Journal ArticleDOI
Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study
Sean J. Pittock,Vanda A. Lennon,Andrew McKeon,Jay Mandrekar,Brian G. Weinshenker,Claudia F. Lucchinetti,Orna O'Toole,Dean M. Wingerchuk +7 more
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TLDR
Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders.Abstract:
Summary Background Complement activation after binding of an IgG autoantibody to aquaporin 4 (AQP4) is thought to be a major determinant of CNS inflammation and astrocytic injury in neuromyelitis optica. The aim of this study was to investigate the use of eculizumab—a therapeutic monoclonal IgG that neutralises the complement protein C5—in neuromyelitis optica spectrum disorders. Methods Between Oct 20, 2009, and Nov 3, 2010, we recruited patients from two US centres into an open-label trial. Patients were AQP4-IgG-seropositive, aged at least 18 years, had a neuromyelitis optica spectrum disorder, and had at least two attacks in the preceding 6 months or three in the previous 12 months. Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment. They received 600 mg intravenous eculizumab weekly for 4 weeks, 900 mg in the fifth week, and then 900 mg every 2 weeks for 48 weeks. The coprimary endpoints were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 h and not attributable to an identifiable cause]) and safety. Secondary endpoints were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity. At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed. This trial is registered with ClinicalTrials.gov, number NCT00904826. Findings We enrolled 14 patients, all of whom were women. After 12 months of eculizumab treatment, 12 patients were relapse free; two had had possible attacks. The median number of attacks per year fell from three before treatment (range two to four) to zero (zero to one) during treatment (p Interpretation Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders. The apparent effects of eculizumab deserve further investigation in larger, randomised controlled studies. Funding Alexion Pharmaceuticals.read more
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Journal ArticleDOI
Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS)
Corinna Trebst,Sven Jarius,Achim Berthele,Friedemann Paul,Friedemann Paul,Sven Schippling,Brigitte Wildemann,Nadja Borisow,Ingo Kleiter,Orhan Aktas,Tania Kümpfel +10 more
TL;DR: The Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings.
Journal ArticleDOI
Neuroinflammation: the role and consequences.
TL;DR: It is indicated that neuroinflammation causes and accelerates long-term neurodegenerative disease, playing a central role in the very early development of chronic conditions including dementia, and combinations of different preventative and therapeutic approaches may be efficacious.
Journal ArticleDOI
Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder
Sean J. Pittock,Achim Berthele,Kazuo Fujihara,Kazuo Fujihara,Ho Jin Kim,Michael J. Levy,Michael J. Levy,Jacqueline Palace,Ichiro Nakashima,Ichiro Nakashima,Murat Terzi,N. A. Totolyan,Shanthi Viswanathan,Kai-Chen Wang,A Pace,Kenji P Fujita,R Armstrong,Dean M. Wingerchuk +17 more
TL;DR: Patients with AQP4-IgG-positive NMOSD who received eculizumab had a significantly lower risk of relapse than those who received placebo, and there was no significant between-group difference in measures of disability progression.
Journal ArticleDOI
Complement and Its Receptors: New Insights into Human Disease
TL;DR: This review includes an overview of complement activation, regulatory, and effector mechanisms, and focuses on new understandings gained from genetic studies, ex vivo analyses, therapeutic trials, and animal models as well as on new research opportunities.
Journal ArticleDOI
Mechanisms of Autoantibody-Induced Pathology.
Ralf Ludwig,Karen Vanhoorelbeke,Frank Leypoldt,Ziya Kaya,Katja Bieber,Sandra M. McLachlan,Lars Komorowski,Jie Luo,Otavio Cabral-Marques,Christoph M. Hammers,Jon Lindstrom,Peter Lamprecht,Andrea Fischer,Gabriela Riemekasten,Claudia Tersteeg,Peter Sondermann,Basil Rapoport,Klaus-Peter Wandinger,Christian Probst,Asmaa El Beidaq,Enno Schmidt,Alan S. Verkman,Rudolf A. Manz,Falk Nimmerjahn +23 more
TL;DR: autoantibodies can be classified into the following categories: mimic receptor stimulation, blocking of neural transmission, induction of altered signaling, triggering uncontrolled microthrombosis, cell lysis, neutrophil activation, and (7) induction of inflammation.
References
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Rating neurologic impairment in multiple sclerosis An expanded disability status scale (EDSS)
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A serum autoantibody marker of neuromyelitis optica : distinction from multiple sclerosis
Vanda A. Lennon,Dean M. Wingerchuk,Thomas J. Kryzer,Sean J. Pittock,C. F. Lucchinetti,Kazuo Fujihara,Ichiro Nakashima,Brian G. Weinshenker +7 more
TL;DR: NMO-IgG is a specific marker autoantibody of neuromyelitis optica and binds at or near the blood-brain barrier that distinguishes neuromyleitis opticas from multiple sclerosis.
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Revised diagnostic criteria for neuromyelitis optica
TL;DR: Revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity.
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IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
TL;DR: It is shown that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier, which may represent the first example of a novel class of autoimmune channelopathy.
Journal ArticleDOI
The spectrum of neuromyelitis optica
Dean M. Wingerchuk,Vanda A. Lennon,Claudia F. Lucchinetti,Sean J. Pittock,Brian G. Weinshenker +4 more
TL;DR: Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica.
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