Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Marios C Papadopoulos,Alan S Verkman,Jeffrey L Bennett

doi:10.1038/nrneurol.2014.141

Marios C Papadopoulos, Alan S Verkman + Show 1 more

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https://doi.org/10.1038/nrneurol.2014.141

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Abstract

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date.

Highlights

Neuromyelitis optica (NMO) is a rare inflammatory demyelinating disease of the CNS, with a predilection for the optic nerves and spinal cord
NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4)
In a proof-of-concept study, AQP4-IgG was administered to rats by intracerebral injection, and the size of the resulting neuroinflammatory demyelinating lesions was reduced by about 50% when Intravenous immunoglobulin (IVIg) was subsequently administered by intraperitoneal injection to yield serum levels of 10–25 mg/ml IgG, which is comparable to human therapeutic levels.[139]

Summary

Introduction

Neuromyelitis optica (NMO) is a rare inflammatory demyelinating disease of the CNS, with a predilection for the optic nerves and spinal cord. IVIg showed efficacy in the prevention of relapses in eight NMO patients, with a reduction in mean ARR from 1.8 in the year before IVIg treatment to 0.006 during a mean follow-up of 19.3 months.[136] Other case studies support a beneficial effect of IVIg in preventing relapse in NMO,[137,138] and potentially in acute NMO relapses.[61] In a proof-of-concept study, AQP4-IgG was administered to rats by intracerebral injection, and the size of the resulting neuroinflammatory demyelinating lesions was reduced by about 50% when IVIg was subsequently administered by intraperitoneal injection to yield serum levels of 10–25 mg/ml IgG, which is comparable to human therapeutic levels.[139] In vitro studies suggested that inhibition of AQP4-IgG-mediated CDC and ADCC were the primary mechanisms mediating the beneficial effects found in vivo. The differences in lesion pathology and recovery are reflected in the clinical outcomes of MOG-IgG+ NMO and AQP4-IgG+ NMO patients.[173,174,175,176,177] Further studies are needed to understand the pathogenesis of seronegative NMO, and to determine whether MOG-IgG+ NMO is pathologically related to or is a phenocopy of AQP4-IgG+ NMO

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