Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies

Abstract

Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19⁺ B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.

Keywords: Aquaporin-4-antibody; Astrocyte; Complement; Neuroinflammation; Neuromyelitis optica spectrum disorders (NMOSD); Ongoing trials; Treatment.

Fig. 1

Timeline and relevant milestones in NMOSD. During the last two decades, significant advances have been made in NMOSD, including: introduction of new diagnostic criteria (gray arrows), identification of biomarkers, better characterization of clinical phenotypes, improved prognosis and new therapeutic approaches (black arrows). AQP4 aquaporin-4, AQP4-ab aquaporin-4-antibodies, IgG immunoglobulin G, IPND International Panel for NMO Diagnosis, MOG myelin-oligodendrocyte glycoprotein, NMO neuromyelitis optica, NMOSD neuromyelitis optica spectrum disorder, TM transverse myelitis

Fig. 2

Pathophysiologic mechanisms and therapeutic targets for approved and experimental treatment options in NMOSD. AQP4-specific B cells differentiate in the periphery to plasma cells capable of producing anti-AQP4 antibodies (1), which penetrate the CNS and are deposited mainly on the feet of astrocytes. Specific T cells interact with B cells or dendritic cells, and in the presence of IL-6, IL-23, and TGF-β differentiate into Th17 cells. These in turn penetrate the CNS, facilitate the passage of AQP4-ab into the CNS via opening the blood brain barrier (BBB), and contribute to the recruitment of neutrophils (2). This inflammatory environment activates complement through C1q which binds to anti-AQP4-ab, induces C5 cleavage into activated fractions C5a and C5b, causing astrocyte injury through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). When C1q binds to conformational Fc determinants on IgG or IgM antibody–antigen complexes, it produces cellular injury by formation of the pore-like membrane attack complex (MAC) (3). In addition to MAC formation, complement activation produces factors C3a and C5a, which together with VEGF increase vascular permeability and provide a chemotactic gradient, resulting in recruitment of neutrophils, eosinophils, basophils, mast cells, NK cells and macrophages (4). These cells produce complement-independent damage of astrocytes through ADCC or degranulation involving Fc receptors. Mechanisms described above may also generate cytotoxicity in neighboring cells including oligodendrocytes and neurons through bystander effects (5). Experimental treatments or those in ongoing studies are represented in dotted line spaces. AQP4 aquaporin-4, CCP cytotoxic cationic proteins, IL interleukin, NE neutrophil elastase, NOS nitric oxide species, VEGF vascular endothelial growth factor