Elsevier

The Lancet Neurology

Volume 12, Issue 6, June 2013, Pages 554-562
The Lancet Neurology

Articles
Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study

https://doi.org/10.1016/S1474-4422(13)70076-0Get rights and content

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<0·0001). No patient had worsened disability by any outcome measure. Median score on the expanded disability status scale improved from 4·3 (range 1·0–8·0) before treatment to 3·5 (0–8·0) during treatment (p=0·0078). Two patients improved by two points and three improved by one point on the Hauser score; no change was recorded for the other patients. Visual acuity had improved in at least one eye by one point in four patients, and by two points in one patient; no change was recorded for other patients. One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery. No other drug-related serious adverse events occurred. Eight attacks in five patients were reported within 12 months of eculizumab withdrawal.

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.

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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