Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorders (NMOSDs) are rare demyelinating diseases of the central nervous system that affect 0.52 to 10 per 100,000 people globally. Relapses are common in patients with NMOSD, and complete recovery from a relapse is less likely than in multiple sclerosis. As a result, disability develops over time that is usually relapse-dependent, and preventing attacks with immunomodulatory medications is now the most effective treatment for NMOSD. However, the responses to conventional immunosuppressive therapy range widely, and additional therapeutic options or regimens are clearly needed. Because NMOSD is a rare condition, medication research may benefit from orphan drug classification, and drug companies are increasingly viewing NMOSD as an expanding market.¹ 

B lymphocytes play a key role in the immunopathophysiology of NMOSD through the production of aquaporin-4 auto-antibodies (AQP4-Abs), proinflammatory B-cell and plasmablast activity, and other mechanisms. Therefore, B-cell depletion is a potential approach to the treatment of NMOSD. Agents that deplete B cells have been tested to prevent relapse in NMOSD; prevention of NMOSD relapse was previously an off-label use of these drugs.^2,3 

Rituximab 

In 2004, B-cell depletion with the anti-CD20 monoclonal antibody rituximab as a treatment for autoimmune disease was first tested in rheumatoid arthritis. Since then, rituximab has been used to treat a variety of autoimmune diseases, including myasthenia gravis, lupus, and multiple sclerosis, all of which have the same immunopathogenic mechanism as NMOSD.⁴ 

The first open-label tests of rituximab in NMOSD showed promise in 2005, and 14 further prospective and retrospective studies with a total of more than 300 participants have been conducted around the world. Despite the fact that none of these studies was placebo-controlled, all of them revealed a long-term and significant effect of rituximab as a treatment for NMOSD.⁴ Remission rates of up to 83% were reported in a study in which persistent B-cell depletion was used. In retrospective head-to-head studies comparing azathioprine, mycophenolate, and rituximab in NMOSD, retixumab was the most effective option, followed by mycophenolate and then azathioprine.⁵ 

The most common regimen is the intravenous injection of two 1000-mg doses separated by 2 weeks, followed by two 1000-mg doses separated by 2 weeks every 6 months.² Infusion-related symptoms such as pruritus, headache, rash, and fever are common. Premedication with an analgesic/antipyretic and an antihistamine is indicated to lessen the risk for these effects. The risk for infections and severe skin manifestations such as Lyell syndrome and Stevens-Johnson syndrome is increased. Cardiac arrhythmias and cardiac insufficiency have also been documented. Furthermore, neurologists should keep in mind the possible development of hypogammaglobulinemia during long-term treatment with rituximab.⁶ Rituximab was the first B-cell-depleting drug used to prevent relapse in patients with NMOSD.² It depletes B-lineage cells (late pro-B cells through early plasmablasts) by targeting CD20. Reductions in annualized relapse rates in patients taking rituximab range from 88.2% to 97%, and some studies have found it to be superior to azathioprine.⁷ 

Inebulizumab

Inebulizumab (Uplizna®) is a humanized monoclonal antibody that targets CD19 and depletes CD19+ B cells, CD19-expressing plasmablasts, and plasma cells that produce and secrete anti-AQP4 immunoglobulin G (IgG). In addition to anti-inflammatory and B cell-suppressive properties, Uplizna has an inhibitory effect on anti-AQP4 IgG synthesis and secretion from antibody-secreting cells.² It is indicated for the treatment of patients with anti-AQP4-positive NMOSD. Inebulizumab treatment significantly extends the time to the onset of an attack in patients with NMOSD, with a 77% relative reduction in the risk for relapse.⁸

The US Food and Drug Administration (FDA) approved inebulizumab for the prevention of relapse in adults with AQP4 IgG-seropositive NMOSD in 2020. Because B-cell-depleting medications are linked to a higher probability of cancer and infection, such as promyelocytic leukemia, long-term monitoring and evaluation in large-scale investigations are needed to assess the long-term safety of inebulizumab in NMOSD.² 

Inebulizumab is supplied in single-dose vials at a concentration of 100 mg/10 mL and is administered as an intravenous infusion. The recommended initial dose is 300 mg administered 2 times 2 weeks apart. Beginning at 6 months following the first dose, a single 300-mg intravenous infusion of inebilizumab should be administered every 6 months.⁹ Administration can cause infusion reactions manifesting as headache, nausea, fever, muscle pain, sleepiness, and rash. The reactions are most common after the first infusion and are generally mild to moderate.^9,10 Steroids, antihistamines, and antipyretic medications can be prescribed by the medical team and administered before an infusion to reduce the frequency and severity of potential reactions.⁹

Patients with active hepatitis B and active or untreated latent tuberculosis should avoid inebulizumab. Immunoglobulin levels should be checked before and during treatment because this drug can cause hypogammaglobulinemia, which may be associated with recurrent infections or serious opportunistic infections. If hypogammaglobulinemia develops, it may be necessary to stop treatment or administer supplementary immunoglobulins intravenously.³ 

References

1. Held F, Klein AK, Berthele A. Drug treatment of neuromyelitis optica spectrum disorders: out with the old, in with the new?. ImmunoTargets Ther. 2021;10:87-101. doi:10.2147/ITT.S2876542
2. Chan KH, Lee CY. Treatment of neuromyelitis optica spectrum disorders. Int J Mol Sci. 2021;22(16):8638. doi:10.3390/ijms22168638
3. Wallach AI, Tremblay M, Kister I. Advances in the treatment of neuromyelitis optica spectrum disorder. Neurol Clin. 2021;39(1):35-49. doi:10.1016/j.ncl.2020.09.003
4. Kessler RA, Mealy MA, Levy M. Treatment of neuromyelitis optica spectrum disorder: acute, preventive, and symptomatic. Curr Treat Options Neurol. 2016;18(1):2. doi:10.1007/s11940-015-0387-9
5. 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
6. Borisow N, Mori M, Kuwabara S, Scheel M, Paul F. Diagnosis and treatment of NMO spectrum disorder and MOG-encephalomyelitis. Front Neurol. 2018;9:888.  doi:10:3389/fneur.201800888
7. Holmøy T, Høglund RA, Illes Z, Myhr KM, Torkildsen Ø. Recent progress in maintenance treatment of neuromyelitis optica spectrum disorder. J Neurol. 2021;268:4522-4536. doi:10.1007/s00415-020-10235-5
8. 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
9. Uplizna (inebilizumab-cdon) prescribing information. Horizon Therapeutics; 2021. Accessed March 12, 2022.
10. Uplizna efficacy. Horizon Therapeutics; 2022. Accessed March 12, 2022.

Reviewed by Hasan Avcu, MD, on 3/19/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.