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  • Title: Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder.
    Author: Ringelstein M, Ayzenberg I, Harmel J, Lauenstein AS, Lensch E, Stögbauer F, Hellwig K, Ellrichmann G, Stettner M, Chan A, Hartung HP, Kieseier B, Gold R, Aktas O, Kleiter I.
    Journal: JAMA Neurol; 2015 Jul; 72(7):756-63. PubMed ID: 25985228.
    Abstract:
    IMPORTANCE: Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. OBJECTIVE: To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). MAIN OUTCOMES AND MEASURES: Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. RESULTS: Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. CONCLUSIONS AND RELEVANCE: Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.
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