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Vol. 36. Issue 8.
Pages 642-643 (October 2021)
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Vol. 36. Issue 8.
Pages 642-643 (October 2021)
Letter to the Editor
Open Access
Should tocilizumab be the first line treatment for neuromyelitis optica together with rituximab?
¿Debería ser el tocilizumab el tratamiento de primera línea para la neuromielitis óptica junto con el rituximab?
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R. Sawaya
Corresponding author
rs01@aub.edu.lb

Corresponding author.
, G. Saab, H. Moussa
Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
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Dear Editor,

Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system (CNS). The disorder affects the optic nerves, spinal cord and area postrema of the brain stem. 75% of patients diagnosed with NMOSD will have antibodies against the aquaporin 4 water channel (AQP4-abs) expressed on the astrocytes. Of the patients who do not have the AQP4-abs, 40% will have antibodies against the myelin oligodendrocyte glycoprotein (MOG-abs) present on the surface of oligodendrocytes which are the cells responsible in forming the CNS myelin. Around 50% of patients suffering from NMOSD will be wheel chair bound and blind within 5 years of their first attack if left untreated, and a third would have died.1,2

Plasmablasts (PB), which are a subpopulation of B cells, are increased in the peripheral blood of patients with NMOSD These B cells upregulate humoral immune response by producing antibodies and activating T cells by antigen presentation. Several studies have indicated a crucial role of B cells in the pathogenesis of NMOSD.3,4

Rituximab (RTX), a B-cell depleting monoclonal antibody, is being used as a first line treatment for NMOSD. RTX reduces relapse rates by up to 84.3% and is either given every 6 months or when the CD 19 counts of the total B-cell population rises above 1%.3,5 On the other hand, patients who develop a longitudinally extensive transverse myelitis (LETM), which is the hallmark for NMOSD, have a 50% risk of a major spinal cord relapse within 12 months if they have the AQP4 abs and did not receive treatment, and a 15.6% relapse rate within 6 months after the induction dose of RTX. The relapse is usually devastating leaving permanent neurologic deficits and may well occur before the time of the second dose of RTX.1,5

Interleukin 6 (IL-6) is produced at the site of inflammation and plays a key role in the acute phase response. IL-6 in combination with its soluble receptor sIL-6Rα, dictates the transition from acute to chronic inflammation by changing the nature of leukocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages). In addition, IL-6 exerts stimulatory effects on T- and B-cells, thus favoring chronic inflammatory responses. Strategies targeting IL-6 and IL-6 signaling led to effective prevention and treatment of models of rheumatoid arthritis and other chronic inflammatory diseases. Studies have shown that IL-6 promotes the survival of PB and their production of AQP4-abs. Data suggests that the AQP4-abs induce IL-6 production in astrocytes expressing the AQP4, and that IL-6 signaling to endothelial cells reduces blood-brain barrier function. This results in further systemic AQP4-abs entering the CNS. Once bound to the AQP4 receptor on the astrocyte, the AQP4 abs result in complement and cell-mediated astrocytic damage. The damaged astrocytes will eventually withdraw support to the nearby oligodendrocyte. Granulocytes will invade further the region resulting in demyelination.1,4

Tocilizumab (TCZ) is an IL-6 receptor inhibitor. It binds soluble as well as membrane bound IL-6 receptors, hindering it from exerting its pro-inflammatory effects. TCZ treatment recently showed efficacy for patients with aggressive NMO who were refractory to the anti-CD20 antibody RTX.4 The efficacy of TCZ could result from its effect on IL-6-dependent inflammatory processes, involving CD20-negative plasmablasts, pathogenic T cells, and regulatory T cells.4 TCZ reduces the level of AQP4-abs in the serum and CSF of patients with NMOSD. It can reduce the frequency of attacks in NMO without concomitant immunosuppression, even in patients with high disease activity.6,7

Zhang et al. compared the efficacy of TCZ to azathioprine in the second line treatment of NMOSD. The incidence of serious adverse events was higher in the azathioprine group than the tocilizumab group. The most commonly reported adverse events were increased alanine transaminase concentrations, upper respiratory tract infections, and urinary tract infections.8,9

We suggest the use of TCZ, together with RTX, as a first line therapy for the treatment of NMOSD. This is important especially in patients with positive AQP4-abs and before relapses occur resulting in major disability. The combined therapy will not result in a critical immunosuppression and will have less side effect than the present combination treatments.

References
[1]
S. Huda, D. Whittam, M. Bhojak, J. Chamberlain, C. Noonan, A. Jacob.
Neuromyelitis optica spectrum disorders.
Clin Med (Lond), 19 (2019), pp. 169-176
[2]
M. Lindner, L. Klotz, H. Wiendl.
Mechanisms underlying lesion development and lesion distribution in CNS autoimmunity.
J Neurochem, 146 (2018), pp. 122-132
[3]
J. Han, L. Sun, X. Fan, Z. Wang, Y. Cheng, J. Zhu, et al.
Role of regulatory b cells in neuroimmunologic disorders.
J Neurosci Res, 94 (2016), pp. 693-701
[4]
M. Araki, T. Matsuoka, K. Miyamoto, S. Kusunoki, T. Okamoto, M. Murata, et al.
Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study.
Neurology, 82 (2014), pp. 1302-1306
[5]
H. Zephir, R. Bernard-Valnet, Lebrun Ch, O. Outteryck, B. Audoin, B. Bourre, et al.
Rituximab as first-line therapy in neuromyelitis optica: efficiency and tolerability.
J Neurol, 262 (2015), pp. 2329-2335
[6]
M. Ringelstein, I. Ayzenberg, J. Harmel, A.S. Lauenstein, E. Lensch, F. Stögbauer, et al.
Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder.
JAMA Neurol, 72 (2015), pp. 756-763
[7]
N. Collongues, D. Brassat, E. Maillart, P. Labauge, J.C. Ouallet, C. Carra-Dalliere, et al.
OFSEP and CFSEP Efficacy of rituximab in refractory neuromyelitis optica.
Mult Scler, 22 (2016), pp. 955-959
[8]
I. Lotan, R. McGowan, M. Levy.
Anti- IL-6 therapies for neuromyelitis optica spectrum disorders: a systematic review of safety and efficacy.
[9]
C. Zhang, M. Zhang, W. Qiu, H. Ma, X. Zhang, Z. Zhu, et al.
Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.
Lancet Neurol, 19 (2020), pp. 391-401
Copyright © 2020. Sociedad Española de Neurología
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