AQP4-IgG-seronegative patient outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder

Marignier, Romain; Pittock, Sean J.; Paul, Friedemann; Kim, Ho Jin; Bennett, Jeffrey L.; Weinshenker, Brian G.; Wingerchuk, Dean M.; Green, Ari J.; Fujihara, Kazuo; Cutter, Gary; Aktaş, Orhan; Hartung, Hans‐Peter; Drappa, Jörn; Ratchford, John N.; She, Dewei; Smith, Michael; Rees, William; Cimbora, Daniel; Katz, Eliezer; Cree, Bruce A. C.

doi:10.1016/j.msard.2021.103356

Cited by 22 publications

(12 citation statements)

References 45 publications

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“…The overall AAR for both the RCP and OLE was 0.092 attacks/person-year [ 25 ]. A post hoc analysis of AARs in AQP4-antibody seronegative patients during the RCP and OLE suggested some benefit of inebilizumab in this subgroup [ 26 ].…”

Section: Therapeutic Efficacy Of Inebilizumabmentioning

confidence: 99%

Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Nie

Blair

2022

CNS Drugs

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Inebilizumab (Uplizna ® ) is a recently approved monoclonal antibody for use in adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody seropositive. Inebilizumab targets the B cell antigen CD19 and effectively depletes circulating B cells, thus suppressing inflammatory NMOSD attacks that are potentially disabling or life-threatening. It is approved as an intravenous infusion in several countries. In the pivotal phase 2/3 N-MOmentum trial, inebilizumab reduced the risk of NMOSD attacks compared with placebo, including in AQP4-antibody seropositive patients. Inebilizumab also significantly reduced the risk of disability score worsening, the number of NMOSD-related hospitalisations and MRI lesion count, but had no significant effect on low-contrast binocular vision. The treatment effect on relapse risk and disability scores was sustained in inebilizumab-treated patients for ≥ 4 years during the open-label extension. Inebilizumab was generally well tolerated, with the most common adverse events being urinary tract infection and arthralgia. Thus, inebilizumab is an effective treatment option for adults with AQP4-antibody seropositive NMOSD. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-022-00949-7.

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Section: Therapeutic Efficacy Of Inebilizumabmentioning

confidence: 99%

Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Nie

Blair

2022

CNS Drugs

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“…Several therapies [64][65][66][67] , with Rituximab, Inebilizumab, Obinutuzumab, were used to target B cells in neuromyelitis optica spectrum disorder, MOG antibody-associated disease, or relapsing-remitting MS. An early intervention, targeting immune cells to prevent early tissue damage and irreversible neuropathological outcomes, seems to a suitable alternative, yet hitherto missing, strategy. Although CD4 + T cell depletion had no clinical benefit 58,68 , a recent study revealed that by inducing apoptosis of reactive CD4 + T cells and immunosuppressive monocytes by targeting oligodendrocyte-released extracellular vesicles the severity of EAE can be reduced 69 .…”

Section: Discussionmentioning

confidence: 99%

Oligodendroglial precursors orchestrate immune network instigating early demyelination in experimental autoimmune encephalomyelitis

Wang,

Huang,

Zheng

et al. 2023

Preprint

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The immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human MS. In mouse experimental autoimmune encephalomyelitis (EAE), pathological OPCs attract CD4+ T-helper 1 (Th1) cells into the spinal cord and brain through CC-chemokine ligand 4 (CCL4), whilst OPCs cooperate with Th1 cells inducing transformation of cytotoxic macrophages that execute early demyelination. Simultaneously, Th1 cells and cytotoxic macrophages upregulate Wnt signaling and CCL4 expression in OPCs, thus exerting positive feedback onto the OPC-immune cascade and establishing a vicious cycle propagating EAE pathogenesis. Breaking this cascade by targeting CCL4 reduces immune cell infiltration, alleviates demyelination, and attenuates EAE severity. Our findings demonstrate a closely coordinated network of OPCs and immune cells therefore providing an alternative insight into MS pathophysiology.

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“…In the inebilizumab clinical trial, 4 out of 17 (23.5%) AQP4-IgG-negative NMOSD patients had a history of brain or brainstem lesions at baseline. 38 Brain imaging features reported in seronegative NMOSD patients include extensive hemispheric white matter lesions, 5 diffuse splenium lesions, 5,39 and lesions adjacent to fourth ventricle. 39 An Oxford study identified brain imaging discriminators via discriminant analysis of principal components combining the magnetic resonance imaging (MRI) features of MOGAD and AQP4-IgG+ NMOSD to differentiate from MS. 40 The use of such a discriminatory model may be helpful in subclassifying patients with DN NMOSD/MS overlapping syndromes 33,39 who in clinical practice are one of the main diagnostic challenges.…”

Section: Brain Lesionsmentioning

confidence: 99%

Double-negative neuromyelitis optica spectrum disorder

Wu,

Geraldes,

Juryńczyk

et al. 2023

Mult Scler

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Most patients with neuromyelitis optica spectrum disorders (NMOSD) test positive for aquaporin-4 antibody (AQP4-IgG) or myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Those who are negative are termed double-negative (DN) NMOSD and may constitute a diagnostic and therapeutic challenge. DN NMOSD is a syndrome rather than a single disease, ranging from a (postinfectious) monophasic illness to a more chronic syndrome that can be indistinguishable from AQP4-IgG+ NMOSD or develop into other mimics such as multiple sclerosis. Thus, underlying disease mechanisms are likely to be heterogeneous. This topical review aims to (1) reappraise antibody-negative NMOSD definition as it has changed over time with the development of the AQP4 and MOG-IgG assays; (2) outline clinical characteristics and the pathophysiological nature of this rare entity by contrasting its differences and similarities with antibody-positive NMOSD; (3) summarize laboratory characteristics and magnetic resonance imaging findings of DN NMOSD; and (4) discuss the current treatment for DN NMOSD.

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AQP4-IgG-seronegative patient outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder

Cited by 22 publications

References 45 publications

Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Inebilizumab: A Review in Neuromyelitis Optica Spectrum Disorder

Oligodendroglial precursors orchestrate immune network instigating early demyelination in experimental autoimmune encephalomyelitis

Double-negative neuromyelitis optica spectrum disorder

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