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Antibody Therapies in Autoimmune Encephalitis.

ABSTRACT: Autoimmune encephalitis (AE) comprises a heterogeneous group of disorders in which the host immune system targets self-antigens expressed in the central nervous system. The most conspicuous example is an anti-N-methyl-D-aspartate receptor encephalitis linked to a complex neuropsychiatric syndrome. Current treatment of AE is based on immunotherapy and has been established according to clinical experience and along the concept of a B cell-mediated pathology induced by highly specific antibodies to neuronal surface antigens. In general, immunotherapy for AE follows an escalating approach. When first-line therapy with steroids, immunoglobulins, and/or plasma exchange fails, one converts to second-line immunotherapy. Alkylating agents could be the first choice in this stage. However, due to their side effect profile, most clinicians give preference to monoclonal antibodies (mAbs) directed at B cells such as rituximab. Newer mAbs might be added as a third-line therapy in the future, or be given even earlier if shown effective. In this chapter, we will discuss mAbs targeting B cells (rituximab, ocrelizumab, inebulizumab, daratumumab), IL-6 (tocilizumab, satralizumab), the neonatal Fc receptor (FCRn) (efgartigimod, rozanolixizumab), and the complement cascade (eculizumab).

SUBMITTER: Smets I

PROVIDER: S-EPMC8775146 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Antibody Therapies in Autoimmune Encephalitis.

Smets I I Titulaer M J MJ

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20220120 3

Autoimmune encephalitis (AE) comprises a heterogeneous group of disorders in which the host immune system targets self-antigens expressed in the central nervous system. The most conspicuous example is an anti-N-methyl-D-aspartate receptor encephalitis linked to a complex neuropsychiatric syndrome. Current treatment of AE is based on immunotherapy and has been established according to clinical experience and along the concept of a B cell-mediated pathology induced by highly specific antibodies to ...[more]

PMID: 35060089

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Project description:BackgroundComprehensive neurocognitive function analyses of autoimmune encephalitis (AE) patients, especially long-term ones, are rare. This study aims to measure cognitive function in patients diagnosed with AE.MethodsThis case-control study included AE patients (n = 11) with antibodies against NMDA receptor (NMDAR) (n = 4), VGKC (n = 3), GAD (3), and one antibody-negative patient. The control group contained 12 pneumococcal meningo-encephalitis patients (PC). Subgroup analyses compared AE patients with and without NMDAR antibodies. Neurocognitive tests were performed to evaluate verbal and visual memory, face recognition, attentional capacity, incidental learning capacity, and overall cognitive function (Montreal cognitive assessment, MoCA). Limbic structural involvement was assessed through magnetic resonance imaging (MRI). Statistical analyses investigated correlations between antibody status, results of neurocognitive tests, and MRI findings.ResultsFollow-up (AE vs. PC) was 33 (11-95) vs. 96 (26-132) months after diagnosis. Neurocognitive functions were normal in both AE and PC groups in all tests except face recognition, which was pathological in both groups. The overall/recognition/long-delay visual memory (p = 0.009/0.008/0.005) and incidental learning (p = 0.017) scores were significantly higher in NMDAR patients compared to non-NMDAR patients. Non-NMDAR patients with right-sided limbic MRI pathologies had significantly lower overall/recognition/long-delay visual memory (p = 0.006/0.044/0.024) and incidental learning (p = 0.009) scores compared to NMDAR patients.ConclusionsWe observed mainly normal neurocognitive functions after autoimmune and bacterial encephalitis. However, compared to NMDAR patients, patients with non-NMDAR autoimmune encephalitis showed a significant and material-specific association between a right-sided hippocampal lesion and limitations in figural-mnestic and incidental learning capacities. Neurocognitive functions in AE patients should be further evaluated prospectively and in more detail.

Project description:Autoimmune diseases of the peripheral nervous system have so far been treated mainly with exogenous high-dose intravenous immunoglobulins (IVIg), that act through several mechanisms, including neutralization of pathogenic autoantibodies, modulation of lymphocyte activity, interference with antigen presentation, and interaction with Fc receptors, cytokines, and the complement system. Other therapeutic strategies have recently been developed, in part to address the increasing shortage of IVIg, prime among which is the use of B cell depleting monoclonal antibodies, or small molecule inhibitors targeting the B-cell specific kinases. Rituximab, a chimeric monoclonal antibody against CD20 + B lymphocytes, is currently the most used, especially in anti-MAG antibody neuropathy and autoimmune neuropathies with antibodies to nodal/paranodal antigens that are unresponsive to IVIg. After several reports of its efficacy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), rituximab is currently under investigation in three Phase 2 trials in CIDP. In addition, the possible role of complement activation in the pathogenesis of chronic autoimmune neuropathies has brought into consideration drugs that can block the complement cascade, such as eculizumab, a monoclonal antibody already assessed in acute polyradiculoneuropathies, and approved for myasthenia gravis. Preliminary data on eculizumab in multifocal motor neuropathy have been published, but randomized controlled studies are pending. Moreover, the neonatal Fc receptor, that recycles IgGs by preventing their lysosome degradation, is an important and attractive pharmacological target. Antibodies against FcRn, which reduce circulating IgG (both pathogenic and non-pathogenic) have been developed. The FcRn blocker efgartigimod, a humanized IgG1-derived Fc fragment, which competitively inhibits the FcRn, has recently been approved for the treatment of myasthenia gravis and is currently under investigation in CIDP. In addition, the anti-human FcRn monoclonal antibody rozanolixizumab is currently being assessed in phase 2 trials in CIDP. However, none of the abovementioned monoclonal antibodies is currently approved for treatment of any immune-mediated neuropathies. While more specific and individualized therapies are being developed, the possibility of combined treatments targeting different pathogenic mechanisms deserves consideration as well.

Dataset Information

Antibody Therapies in Autoimmune Encephalitis.

Publications

Antibody Therapies in Autoimmune Encephalitis.

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