title: Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Ringelstein
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: Ilya
authors.initials: I
authors.lastname: Ayzenberg
authors.affiliation: Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Harmel
authors.affiliation: Deutschen Klinik für Diagnostik Helios Klinik Wiesbaden, Wiesbaden, Germany.
authors.forename: Ann-Sophie
authors.initials: AS
authors.lastname: Lauenstein
authors.affiliation: Deutschen Klinik für Diagnostik Helios Klinik Wiesbaden, Wiesbaden, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Lensch
authors.affiliation: Department of Neurology, Clinic Osnabrück, Osnabrück, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Stögbauer
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hellwig
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: Gisa
authors.initials: G
authors.lastname: Ellrichmann
authors.affiliation: Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Stettner
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kieseier
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kleiter
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000175:diagnosis* / Q000188:drug therapy* / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019947:Receptors, Interleukin-6; C502936:tocilizumab