Immunosuppressive therapy is more effective than interferon in neuromyelitis optica

Papeix, Caroline; Vidal, Jean‐Sébastien; Seze, J. de; Pierrot‐Deseilligny, C; Tourbah, Ayman; Stankoff, Bruno; Lebrun, C.; Moreau, Thibault; Vermersch, Patrick; Fontaine, Bertrand; Lyon-Caen, O.; Gout, Olivier

doi:10.1177/1352458506070732

Cited by 190 publications

(141 citation statements)

References 10 publications

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“…52 Clinical signs include longitudinally extensive spinal cord lesions and bilateral optic nerve demyelination often resulting in blindness. Although the rarity of this disease precludes prospective randomized trials, interferon therapy for neuromyelitis optica has been found to be ineffective in small studies, 53 and in some cases detrimental. 54 Disease modification in neuromyelitis optica currently relies upon the empiric use of chronic steroids with or without azathioprine, and intermittent plasma exchange or intravenous immunoglobulin.…”

Section: Neuromyelitis Opticamentioning

confidence: 99%

Interferon-β Treatment for Multiple Sclerosis

Bermel

Rudick

2007

Neurotherapeutics

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Summary:Multiple sclerosis (MS) is the leading nontraumatic cause of neurologic disability in young adults. Interferon-␤, approved for use in 1993, was the first treatment to modify the course and prognosis of the disease and remains a mainstay of MS treatment. Numerous large-scale clinical trials in early, active patient populations have established the clinical efficacy of interferon-␤ in reducing relapses and delaying disability progression. Although its mechanism of action remains incompletely understood, a reduction in active lesions seen on magnetic resonance imaging implies primary anti-inflammatory properties, a mechanism supported by basic immunologic research. Variation in individual patient responsiveness to interferon-␤ may be due to disease variability or differential induction of interferon-stimulated genes. The magnitude of the therapeutic effect appears to be similar among products, but the optimal dose, route, and frequency of administration of the drug remain uncertain.

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Section: Neuromyelitis Opticamentioning

confidence: 99%

Interferon-β Treatment for Multiple Sclerosis

Bermel

Rudick

2007

Neurotherapeutics

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“…Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2,3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4,5).…”

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confidence: 99%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.N euromyelitis optica (NMO) is a relapsing inflammatory autoimmune demyelinating disease of the central nervous system (CNS), long considered a severe form of multiple sclerosis (MS). Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2, 3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4, 5).The aquaporin-4 (AQP4) water channel is the CNS target (4). Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1, 6-11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6-12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1). The blood-brain barrier (BBB) does not absolutely restrict IgG entry into the CNS, but it does exclude macromolecular C1q, essential for activating the classical complement cascade.Experimental studies of lesional events in vitro and in animal models of NMO have emphasized complement-mediated inflammation and astrocyte cytolysis, late events associated with extensive BBB disruption. A neglected potential initiator of NMO pathophysiology is the AQP4-IgG-activated astrocyte's response: synthesis and secretion of complement, cytokines, chemokines (12-14), and inflammatory mediators attracting NMO-characteristic gra...

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“…Although only assessed by retrospective studies, the marked worsening of disability reported in some patients treated with interferon-β [19,20,[59][60][61][62], natalizumab [63][64][65], and fingolimod [66,67] should prompt us to avoid these therapies. Alemtuzumab, a T-and B-cell-depleting agent, was also shown to exacerbate NMOSD in single patients [51,68,69].…”

Section: Prevention Of Nmosd Attacks General Considerationsmentioning

confidence: 99%

“…Azathioprine (AZA) was among the first immunosuppressants reported to be effective for NMOSD [17]. Subsequently, the new diseasemodifying drugs approved for MS were given for NMOSD, with variable success [18][19][20], while more promising results came from B-cell depletion therapy [21]. The latter approach was a consequence of pathoanatomical and serological studies identifying humoral disease mechanisms, particularly complement activation and NMO-IgG, involved in the pathogenesis of NMOSD [22,23].…”

Section: Introductionmentioning

confidence: 99%

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

Kleiter

Gold

2016

Neurotherapeutics

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Neuromyelitis optica spectrum disorders (NMOSD) are important evolving entities, which have reached much attention in the recent years. NMOSD are characterized by inflammatory lesions in the optic nerves, spinal cord, and central parts of the brain, as well as an autoimmune process directed against aquaporin-4. As disability in NMOSD accumulates by inflammatory damage from attacks, both the treatment and prevention of attacks are decisive for the long-term outcome. NMOSD attacks are treated with highdose intravenous corticosteroids and apheresis therapies, in particular therapeutic plasma exchange. In cases of incomplete remission, escalation of attack treatment is recommended. Preventive therapy is immunosuppressive and should by commenced as early as possible. Apart from classical immunosuppressants such as azathioprine and mycophenolate mofetil, repurposed biologicals are increasingly used. B-cell depletion with rituximab and other agents, inhibition of the interleukin-6 receptor with tocilizumab, and blockade of complement-mediated damage by eculizumab all are promising therapeutic strategies evaluated in randomized controlled trials. In this review, we will discuss present and future immunotherapies for NMOSD and also consider combination of treatments, plasma, cellular and other therapies. Current advances in immunopathological knowledge are translated into innovative concepts and begin a new era of NMOSD therapy.

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Immunosuppressive therapy is more effective than interferon in neuromyelitis optica

Cited by 190 publications

References 10 publications

Interferon-β Treatment for Multiple Sclerosis

Interferon-β Treatment for Multiple Sclerosis

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

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