ArticlesEculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study
Introduction
Neuromyelitis optica is an inflammatory CNS syndrome that is characterised by severe attacks of optic neuritis and myelitis. Unlike multiple sclerosis, neuromyelitis optica attacks commonly spare the brain in early stages, and demyelination is secondary.1 The prognosis for untreated disease is substantially worse than for multiple sclerosis, because recovery from attacks is incomplete and the likelihood of incremental attack-related disability is greater.2, 3 Therefore, early therapeutic intervention to restrict or prevent relapses might have more favourable effects on the course of neuromyelitis optica than on that of multiple sclerosis.
Apart from paraneoplastic CRMP-5 optic neuropathy and myelopathy,4, 5 neuromyelitis optica is the only inflammatory CNS demyelinating disease for which a tissue-specific autoantigen has been identified. The autoantigen is the astrocyte water channel protein aquaporin 4 (AQP4). The biomarker of neuromyelitis optica is an AQP4-specific IgG autoantibody that is implicated as the initiator of autoimmune astrocytopathies that are collectively recognised as neuromyelitis optica spectrum disorders.6, 7 Several disorders are unified by AQP4-IgG seropositivity: neuromyelitis optica, its partial or inaugural forms, and circumventricular organ dysfunction involving AQP4. The discovery of the AQP4-IgG and the corroborating clinical, pathological, and radiological findings of the past 8 years clearly distinguish neuromyelitis optica spectrum disorders from classic multiple sclerosis.8, 9, 10
Reports have suggested that multiple sclerosis treatments such as interferon beta and natalizumab could worsen neuromyelitis optica.11, 12, 13, 14, 15, 16, 17 Immunosuppressant therapies—eg, azathioprine or mycophenolate, with or without concurrent prednisone, and rituximab—are prescribed to prevent attacks of neuromyelitis spectrum disorders. Uncontrolled case series show reductions in annual relapse rates with immunosuppressant therapies, but 25–66% of patients relapsed during follow-up.18, 19, 20, 21, 22 Antigen-specific curative therapies for neuromyelitis optica spectrum disorders might be developed in the future, but effective and safe treatments to prevent relapses are needed now.
Binding of the IgG to AQP4 on astrocytic membranes initiates several molecular outcomes that potentially contribute to disease pathogenesis.23, 24, 25, 26 Most AQP4-IgG is IgG1, readily activating complement, yielding early products that can amplify the inflammatory response, disrupting the blood–brain barrier, and enhancing destruction of opsonised astrocytic membranes. The membrane attack complex of the complement cascade that is finally assembled lyses astrocytic membranes.8, 23, 26, 27 Eculizumab is a therapeutic humanised monoclonal IgG that neutralises the complement protein C5, thereby inhibiting its cleavage to C5a and C5b, which prevents generation of the pro-inflammatory and cell-activating C5a peptide, the lytic terminal complex C5b-9, and the non-cytolytic soluble C5b-9 inflammatory product.28, 29 It is approved for treatment of two life-threatening complement-mediated diseases: paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. The aim of this study was to investigate the safety and preliminary efficacy of eculizumab in reducing attack frequency in relapsing neuromyelitis optica spectrum disorders. Additionally, its effects on disability were to be assessed.
Section snippets
Participants
Between Oct 20, 2009, and Nov 3, 2010, patients were directly recruited into an open-label trial at Mayo Clinics in Rochester, MN, and Scottsdale, AZ, USA, or identified through the Mayo Clinic study-specific repository or clinicoserological database. Several inclusion and exclusion criteria were used (panel 1).
The trial protocol and supporting documentation were approved by the Mayo Clinic institutional review board. Patients provided written informed consent at enrolment.
Procedures
Patients received
Results
We enrolled 14 patients, all of whom were women. More than half fulfilled 2006 diagnostic criteria for neuromyelitis optica (table 1). Five patients did not receive attack prevention treatments before eculizumab treatment; nine patients received immunosuppressant treatments (table 2). Three patients who received immunosuppressant treatments had been given immunomodulatory drugs for presumed multiple sclerosis (interferon beta in three, and glatiramer acetate in one) before the correct diagnosis
Discussion
In this study of eculizumab in 14 patients with aggressive neuromyelitis optica spectrum disorders, the drug significantly reduced attack frequency and stabilised or improved neurological disability measures in most patients. These findings suggest that complement activation has a central role in the genesis of attacks and that eculizumab has a potential therapeutic effect for prevention of attacks. Eculizumab was tolerated well, except for one serious adverse event (meningococcal infection),
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