Targeting the Interleukin 6 Receptor to Treat Neuromyelitis Optica

Irani, Sarosh R.; Vincent, Angela

doi:10.1001/jamaneurol.2015.0579

Cited by 4 publications

(4 citation statements)

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“…Among the autoimmune central nervous system (CNS) disorders, a recent study reported a powerful disease modulation by tocilizumab in rituximab-refractory neuromyelitis optica (NMO) [19][20][21]. Regarding AE, successful treatment of contactin-associated protein-like 2 syndrome by tocilizumab was reported [22], and some experts suggested broader use of tocilizumab in antibody-medicated encephalitis [23]. However, the efficacy of tocilizumab has not yet been evaluated in rituximab-nonresponsive AE.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

et al. 2016

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A considerable portion of autoimmune encephalitis (AE) does not respond to conventional immunotherapies and subsequently has poor outcomes. We aimed to determine the efficacy of tocilizumab, an anti-interleukin-6 antibody, in rituximab-refractory AE compared with other treatment options. From an institutional cohort of AE, 91 patients with inadequate clinical response to first-line immunotherapy and following rituximab were retrospectively reviewed. Patients were grouped according to their further immunotherapy strategies. Thirty (33.0 %) patients were included in the tocilizumab group, 31 (34.0 %) in the additional rituximab group, and 30 (33.0 %) in the observation group. Outcomes were defined as the favorable modified Rankin Scale scores (≤2) at 1 and 2 months from the initiation of each treatment strategy and at the last follow-up. Favorable clinical response (improvement of the modified Rankin Scale scores by ≥ 2 points or achievement of the mRS scores ≤ 2) at the last follow-up was also analyzed. The tocilizumab group showed more frequent favorable mRS scores at 2 months from treatment initiation and at the last follow-up compared with those at the relevant time points of the remaining groups. The majority (89.5 %) of the patients with clinical improvement at 1 month from tocilizumab treatment maintained a long-term favorable clinical response. No serious adverse effects of rituximab or tocilizumab were reported. Therefore, we suggest that tocilizumab might be a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab. The tocilizumab-mediated clinical improvement manifests as early at 1 month after treatment initiation.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

et al. 2016

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“…Promising compounds are likely to be those specifically targeting B cells and plasma cells and associated antibody production, either directly or indirectly (e.g. tocilizumab, which targets the IL-6 receptor on B cells (Irani and Vincent 2015 )). Immunotherapies are associated with a number of potentially serious side effects and should be used with caution in the patients most likely to benefit.…”

Section: Therapeutic Considerationsmentioning

confidence: 99%

Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications

et al. 2015

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Rationale Autoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest. Objectives We aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective. Results The functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed. Conclusions An analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.

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“…1 The potential benefit of blocking the interleukin-6 receptor signaling in NMO has recently been shown in open-labeled trials, implying that ideas for therapy proposed by academia can be very useful in developing new drugs for rare diseases, such as NMO. 2,3 Although not appropriately recognized, an acute attack of NMO can cause complete blindness, serious limb paralysis or neurogenic pain. In contrast, a single symptomatic attack seldom causes such a devastating outcome in MS.…”

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confidence: 99%

“…Analysis of blood and cerebrospinal fluid samples from patients with NMO showed an elevation of inflammatory cytokines and chemokines, including interleukin‐6, as well as increased numbers of plasmablasts, which are capable of producing anti‐AQP4 antibodies . The potential benefit of blocking the interleukin‐6 receptor signaling in NMO has recently been shown in open‐labeled trials, implying that ideas for therapy proposed by academia can be very useful in developing new drugs for rare diseases, such as NMO …”

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confidence: 99%

Vascular endothelial growth factor: A potential target of therapy in neuromyelitis optica?

Yamamura

2015

Clinical & Exp Neuroim

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An open study was conducted to evaluate the safety of bevacizumab, antivascular endothelial growth factor antibody, in patients with neuromyelitis optica developing signs of relapse.Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system, which is associated with elevation of pathogenic autoantibodies against the aquaporin 4 (AQP4) water channel. Anti-AQP4 antibodies are assumed to bind to AQP4 protein abundantly expressed in the astrocyte endfoot processes, and the antibody binding leads to complement-dependent damage to astrocytes and disruption of the blood-brain barrier. Currently, there are no approved drugs for NMO, although corticosteroids and immunosuppressive drugs are commonly used in practice with preventive and therapeutic purposes. Approved drugs for multiple sclerosis, including interferon-b, fingolimod and natalizumab, are not recommended for patients with NMO.Analysis of blood and cerebrospinal fluid samples from patients with NMO showed an elevation of inflammatory cytokines and chemokines, including interleukin-6, as well as increased numbers of plasmablasts, which are capable of producing anti-AQP4 antibodies. 1 The potential benefit of blocking the interleukin-6 receptor signaling in NMO has recently been shown in open-labeled trials, implying that ideas for therapy proposed by academia can be very useful in developing new drugs for rare diseases, such as NMO. 2,3 Although not appropriately recognized, an acute attack of NMO can cause complete blindness, serious limb paralysis or neurogenic pain. In contrast, a single symptomatic attack seldom causes such a devastating outcome in MS. In this regard, development of drugs for NMO should aim for complete prevention of relapses or efficacious suppression of acute inflammation during relapse.In the paper published in this issue of Clinical and Experimental Neuroimmunology, Mealy et al. 4 have evaluated the safety of bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, in patients with NMO during relapse. Vascular endothelial growth factor might play a key role in the disruption of the bloodbrain barrier in the inflammatory processes. In this pilot open-labeled study, 10 patients with NMO or NMO spectrum disorder with elevated levels of anti-AQP4 antibodies were enrolled. These patients presented with an acute attack of transverse myelitis, optic neuritis or brainstem inflammation. Anti-myelin oligodendrocyte glycoprotein antibodies were not measured. In addition to standard intravenous methylprednisolone pulse therapy, bevacizumab was infused on the first day of treatment. As described in the study, bevacizumab add-on therapy was safe in that no adverse event related to the drug was reported by any patient. Bevacizumab might be beneficial in reducing the clinical and pathological signs of NMO relapses, as the patients enrolled in the study did not require plasma exchange as means for escalation ther-

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Targeting the Interleukin 6 Receptor to Treat Neuromyelitis Optica

Cited by 4 publications

References 10 publications

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications

Vascular endothelial growth factor: A potential target of therapy in neuromyelitis optica?

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