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Review
. 2021 Dec;268(12):4522-4536.
doi: 10.1007/s00415-020-10235-5. Epub 2020 Oct 3.

Recent progress in maintenance treatment of neuromyelitis optica spectrum disorder

Trygve Holmøy  1   2 , Rune Alexander Høglund  3   4 , Zsolt Illes  5   6 , Kjell-Morten Myhr  7   8 , Øivind Torkildsen  7   8
Affiliations
Review

Recent progress in maintenance treatment of neuromyelitis optica spectrum disorder

Trygve Holmøy et al. J Neurol. 2021 Dec.

Abstract

Background: Treatment of neuromyelitis optica spectrum disorder (NMOSD) has so far been based on retrospective case series. The results of six randomized clinical trials including five different monoclonal antibodies targeting four molecules and three distinct pathophysiological pathways have recently been published.

Methods: Literature search on clinical trials and case studies in NMOSD up to July 10. 2020.

Results: We review mechanism of action, efficacy and side effects, and consequences for reproductive health from traditional immunosuppressants and monoclonal antibodies including rituximab, inebilizumab, eculizumab, tocilizumab and satralizumab.

Conclusion: In NMOSD patients with antibodies against aquaporin 4, monoclonal antibodies that deplete B cells (rituximab and inebilizumab) or interfere with interleukin 6 signaling (tocilizumab and satralizumab) or complement activation (eculizumab) have superior efficacy compared to placebo. Tocilizumab and rituximab were also superior to azathioprine in head-to-head studies. Rituximab, tocilizumab and to some extent eculizumab have well-known safety profiles for other inflammatory diseases, and rituximab and azathioprine may be safe during pregnancy.

Keywords: Demyelinating diseases; Monoclonal antibodies; Neuromyelitis optica spectrum disorder; Treatment.

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Conflict of interest statement

Trygve Holmøy has received speakers’ honoraria and/or unrestricted research grants from Biogen, Roche, Sanofi and Merck, and has been principal investigator in studies sponsored by Biogen, Merck and Roche. Rune A. Høglund has received speakers’ honoraria and/or unrestricted grants from Biogen, Merck, Roche and Novartis, and participated as investigator in study sponsored by Roche. Zsolt Illes has received speakers’ honoraria and/or research grants from Biogen, Roche, Sanofi, Novartis and Merck, has been member of advisory boards at Alexion, Biogen, Sanofi, Merck, Roche, Novartis, was member of the adjudication relapse committee in the SAkuraStar and SAkuraSky trials, and has been principal investigator in studies sponsored by Biogen, Merck and Sanofi. Øivind Torkildsen has received speakers’ honoraria and/or unrestricted research grants from Biogen, Roche, Novartis, Merck and Sanofi and has been principal investigator in studies sponsored by Sanofi. Kjell-Morten Myhr has received unrestricted research grants to his institution; scientific advisory board, and speakers’ honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, or Teva; and has participated in clinical trials organized by Biogen, Merck, Novartis, or Roche.

Figures

Fig. 1
Fig. 1
Pathogenesis and drug targets in NMOSD. Aquaporin 4 (AQP4)-specific B cells mature and differentiate in the periphery to memory cells or AQP4-IgG secreting cells (1). T cells may interact with B cells or dendritic cells, and upon stimuli including IL-6 T cells differentiate to pro-inflammatory Th17 cells that can cross the blood brain barrier (2). Inflammatory conditions allow both antibodies and complement factors to traverse the blood brain barrier and bind to AQP4 on astrocytic end feet (3). This activates complement through C1q ligation leading to formation of C5a and C5b. C5b is part of the membrane attack complexes (MAC) (4). C5a recruits pro-inflammatory leukocytes, including eosinophils, neutrophils, natural killer (NK) cells, and macrophages (5), capable of antibody dependent cellular cytotoxicity or inflammatory degranulation through Fc receptor activation (6). Astrocytes targeted by these mechanisms undergo destruction, and oligodendrocytes and neurons lose their supportive functions (7). The IL-6R blockers satralizumab and tocilizumab (A) suppress differentiation of AQP-IgG antibody secreting cells (ASC), as well as generation of pro-inflammatory Th17 T cells and M1 macrophages in favour of regulatory T cells and M2 macrophages. Rituximab (B1) kills cells expressing CD20 (mainly naïve and memory B cells, but also some T cells), while inebilizumab (B2) depletes a wider proportion of the B cell repertoire expressing CD19, including some antibody secreting cells. Both rituximab and inebilizumab deplete antigen presenting memory B cells. Eculizumab (C) blocks the complement cascade by binding complement component 5 (C5), halting generation of MAC through C5b and recruitment of pro-inflammatory cells through C5a. Printed with permission from © Kari C. Toverud
Fig. 2
Fig. 2
Endosomal processing of tocilizumab and satralizumab. The IL-6 receptor (IL6R) is present on a vast array of cells in the immune system, and also exists in soluble form in circulation. Membrane bound IL-6R (mIL-6R) or the soluble variant (sIL-6R) interacts with glycoprotein 130 (gp130) upon ligation with IL-6. Gp130 acts as a signal transducer into the cell that regulates expression of proteins involved in inflammation and cell homeostasis. Upon binding to mIL-6R, the receptor is brought intracellularly into endosomal compartments, where pH drops. Satralizumab, unlike the closely related tocilizumab, was specifically engineered with alterations in both variable regions to dissociate from IL-6R at low pH, and changes in the constant regions to simultaneously maintain affinity for neonatal Fc receptors (FcRn). FcRn are present in the endosomes, and allow satralizumab to recirculate to the cell surface and re-bind another s/mIL-6Rs thus enabling extended dosage protocol. Printed with permission from © Kari C. Toverud
Fig. 3
Fig. 3
Mechanism of eculizumab. Eculizumab binds complement component 5 (C5) and prevents cleavage into C5a and C5b by C5 convertase. C5a is a potent attractant for leukocytes. C5b can form a complex with C6, and form the basis for formation of the membrane attack complex (MAC), which includes additional complement components. Printed with permission from © Kari C. Toverud
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