Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

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 PARTICIPANTSRetrospective 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 MEASURESAnnualized 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. RESULTSPatients 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 (Ն40 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 RELEVANCEProlonged 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.

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

“…Owing to the crucial role of IL-6 in stimulating both B and T cells in autoimmune processes [13][14][15], tocilizumab was established as efficient in various autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus [16][17][18]. Among the autoimmune central nervous system (CNS) disorders, a recent study reported a powerful disease modulation by tocilizumab in rituximab-refractory neuromyelitis optica (NMO) [19][20][21]. Regarding AE, successful treatment of contactin-associated protein-like 2 syndrome by tocilizumab was reported [22], and some experts suggested broader use of tocilizumab in antibody-medicated encephalitis [23].…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…The efficacy of tocilizumab is supported by the congruent results of 2 recent open-label studies reporting a total of 15 patients from Germany and Japan with AQP-IgG-positive NMOSD [121,122]. Araki et al [121] treated 6 females and 1 male with high disease activity (mean ARR 2.9±1.1, mean EDSS 5.1±1.7) monthly with 8 mg/kg tocilizumab as add-on therapy to either prednisolone, AZA, ciclosporin, or tacrolimus.…”

“…Theoretically, the absence of attack-related inflammation could also release repair processes such as remyelination. Indeed, several studies investigating broad or selective immunosuppression reported an improvement of disability during the course of treatment [21,81,83,84,87,92,102,121,122].…”

“…During 12 months of therapy, both ARR (0.4±0.8) and EDSS (4.1±1.6) significantly decreased and fatigue improved. Ringelstein et al [122] reported the disease course of 8 female patients with severe NMOSD nonresponsive to rituximab (median ARR 4.0, median EDSS 7.3), which significantly improved during monotherapy with tocilizumab (median ARR 0.4, median EDSS 5.5) for up to 4 years. Relapses were mostly mild and occurred either in the first 2.5 months of therapy or after a reduction of application frequency (>40 days) or dosage (6 mg/kg instead of 8 mg/kg).…”

“…Infections, hypercholesterolemia, elevation of transaminases, and leukopenia are the most common adverse effects of tocilizumab, and were observed in patients with NMOSD [121,122]. Possible tuberculosis reactivation and opportunistic infections make careful observations essential.…”