett
Presentation Number
FC01.03
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
13:24 - 13:36

Abstract

Background

NMOSD is an autoimmune disorder characterized by acute, unpredictable relapses that result in accumulating disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced relapse frequency and had a favourable safety profile vs placebo in two randomized, phase 3 clinical trials: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To assess the impact of satralizumab on relapse severity in patients with NMOSD.

Methods

Patients in the SAkura studies received satralizumab 120mg or placebo at Weeks 0, 2, 4, and Q4W thereafter. This analysis was performed using data from the pooled intention-to-treat population across the double-blind periods of both studies. We assessed the severity of protocol-defined relapses (PDRs) by comparing patients’ Expanded Disability Status Scale (EDSS) score at PDR vs their score prior to relapse (last scheduled study visit). A similar analysis on optic neuritis PDRs was performed using visual Functional Systems Score (FSS). A PDR was categorised as severe if it resulted in a change of ≥2 points on the EDSS or visual FSS (optic neuritis analysis). Kaplan-Meier analyses were performed to assess time to first severe PDR. Additionally, the number of patients receiving acute therapy for any relapse was compared between treatment groups.

Results

Overall, 178 patients were included in the analyses. In the satralizumab group, 27 of 104 patients (26%) experienced a PDR vs 34 of 74 patients (46%) in the placebo group. The proportion of PDRs that were severe was lower in patients receiving satralizumab vs placebo (5 of 27 events [19%] vs 12 of 34 events [35%]). Similarly, the proportion of optic neuritis PDRs that were severe was lower in patients receiving satralizumab vs placebo (2 of 8 events [25%] vs 5 of 13 events [39%]). Across all patients, there was a 79% reduction in severe PDR risk with satralizumab vs placebo (hazard ratio [95% CI]; 0.21 [0.07–0.61]; p=0.002). A lower proportion of patients receiving satralizumab were prescribed acute relapse therapy vs placebo (38% vs 58%; odds ratio [95% CI] 0.46 [0.25–0.86], p=0.015).

Conclusions

Patients treated with satralizumab had a lower risk of severe relapse, and were less likely to receive acute relapse therapy compared with placebo. The number of patients with severe PDRs was low, so results should be interpreted with caution.

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Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

FC01.04 - Ependymocyte: a new target for aquaporin4-IgG in NMO?

Speakers
  • M. Bigotte
Authors
  • M. Bigotte
  • A. Ruiz
  • M. Poinsot
  • P. Giraudon
  • G. Malleret
  • P. Salin
  • R. Marignier
Presentation Number
FC01.04
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
13:36 - 13:48

Abstract

Background

Ependyma forms the epithelial interface boarding the ventricular walls and the spinal cord’s central canal, maintaining crucial central nervous system functions such as the regulation of cerebrospinal fluid (CSF) circulation by synchronous ciliary beating and the monitoring of molecular exchanges between CSF and parenchyma. These functions are dependent of the cellular coupling via gap junction channels.

Neuromyelitis Optica (NMO) is associated with autoantibodies (NMO-IgG), directed against aquaporin 4 (AQP4). NMO-IgG are present in patient’s serum and CSF during attacks, and are known to trigger astrocyte dysfunction leading to demyelination and axonal loss. Interestingly, ependymal cells also express AQP4 and evidences of ependymal alteration have been reported in NMO. Indeed, MRI abnormalities of the ventricles have been reported, and pathological analyses showed AQP4 loss in the ventricular walls of NMO patients.

Objectives

Our aim is to evaluate if NMO-IgG target ependymal cells, and lead to ependymal morphological changes and dysfunctions.

Methods

We used purified NMO-IgG from AQP4 antibodies positive patients’ plasma (NMO-IgG AQP4+). IgG from healthy donors (CTRL-IgG) and IgG from AQP4-antibodies negative patients (NMO-IgG AQP4-) were used as controls. We evaluated ependymal cells on two models: primary ependymal cell cultures and cultured wholemount dissections (“en-face” view of the entire ependyma) of adult rat lateral ventricular walls. We first looked at the effect of different IgGs on the expression of AQP4 and Connexin43, the main gap junction channel expressed by ependymal cells. Then, we assessed the ciliary beating of ependymal cells by analyzing the diffusion of india ink deposited on wholemount preparations. Coupling of ependymal cells in culture was evaluated by measuring the diffusion of Lucifer Yellow (LY), a gap junction specific dye incorporated in cells by scrape loading.

Results

We showed that NMO-IgG AQP4+ exposure induced: 1) the delocalization of AQP4 membrane expression and morphological changes of ependymal cells from primary cultures and wholemounts, by contrast different IgG controls had no effect; 2) morphological changes of cilia in primary cultures and alteration of the ciliary dynamic; 3) the alteration of Connexin43 expression and function, demonstrated by the decrease of LY spreading after scrape loading.

Conclusions

These results suggest that NMO-IgG directly induce dysfunctions of ependymal cells, through the perturbation of AQP4 and Cx43 expression and functions.

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Diagnostic Criteria and Differential Diagnosis Oral Presentation

FC01.05 - GFAP auto-immunity: a French cohort study

Speakers
  • A. Gravier Dumonceau
Authors
  • A. Gravier Dumonceau
  • R. Ameli
  • V. Rogemond
  • G. Picard
  • M. Benaiteau
  • K. Deiva
  • T. De Broucker
  • L. Kremer
  • J. Honnorat
  • R. Marignier
Presentation Number
FC01.05
Presentation Topic
Diagnostic Criteria and Differential Diagnosis
Lecture Time
13:48 - 14:00

Abstract

Background

Glial fibrillar acidic protein (GFAP) autoimmunity is a recently identified disease, at the frontier of auto-immune encephalitis and gliopathies. Clinical features associated to this new entity are still not fully evaluated; especially the risk of relapse and the disability outcome.

Objectives

To report the clinical, biological, imaging features, and the clinical course of a French cohort of patients with GFAP autoantibodies.

Methods

We retrospectively included all patients tested positive for GFAP antibodies since 2017, from two French referral centers (auto-immune encephalitis and rare inflammatory disorders of the brain and the spinal cord). GFAP autoantibodies were detected exclusively in the CSF, by immunohistochemistry and their specificity confirmed by cell-based assay using cells expressing human GFAPα.

Results

We identified 46 patients with GFAP antibodies. Median age at onset was 43 years and men were more affected (30/46). Infectious prodromal symptoms were found in 82% of cases. Other autoimmune diseases were found in 22% of cases and coexisting neural autoantibodies in 11% of cases, including MOG-IgG and AQP4-IgG positive cases. Tumors were present in 24%, and T cell dysfunction in 23% of cases, respectively. The most frequent presentation was acute/subacute menigoencephalitis (85%) with cerebellar dysfunction in 57% of cases. Other/associated clinical presentation included: myelitis (30%), visual tract involvement (35%) and peripheral nervous system involvement (28%). CSF showed pleocytosis (98%), oligoclonal bands (77%) and low glucose level (15%). MRI findings were heterogeneous: radial enhancement was found in 26%, periventricular diffuse T2 hyperintensity in 39%, brainstem involvement in 33%, leptomeningeal enhancement in 23%, and reversible splenial lesions in 4 cases.

39/46 patients have a monophasic course, associated to a good outcome at last follow-up (Rankin Score≤2: 89% at 15,5 months), despite a frequently severe clinical presentation (intensive care unit hospitalization: 42%). Seventy patients were treated with immunotherapy. 11/22 patients showed negativation of GFAP antibodies (median time: 2 months).

Conclusions

GFAP autoimmunity was generally associated to a good outcome and a low risk of relapse. Identification of factors associated to risk of relapse or disability, to monitor immunotherapy, is needed.

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