Neuromyelitis Optica Spectrum Disorder (NMOSD)


Treatment of neuromyelitis optica spectrum disorder (NMOSD) aims to achieve disease remission, treat acute flares and relapse-associated symptoms, prevent future relapses, and manage any residual disability. 

Acute Attack 

Treatment of acute attacks is not affected by antibody status and is identical for both seropositive and seronegative patients. 

First-line therapy for an acute attack is intravenous methylprednisolone pulse (IVMP) at a dose of 1 g per day for 5 consecutive days.1 IVMP is effective for the treatment of acute flares through several proposed mechanisms, including reducing the proportion of circulating regulatory B-cells to memory B-cells, reducing B-cell interferon gamma (IFN-γ) expression, and increasing B-cell interleukin (IL)-10 production.2 IVMP alone is not sufficient to preserve visual function and prevent permanent neuronal damage in NMOSD, and chronic therapy is required for patients with recurrent disease.1 

Second-line therapy involves 5 to 7 cycles of therapeutic plasma exchange (TPE). TPE can be performed if the initial course of corticosteroid (CS) treatment was unsuccessful or if the acute attack is severe in intensity. Patients who have responded well to TPE in the past are candidates for receiving TPE as part of the initial therapy for future acute attacks. It is unclear whether early TPE improves outcomes in patients with an acute NMOSD attack, however, evidence is favorable. Human immunoglobulins (Ig) may also be considered when available for patients who are not responsive to therapy, but evidence is limited.3 

Long-Term Management

Therapies to prevent attack recurrence and associated long-term disability fall into 1 of 4 categories: traditional immunosuppressive treatment, IL-6 pathway inhibitors, complement-blocking therapy, and B-cell-depleting therapy. Due to the relapsing and remitting course of NMOSD, frequent incomplete recovery after attacks, and associated disability, it is important to initiate therapy as soon as possible.3 

Traditional immunosuppressive treatment – Includes treatment with either azathioprine (AZA) or mycophenolate mofetil alone or in combination with low-dose CS. Combination treatment with AZA and low-dose CS reduces the annualized relapse rate by 72.1% but has a high failure rate (>50%) due to adverse events.4 These include liver toxicity, leukopenia, recurrent infections, nausea, diarrhea, and rash. There is also an increased risk of lymphoma with AZA treatment.1 Mycophenolate reduces the annualized relapse rate by 87.4% and carries a 36% treatment failure rate.4 

IL-6 pathway inhibitors – Blockade of the IL-6 pathway is the basis of most novel therapies for NMOSD. IL-6 levels are elevated in the serum and cerebrospinal fluid of patients with NMOSD, and they correlate with aquaporin 4 (AQP4)-IgG levels (increased IL-6 appears to increase AQP4-IgG production) and disease severity. IL-6 also facilitates disruption of the blood–brain barrier and enhances lesion severity. Treatment options include:

  • Tocilizumab – A monoclonal antibody against the IL-6 receptor (IL-6R). Compared to AZA, tocilizumab prolongs time to relapse (78.9 vs 56.7 weeks; P =.0026) and reduces the relative risk of 24 weeks confirmed disability progression by 78%.5 Tocilizumab is not US Food and Drug Administration (FDA)-approved for the treatment of NMOSD. 
  • Enspryng™ (satralizumab-mwge) – Modified form of tocilizumab. It is an IL-6R antagonist indicated for the treatment of NMOSD in adult patients with seropositivity for the AQP4 antibody. In combination with immunosuppressive therapy, satralizumab reduces the risk of relapse by 78%. When used as monotherapy, the risk of relapse is reduced by 74%.6 

Complement-blocking therapy – About 75% to 90% of patients with NMOSD present with IgG autoantibodies in their serum directed at the AQP4 protein. AQP4-IgG binding to the AQP4 protein activates the complement cascade and consequently induces damage of cells in the central nervous system.7 Soliris® (eculizumab) is a terminal complement protein inhibitor that is indicated for the treatment of NMOSD in adults who are AQP4-positive. Data from the PREVENT study reported that patients receiving eculizumab benefited from a 94% reduction in risk of relapse.8  

B-Cell-depleting therapy – The 2 major drugs in this group are Rituximab and Uplizna™ (inebilizumab-cdon). Rituximab is not FDA-cleared for the treatment of NMOSD despite its use for the past 15 years in the management of this condition and endorsements by expert panels.9 

  • Rituximab targets CD20 and depletes B-cell lineage cells from late pro-B-cells through early plasmablasts. Annualized relapse rates for patients on rituximab range from 88.2% to 97%, and some studies have reported superiority to AZA.5  
  • Uplizna is a cytolytic monoclonal antibody directed at CD19 and is indicated for the treatment of AQP4-positive patients with NMOSD. When treated with inebilizumab, patients experienced a significant extension in the time to onset of an NMOSD attack, with a 77% relative reduction in the risk of relapse.10

References

1. Wu Y, Zhong L, Geng J. Neuromyelitis optica spectrum disorder: pathogenesis, treatment, and experimental models. Mult Scler Relat Disord. 2019;27:412-418. doi:10.1016/j.msard.2018.12.002

2. Quan C, ZhangBao J, Lu J, et al. The immune balance between memory and regulatory B cells in NMO and the changes of the balance after methylprednisolone or rituximab therapy. J Neuroimmunol. 2015;282:45-53. doi:10.1016/j.jneuroim.2015.03.016

3. Trebst C, Jarius S, Berthele A, et al.; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014;261(1):1-16. doi:10.1007/s00415-013-7169-7

4. Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M. Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol. 2014;71(3):324-330. doi:10.1001/jamaneurol.2013.5699

5. Holmøy T, Høglund RA, Illes Z, Myhr KM, Torkildsen Ø. Recent progress in maintenance treatment of neuromyelitis optica spectrum disorder. J Neurol. Published online October 3, 2020. doi:10.1007/s00415-020-10235-5

6. Enspryng. Package insert. Genentech, Inc.; 2020. Accessed October 20, 2021.

7. Hinson SR, Romero MF, Popescu BFG, et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A. 2012;109(4):1245-1250. doi:10.1073/pnas.1109980108

8. Soliris. Package insert. Alexion Pharmaceuticals, Inc.; 2020. Accessed October 20, 2021.

9. Ciron J, Audoin B, Bourre B, et al.; NOMADMUS group, under the aegis of OFSEP, SFSEP. Recommendations for the use of rituximab in neuromyelitis optica spectrum disorders. Rev Neurol (Paris). 2018;174(4):255-264. doi:10.1016/j.neurol.2017.11.005

10. Cree BAC, Bennett JL, Kim HJ, et al.; N-MOmentum study investigators. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352-1363. doi:10.1016/S0140-6736(19)31817-3

Reviewed by Harshi Dhingra, MD, on 10/22/2021.

READ MORE ON NMOSD