Neuromyelitis Optica Spectrum Disorder (NMOSD)


Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that affects the central nervous system (CNS). NMOSD is characterized by recurrent attacks of optic neuritis and myelitis, which result in severe disabilities.1

Patients with NMOSD experiencing recurrent attacks typically present with disability progression.1 The current treatment of this disease aims to reduce the levels of inflammation in acute attacks and prevent future relapses.1,2 A preventive therapeutic approach can minimize the damage caused to the CNS and delay disability progression.1

NMOSD Acute Treatment

The first-line treatment for acute attacks in NMOSD typically relies on the administration of corticosteroids in high doses.3,4 One gram of intravenous methylprednisolone (IVMP) is administered for 2 to 7 days, followed by oral prednisolone (1 mg/kg).4,5 Oral treatment should be maintained for several weeks before being tapered over several months.4 The administration of IVMP impacts the inflammation cascade by reducing the production of inflammatory cytokines and T cell activation, as well as by increasing CD14+CD16++ monocyte levels.6

The administration of IVMP does not always lead to a full recovery following a relapse, and may fail to prevent neuronal damage and preserve visual acuity in patients with NMOSD.7,8 Plasma exchange (PLEX) may be considered as a second-line treatment for these patients,5 and an early initiation of the treatment may improve clinical outcomes.8 In PLEX, the patient’s blood is sampled, and the blood cells are mechanically separated from the plasma, mixed with a replacement solution, and delivered to the patient again.3 Patients that do not respond to treatment with intravenous corticosteroids may also benefit from this therapy.3 Reports show that PLEX and immunoadsorption can improve visual acuity and reduce disability.9,10 Few reports support the use of PLEX as a first-line therapy, however, a recent randomized trial showed no difference in the expanded disability status scale (EDSS) after 6 months of treatment with PLEX between patients who responded to IVMP and those who did not. The study also revealed a trend for faster recovery and an improvement in disability level in patients treated initially with both IVMP and PLEX.11

Long-Term Immunosuppression in NMOSD

If left untreated, about 50% of patients with NMOSD will lose vision function and become wheelchair-bound.12 Relapses are strongly associated with neurological deficits, and approximately one-third of patients die within 5 years of the first attack.8,12 Conventional immunosuppressive drugs may be used for the long-term management and relapse prevention of NMOSD. These drugs include azathioprine, mycophenolate mofetil, and rituximab. Their use in NMOSD has been based on their efficacies in other immunologic conditions,13 and their use carries an associated risk of broad inhibition of the immune system.14 Azathioprine inhibits lymphocyte differentiation, resulting in antiproliferative effects. Treatment with azathioprine may lead to bone marrow depression with perturbation of the levels of blood cells.8 Mycophenolate mofetil inhibits B- and T-lymphocyte proliferation by inhibiting inosine monophosphate dehydrogenase. The use of this drug may lead to an increased risk of developing malignant tumors, particularly if used in combination with other immunosuppressants. Oral prednisone or prednisolone in low doses may be used in combination with both azathioprine and mycophenolate mofetil.8

Rituximab is a monoclonal antibody (mAb) that targets the CD20 antigen expressed on B-lymphocytes. Rituximab leads to a decrease in antibody production,8 and it has shown positive results in patients who have been unsuccessfully treated with other immunosuppressants.3 Despite these positive outcomes, relapses still occur in patients treated with rituximab.14 Other immunosuppressant drugs that are effective in multiple sclerosis, such as interferon beta, natalizumab, fingolimod, and alemtuzumab, should not be used in NMOSD due to the risk of disease exacerbation.3,7

After the discovery of the aquaporin-4 immunoglobulin G (IgG) present in the serum of approximately 75% to 90% of patients with NMOSD, other potential targets for NMOSD therapy were revealed and different drugs consequently developed, including eculizumab, satralizumab, and inebilizumab.5 

Eculizumab is a humanized mAb that targets the human complement component 5 and blocks the activation of the complement pathway.1 The efficacy of eculizumab was revealed in the PREVENT trial, in which the eculizumab-treated group had a 94% reduction in the risk of relapse compared to the placebo group. Upper respiratory infections and the risk of developing severe meningococcal infections are associated with eculizumab treatment.15 

Satralizumab is a humanized mAb that binds to the interleukin (IL)-6 receptor. IL-6 is a proinflammatory cytokine that crosses the blood-brain barrier and leads to an increased inflammatory response in NMOSD. This cytokine is increased in the blood and cerebrospinal fluid of some patients with NMOSD during relapses.13 By blocking the IL-6 receptor, satralizumab may benefit patients in the prevention of relapses. An additional advantage associated with satralizumab treatment relies on the novel antibody-recycling technology used for the development of the drug, which allows a longer circulation time of the antibodies.13 Inebilizumab is an mAb that targets the CD19 B-lymphocyte antigen and leads to the depletion of B cells, similar to rituximab. This drug, however, also allows for the removal of B-cell precursors and plasmablasts from the circulation.13

References

1.Frampton JE. Eculizumab: a review in neuromyelitis optica spectrum disorder. Drugs. 2020;80(7):719-727. doi:10.1007/s40265-020-01297-w

2.Ramakrishnan P, Nagarajan D. Neuromyelitis optica spectrum disorder: an overview. Acta Neurobiol Exp (Wars). 2020;80(3):256-272.

3. Neuromyelitis optica spectrum disorder. National Organization for Rare Disorders. Accessed October 14, 2021

4. Huda S, Whittam D, Bhojak M, Chamberlain J, Noonan C, Jacob A. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19(2):169-176. doi:10.7861/clinmedicine.19-2-169

5. Holroyd KB, Manzano GS, Levy M. Update on neuromyelitis optica spectrum disorder. Curr Opin Ophthalmol. 2020;31(6):462-468. doi:10.1097/ICU.0000000000000703

6. Zeng Q, Dong X, Ruan C, et al. CD14+CD16++monocytes are increased in patients with NMO and are selectively suppressed by glucocorticoids therapy. J Neuroimmunol. 2016;300:1-8. doi:10.1016/j.jneuroim.2016.09.011

7. 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

8. 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.2018.00888

9. Srisupa-Olan T, Siritho S, Kittisares K, Jitprapaikulsan J, Sathukitchai C, Prayoonwiwat N. Beneficial effect of plasma exchange in acute attack of neuromyelitis optica spectrum disorders. Mult Scler Relat Disord. 2018;20:115-121. doi:10.1016/j.msard.2018.01.010

10. Mori S, Kurimoto T, Ueda K, Nakamura M. Short-term effect of additional apheresis on visual acuity changes in patients with steroid-resistant optic neuritis in neuromyelitis optica spectrum disorders. Jpn J Ophthalmol. 2018;62(4):525-530. doi:10.1007/s10384-018-0602-9

11. Songthammawat T, Srisupa-Olan T, Siritho S, et al. A pilot study comparing treatments for severe attacks of neuromyelitis optica spectrum disorders: intravenous methylprednisolone (IVMP) with add-on plasma exchange (PLEX) versus simultaneous IVMP and PLEX. Mult Scler Relat Disord. 2020;38:101506. doi:10.1016/j.msard.2019.101506

12. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53(5):1107-1114. doi:10.1212/wnl.53.5.1107

13. Levy M, Fujihara K, Palace J. New therapies for neuromyelitis optica spectrum disorder. Lancet Neurol. 2021;20(1):60-67. doi:10.1016/S1474-4422(20)30392-6

14. Kim W, Kim HJ. Monoclonal antibody therapies for multiple sclerosis and neuromyelitis optica spectrum disorder. J Clin Neurol. 2020;16(3):355-368. doi:10.3988/jcn.2020.16.3.355

15. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614-625. doi:10.1056/NEJMoa1900866

Reviewed by Kyle Habet, MD, on 10/14/2021.

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