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DTT 2024; 3(2): 198-205
Published online September 30, 2024
https://doi.org/10.58502/DTT.24.0003
Copyright © The Pharmaceutical Society of Korea.
Haw-Hyeong Lee 
, Sang-Bae Han , Key-Hwan Lim
Correspondence to:Key-Hwan Lim, khlim@chungbuk.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Neuromyelitis optica spectrum disorder (NMOSD) is an infrequent inflammatory autoimmune disorder of the central nervous system, that affects the spinal cord and optic nerves. Aquaporin 4 IgG (AQP4-IgG) is a seropositive-specific antibody detected in the serum of a patient with NMO. AQP4-IgG binds to AQP4 via the astrocyte end-feet, causing a classical complement cascade that results in an inflammatory response-induced astrocyte injury and a secondary response involving oligodendrocyte loss and demyelination. NMO causes severe relapses and affects women more than men. A patient with NMO experiences pain primarily as transverse myelitis with longitudinally extensive recurrences or bilateral optic neuritis. Treating NMOSD poses considerable clinical challenges. This review provides an overview of the state-of-the-art studies summarizing the pain, prevalence, and primary pathology of NMOSD and discusses several potential therapeutic targets for its treatment.
Keywordsneuromyelitis optica, AQP4-IgG, optic neuritis, multiple sclerosis, rituximab
Neuromyelitis optica spectrum disorder (NMOSD) is an infrequent, mediated neuroinflammatory autoimmune disorder of the central nervous system (CNS) characterized by recurrent severe attacks on the spinal cord and optic nerves caused by transverse myelitis with longitudinally extensive recurrences or bilateral optic neuritis. (Kim et al. 2011; Chan et al. 2012; Mao-Draayer et al. 2020; Siriratnam et al. 2023). Previously, NMO was recognized as multiple sclerosis (MS); however, a patient with NMO was seropositive for the specific aquaporin 4 immunoglobulin G antibody (AQP4-IgG). This antibody was detected in sera of 70-80% of patients with NMO, differentiating NMO from MS (Wingerchuk and Lucchinetti 2007). Several factors contribute to NMO pathogenesis, among which the presence of the aquaporin 4 immunoglobulin G antibody (AQP4-IgG) is prominent. This antibody triggers severe relapses characterized by symptoms such as blindness, paralysis, and muscle spasms. In addition, AQP4-IgG was undetected in several patients with NMO; only a seronegative subset of a myelin oligodendrocyte glycoprotein (MOG-IgG) was detected in patient sera (Mao-Draayer et al. 2020; Marignier et al. 2021; Wu et al. 2023). AQP4-IgG binds to AQP4, a water channel protein expressed in the perivascular astrocyte end-feet and ependymal cells of the CNS (Bradl et al. 2014; Jarius et al. 2020). Its binding activates the classical complement cascade, dystrophic astrocytes, as well as monocytes, neutrophils, and eosinophils, resulting in inflammatory cell recruitment and activation; the secondary responses include demyelination, oligodendrocyte, and neuronal loss (Papadopoulos et al. 2014). The prevalence of NMO ranges from 0.1 to 4.4 cases per 100,000 individuals, with a disease onset age of 35-45 years; this distinguishes NMO from MS, where the disease onset is much earlier at 25-29 years of age (Papadopoulos et al. 2014). The ratio of female and male patients with NMO revealed that the disease was more prevalent in women at a ratio of approximately 9:1. Additionally, the NMO mortality rate was 9-32% depending on individual patient treatment, age, and relapsing course (Mealy et al. 2018). The onset and progression of NMO is clinically variable; hence, the underlying molecular mechanisms and biomarkers remain unclear. Therefore in this review, we compared recurrent reviews and up-to-date advanced pathogenetic mechanisms of NMO, and summarized several clinical drugs utilized for NMO treatment.
MS is an associated autoimmune demyelinating disorder of the CNS. It has similar clinical characteristics as that of NMO (Yang et al. 2022), which was recognized as MS previously. In 1894, Dr. Eugene Devic first described NMO and initiated a diagnostic criterion, which was established based on the patient’s reported symptoms of optic neuritis and myelitis, finalized in 1999 (Pereira et al. 2015). Devic discovered a patient with NMO who was seropositive for specific AQP4-IgG in 2004. This antibody was detected in the sera of approximately 70-80% of patients with NMO, a crucial factor in distinguishing NMO from MS (Carnero Contentti and Correale 2021). This seropositive antibody was one of the NMO diagnostic criteria, which now also involved a new condition a brain lesion and Longitudinal extensive transverse myelitis (LETM) in 2006. After this discovery, the condition was clinically described as NMOSD, involving seropositive patients. Finally, in 2015, Dean M. Wingerchuk published the NMO diagnostic criteria as per the International Panel for NMO Diagnosis, of which an important criterion is the presence of AQP4-IgG (Wingerchuk et al. 2015; Chang and Chang 2020). According to Wingerchuk et al., at least one core clinical characteristic must be present to accurately diagnose NMOSD, in addition to AQP4-IgG. A positive AQP4-IgG test must also be obtained using the best available detection technique, as well as the exclusion of alternative diagnoses. In addition, the myelin oligodendrocyte glycoprotein antibody (MOG-IgG) was ~15% seronegative in patients with NMO. MOG-IgG has a different immunopathogenesis from AQP4-IgG seropositive NMOSD (Carnero Contentti and Correale 2021).
Several reviews have already described the prevalence of NMOSD, which ranges from approximately 0.1-4.4 cases per 100,000 individuals, with a prevalence of 0.06-0.22 per 100,000 children (Poisson et al. 2023). In 2015, the highest prevalence was observed in South Korea and Brazil (Kim et al. 2020; Min et al. 2023). The average age of disease onset is 35-45 years, which is later than that of MS (25-29 years) (Zekeridou and Lennon 2015). This disease is more prevalent in women. A ratio of 10:1 women to men are more likely to undergo surgery, and a ratio of 2:1 women to men are seropositive for NMO. This ratio is more than that of MS and seronegative NMOSD (Wu et al. 2019; Huda et al. 2019). The primary symptoms of this disease are recurrent or bilateral optic neuritis and LETM. Other common symptoms include intractable hiccups, nausea, and vomiting as major manifestations (Chang and Chang 2020; Wallach et al. 2021). A relapsing course usually occurs, resulting in blindness, paralysis, and muscle spasms in many patients (Bradl et al. 2014). Patients with severe NMO die within a month after onset. During the third trimester of pregnancy and the postpartum period, there is a notable rise in the frequency of relapses, potentially attributed to heightened levels of estrogen. Pregnant women face an elevated risk of issues like miscarriages and preeclampsia during gestation (Siriratnam et al. 2023).
Aquaporin has 12 identified members; aquaporin 4 is encoded by the AQP4 gene in humans and is a water channel protein. Its expression is the highest in the CNS of perivascular astrocyte end-feet and ependymal cells (Verkman et al. 2017). AQP4 essentially regulates various organs, including the kidney, the gastrointestinal, internal ear, nervous system, and muscles (Benarroch 2007). AQP4 monomer consists of six membrane-spanning alpha-helical tract domains and two short helical segments that surround a narrow aqueous pore (Vaishnav et al. 2013). Aquaporin 4 monomers aggregate to form tetramers, and they form a supramolecular complex and structure component in plasma membrane using the orthogonal array of particles (OAPs) (Crane and Verkman 2009). AQP4 has two major different isoforms produced via alternative splicing: a long isoform with translation initiated at Met-1 (AQP4-M1), and a short isoform with translation initiated at Met-23 (AQP4-M23) (Verkman et al. 2011; Zhu et al. 2022). Two isoforms are expressed in astrocytes. Aquaporin 4 regulates the extracellular space volume, spatial buffering of potassium ions, cerebrospinal fluid circulation, absorption of interstitial fluid, clearance of waste products, modulation of neuroinflammation, osmosensation, facilitation of cell migration, and modulation of calcium (Ca2+) signaling (Nagelhus and Ottersen 2013).
Previous studies have shown that approximately 70–80% of NMO patient serum was detected with AQP4 autoantibodies. This antibody type is IgG1, and the pathology of aquaporin-4 IgG is shown in Fig. 1. This mechanism is B and helper T cell-mediated, which divides into a plasma cell. AQP4-IgG is initially produced here and crosses the blood-brain barrier, binding to AQP4 in the astrocyte end-feet. This causes complement activation, and the classical complement cascade begins. The binding of C1q to the conformational Fc determinants on IgG or IgM antibody-antigen complexes is a pivotal step in the activation of the classical complement pathway (Soltys et al. 2019). AQP4-IgG binding AQP4 is caused by a classical complement cascade that activates two cytotoxicity types: antibody-dependent cellular cytotoxicity (ADCC), which also involves complement-dependent cytotoxicity (CDC). (Mader and Brimberg 2019; Duan et al. 2020) First, ADCC plays a role in astrocyte injuries initiated by the interaction of AQP4-IgG with extracellular epitopes of AQP4 on the astrocyte plasma membrane, particularly in the case of AQP4-IgG seropositive in NMOSD (Tuller et al. 2016). In the process of ADCC, the Fc region of AQP4-IgG interacts with Fcγ receptors on effector leukocytes, leading to the activation and degranulation of neutrophils, macrophages, and natural killer cells (Ratelade and Verkman 2012). This cascade leads to localized cellular injury and tissue damage (Ratelade et al. 2013; Duan et al. 2019; Kim et al. 2024). Second, complement-dependent cytotoxicity is an innate immune system in part of the complement system, and its overactivation or misdirected activation can be deleterious (Xu et al. 2025). In NMOSD, C1q binding to the Fc region of AQP4-IgG initiates activation of the classical complement pathway, amplifying the inflammatory reaction by producing proinflammatory (C3a, C4a, and C5a), and this cascade culminates in the generation of the membrane attack complex (MAC), which inserts into the target cell membrane, forming pores that compromise membrane integrity, ultimately resulting in target cell lysis and prompting the infiltration and activation of monocytes, neutrophils, and eosinophils (such as inflammatory cells) (Phuan et al. 2012; Tradtrantip et al. 2021; Nishiyama et al. 2024). AQP4-IgG activated astrocytes therefore induce prominent microglia activation (Fukuda and Badaut 2012). This results in the activated pro-inflammatory cytokine as well as including TNF-A, IL-1beta, and IL-6 (Yick et al. 2023). Subsequently, NMO is characterized pathologically by significant astrocyte injuries, initiating secondary responses, such as demyelination, oligodendrocyte, and neuronal loss (Siriratnam et al. 2023).
Figure 1.B-cell initiation by helper T-cell produces a plasma cell that generates an NMO-specific antibody termed as aquaporin 4 IgG (AQP4-IgG). This antibody crosses the blood-brain barrier (BBB) and binds to Aquaporin 4, activating the complement and classical complement cascade that causes astrocyte injury. Neutrophils, monocytes, and eosinophils (such as inflammatory cells) enter the BBB, followed by recruitment and activation. Secondary responses involve oligodendrocyte loss, demyelination, and neuron loss.
Eculizumab is a monoclonal IgG2 antibody that functions by selectively inhibiting the terminal complement protein C5. This inhibition prevents the cleavage of C5 into C5a and C5b, complements involved in the formation of the membrane attack complex (Levy et al. 2021; Wallach et al. 2021). It downregulates the adaptive and innate immune response through C5a in the periphery, and C5b on astrocytes in the CNS (Holmøy et al. 2021; Wingerchuk and Lucchinetti 2022). Eculizumab was approved by the US Food and Drug Administration in 2019 and is administered via intravenous injection (weekly for the first four doses, followed by every 2 weeks thereafter) (Giglhuber and Berthele 2020). The effectiveness of Eculizumab is particularly pronounced in lowering the relapse rate among individuals with detectable AQP4-IgG antibodies (Davis 2008; Frampton 2020). However, this treatment increases the risk of infection, particularly for meningococcal infections, necessitating vaccination or prophylactic antibiotics before administration, which causes headache and nausea (Sudhakar et al. 2023).
Satralizumab is an immunoglobulin G2 monoclonal antibody that inhibits relapses in NMO disorders by inhibiting intracellular interleukin-6 (IL-6) signaling (Wingerchuk and Lucchinetti 2022). The mechanism of action of Satralizumab involves inhibition of IL-6-mediated autoimmune responses through blocking IL-6 receptor binding and subsequent interference with IL-6 signaling pathways associated with inflammation (Giglhuber and Berthele 2022). It received approval from the food and drug administration in 2020 and is administered via subcutaneous injection; it is initially administered three times at 2 week intervals, followed by maintenance doses every 4 weeks, allowing patients to self-administer the drug at home (Heo 2020). Satralizumab is reported to be significantly effective in patients exhibiting several relapses that are seropositive for the AQP4-IgG antibody (Yamamura et al. 2019; Fung and Shirley 2023). Some of the most observed adverse reactions include headaches, joint pain, and infusion-related reactions (Sudhakar et al. 2023).
Rituximab is a chimeric monoclonal/recombinant antibody and a type of “target” anticancer drug. It selectively binds to the CD20 antigen primarily expressed on the surface of memory B cells, which is widely distributed among B cell precursors to mature B cell stages but is not present on stem and plasma cells (Papadopoulos et al. 2014; Wingerchuk and Lucchinetti 2022; Demuth et al. 2023). It shows promising effects in treating autoimmune disorders primarily by targeting the CNS, where antibody-associated humoral immunity is the main pathological mechanism. Rituximab induces B cell depletion by triggering antibody-dependent cellular cytotoxicity, which is executed by natural killer cells. Complement-dependent cytotoxicity occurs and activates neutrophils, causing macrophage phagocytosis (Yong and Burton 2023). Current therapy using this drug reportedly exhibits the longest-lasting therapeutic effects and is more effective in approximately 70% of patients in reducing the relapse rate during the treatment period in comparison with azathioprine or mycophenolate; it also improved disability stabilization in 93% of patients (Kim et al. 2013). The most common side effects of rituximab are acute injection-related reactions that occur during drug administration, which are mild; however, hypotension, rash, and acute respiratory dyspnea syndrome can occur, in some severe cases, which can be a risk factor for severe opportunistic infections. In addition, it causes a risk of neutropenia and increased liver enzymes (Tahara et al. 2020; Shi et al. 2022).
Inebilizumab is similar to rituximab and, achieves relapse prevention in CNS disorders by depleting CD-19 expressing B cells through the action of its afucosylated monoclonal antibody (Yong and Burton 2023). It is administered via intravenous injection (initially at 2 week intervals and then every 6 months) for maintenance. Commonly observed adverse reactions include urinary tract infections, joint pain, lower back pain, and headaches (Tullman et al. 2021; Nie and Blair 2022).
Azathioprine is metabolized in the body into thiopurine nucleotides, which interfere with DNA synthesis and block de novo synthesis of purines, inhibiting humoral and cell-mediated immunity, thereby reducing lymphocyte levels and monocyte counts (Wingerchuk and Lucchinetti 2022). It is administered at a dosage of 2.0-3.0 mg/kg per day, with a therapeutic effect that may take several months to manifest (Kessler et al. 2016). Therefore, concurrent use of oral steroid preparations for approximately 6 months is necessary. Retrospective studies in patients with CNS disorders have reported a 70-89% reduction in relapse rates, with 38% of patients experiencing no relapse over a span of 2 years (Chan and Lee 2021). However, 38-46% of patients ultimately discontinued the medication because of side effects or inadequate therapeutic effects. Despite being relatively cost-effective compared to mycophenolate mofetil and rituximab, azathioprine exhibits a lower relapse prevention effect and cause adverse effects such as leukopenia, hemolytic anemia, gastrointestinal symptoms, hepatic dysfunction, and opportunistic infections. We have summarized NMO targeted drugs in Table 1.
Table 1 An overview of NMO target treatments
| Drug | Function | Reference |
|---|---|---|
| Eculizumab | Complement cascade blocking and suppressing relapses in NMO disorders of the central nervous system | Holmøy et al. 2021; Levy et al. 2021; Wallach et al. 2021 |
| Satralizumab | Interleukin 6 receptor inhibitor, reduces relapses in adults with aquaporin 4 autoantibody seropositive NMOSD | Fujihara et al. 2020; Wingerchuk and Lucchinetti 2022 |
| Rituximab | Monoclonal antibody against the CD20 antigen, which leads to B-cell depletion due to complement cytotoxicity and phagocytosis, and reduceds relapse in NMOSD | Papadopoulos et al. 2014; Wingerchuk and Lucchinetti 2022; Demuth et al. 2023 |
| Inebilizumab | Monoclonal antibody against the CD19 antigen, which depletes circulating B cells, suppressing inflammatory NMOSD attacks and reducing relapses in NMOSD | Yong and Burton 2023 |
| Azathioprine | Immunosuppressive medication to prevent relapses | Wingerchuk and Lucchinetti 2022 |
Most commonly reported clinical trials involve the preemptive administration of chemical or antibody-based agents for NMO therapies. Although many trials with these agents have been applied for NMO treatment, failures accompanied by immune suppression, headache, hypertension, and hematologic abnormalities have led to the development of new NMO-targeted therapies (Patejdl et al. 2016; Masters-Israilov and Robbins 2017; Waliszewska-Prosół et al. 2021). Recently, clinical trials have been initiated to investigate cell transplantation using hematopoietic or mesenchymal stem cells as a potential strategy to overcome the limitations of NMO treatment (Ramírez Camacho et al. 1988; Burt et al. 2019; Burton et al. 2021). While several therapeutic strategies for NMO treatment have been suggested, developing predictive biomarkers to guide or monitor the application of NMO treatment is important. In addition, unveiling molecular mechanisms during disease progression is particularly important when considering and monitoring patients with NMO. Although functional validation of NMO-specific biomarkers requires robust biopharmaceutical research, this can lead to the development of novel therapies to improve treatment for patients with NMO.
The authors declare that they have no conflict of interest.
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (2022R1C1C1002933), Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2024-00440787), and the research grant of the Chungbuk National University in 2022. The figure was created in BioRender.com.
DTT 2024; 3(2): 198-205
Published online September 30, 2024 https://doi.org/10.58502/DTT.24.0003
Copyright © The Pharmaceutical Society of Korea.
Haw-Hyeong Lee , Sang-Bae Han , Key-Hwan Lim
College of Pharmacy, Chungbuk National University, Cheongju, Korea
Correspondence to:Key-Hwan Lim, khlim@chungbuk.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Neuromyelitis optica spectrum disorder (NMOSD) is an infrequent inflammatory autoimmune disorder of the central nervous system, that affects the spinal cord and optic nerves. Aquaporin 4 IgG (AQP4-IgG) is a seropositive-specific antibody detected in the serum of a patient with NMO. AQP4-IgG binds to AQP4 via the astrocyte end-feet, causing a classical complement cascade that results in an inflammatory response-induced astrocyte injury and a secondary response involving oligodendrocyte loss and demyelination. NMO causes severe relapses and affects women more than men. A patient with NMO experiences pain primarily as transverse myelitis with longitudinally extensive recurrences or bilateral optic neuritis. Treating NMOSD poses considerable clinical challenges. This review provides an overview of the state-of-the-art studies summarizing the pain, prevalence, and primary pathology of NMOSD and discusses several potential therapeutic targets for its treatment.
Keywords: neuromyelitis optica, AQP4-IgG, optic neuritis, multiple sclerosis, rituximab
Neuromyelitis optica spectrum disorder (NMOSD) is an infrequent, mediated neuroinflammatory autoimmune disorder of the central nervous system (CNS) characterized by recurrent severe attacks on the spinal cord and optic nerves caused by transverse myelitis with longitudinally extensive recurrences or bilateral optic neuritis. (Kim et al. 2011; Chan et al. 2012; Mao-Draayer et al. 2020; Siriratnam et al. 2023). Previously, NMO was recognized as multiple sclerosis (MS); however, a patient with NMO was seropositive for the specific aquaporin 4 immunoglobulin G antibody (AQP4-IgG). This antibody was detected in sera of 70-80% of patients with NMO, differentiating NMO from MS (Wingerchuk and Lucchinetti 2007). Several factors contribute to NMO pathogenesis, among which the presence of the aquaporin 4 immunoglobulin G antibody (AQP4-IgG) is prominent. This antibody triggers severe relapses characterized by symptoms such as blindness, paralysis, and muscle spasms. In addition, AQP4-IgG was undetected in several patients with NMO; only a seronegative subset of a myelin oligodendrocyte glycoprotein (MOG-IgG) was detected in patient sera (Mao-Draayer et al. 2020; Marignier et al. 2021; Wu et al. 2023). AQP4-IgG binds to AQP4, a water channel protein expressed in the perivascular astrocyte end-feet and ependymal cells of the CNS (Bradl et al. 2014; Jarius et al. 2020). Its binding activates the classical complement cascade, dystrophic astrocytes, as well as monocytes, neutrophils, and eosinophils, resulting in inflammatory cell recruitment and activation; the secondary responses include demyelination, oligodendrocyte, and neuronal loss (Papadopoulos et al. 2014). The prevalence of NMO ranges from 0.1 to 4.4 cases per 100,000 individuals, with a disease onset age of 35-45 years; this distinguishes NMO from MS, where the disease onset is much earlier at 25-29 years of age (Papadopoulos et al. 2014). The ratio of female and male patients with NMO revealed that the disease was more prevalent in women at a ratio of approximately 9:1. Additionally, the NMO mortality rate was 9-32% depending on individual patient treatment, age, and relapsing course (Mealy et al. 2018). The onset and progression of NMO is clinically variable; hence, the underlying molecular mechanisms and biomarkers remain unclear. Therefore in this review, we compared recurrent reviews and up-to-date advanced pathogenetic mechanisms of NMO, and summarized several clinical drugs utilized for NMO treatment.
MS is an associated autoimmune demyelinating disorder of the CNS. It has similar clinical characteristics as that of NMO (Yang et al. 2022), which was recognized as MS previously. In 1894, Dr. Eugene Devic first described NMO and initiated a diagnostic criterion, which was established based on the patient’s reported symptoms of optic neuritis and myelitis, finalized in 1999 (Pereira et al. 2015). Devic discovered a patient with NMO who was seropositive for specific AQP4-IgG in 2004. This antibody was detected in the sera of approximately 70-80% of patients with NMO, a crucial factor in distinguishing NMO from MS (Carnero Contentti and Correale 2021). This seropositive antibody was one of the NMO diagnostic criteria, which now also involved a new condition a brain lesion and Longitudinal extensive transverse myelitis (LETM) in 2006. After this discovery, the condition was clinically described as NMOSD, involving seropositive patients. Finally, in 2015, Dean M. Wingerchuk published the NMO diagnostic criteria as per the International Panel for NMO Diagnosis, of which an important criterion is the presence of AQP4-IgG (Wingerchuk et al. 2015; Chang and Chang 2020). According to Wingerchuk et al., at least one core clinical characteristic must be present to accurately diagnose NMOSD, in addition to AQP4-IgG. A positive AQP4-IgG test must also be obtained using the best available detection technique, as well as the exclusion of alternative diagnoses. In addition, the myelin oligodendrocyte glycoprotein antibody (MOG-IgG) was ~15% seronegative in patients with NMO. MOG-IgG has a different immunopathogenesis from AQP4-IgG seropositive NMOSD (Carnero Contentti and Correale 2021).
Several reviews have already described the prevalence of NMOSD, which ranges from approximately 0.1-4.4 cases per 100,000 individuals, with a prevalence of 0.06-0.22 per 100,000 children (Poisson et al. 2023). In 2015, the highest prevalence was observed in South Korea and Brazil (Kim et al. 2020; Min et al. 2023). The average age of disease onset is 35-45 years, which is later than that of MS (25-29 years) (Zekeridou and Lennon 2015). This disease is more prevalent in women. A ratio of 10:1 women to men are more likely to undergo surgery, and a ratio of 2:1 women to men are seropositive for NMO. This ratio is more than that of MS and seronegative NMOSD (Wu et al. 2019; Huda et al. 2019). The primary symptoms of this disease are recurrent or bilateral optic neuritis and LETM. Other common symptoms include intractable hiccups, nausea, and vomiting as major manifestations (Chang and Chang 2020; Wallach et al. 2021). A relapsing course usually occurs, resulting in blindness, paralysis, and muscle spasms in many patients (Bradl et al. 2014). Patients with severe NMO die within a month after onset. During the third trimester of pregnancy and the postpartum period, there is a notable rise in the frequency of relapses, potentially attributed to heightened levels of estrogen. Pregnant women face an elevated risk of issues like miscarriages and preeclampsia during gestation (Siriratnam et al. 2023).
Aquaporin has 12 identified members; aquaporin 4 is encoded by the AQP4 gene in humans and is a water channel protein. Its expression is the highest in the CNS of perivascular astrocyte end-feet and ependymal cells (Verkman et al. 2017). AQP4 essentially regulates various organs, including the kidney, the gastrointestinal, internal ear, nervous system, and muscles (Benarroch 2007). AQP4 monomer consists of six membrane-spanning alpha-helical tract domains and two short helical segments that surround a narrow aqueous pore (Vaishnav et al. 2013). Aquaporin 4 monomers aggregate to form tetramers, and they form a supramolecular complex and structure component in plasma membrane using the orthogonal array of particles (OAPs) (Crane and Verkman 2009). AQP4 has two major different isoforms produced via alternative splicing: a long isoform with translation initiated at Met-1 (AQP4-M1), and a short isoform with translation initiated at Met-23 (AQP4-M23) (Verkman et al. 2011; Zhu et al. 2022). Two isoforms are expressed in astrocytes. Aquaporin 4 regulates the extracellular space volume, spatial buffering of potassium ions, cerebrospinal fluid circulation, absorption of interstitial fluid, clearance of waste products, modulation of neuroinflammation, osmosensation, facilitation of cell migration, and modulation of calcium (Ca2+) signaling (Nagelhus and Ottersen 2013).
Previous studies have shown that approximately 70–80% of NMO patient serum was detected with AQP4 autoantibodies. This antibody type is IgG1, and the pathology of aquaporin-4 IgG is shown in Fig. 1. This mechanism is B and helper T cell-mediated, which divides into a plasma cell. AQP4-IgG is initially produced here and crosses the blood-brain barrier, binding to AQP4 in the astrocyte end-feet. This causes complement activation, and the classical complement cascade begins. The binding of C1q to the conformational Fc determinants on IgG or IgM antibody-antigen complexes is a pivotal step in the activation of the classical complement pathway (Soltys et al. 2019). AQP4-IgG binding AQP4 is caused by a classical complement cascade that activates two cytotoxicity types: antibody-dependent cellular cytotoxicity (ADCC), which also involves complement-dependent cytotoxicity (CDC). (Mader and Brimberg 2019; Duan et al. 2020) First, ADCC plays a role in astrocyte injuries initiated by the interaction of AQP4-IgG with extracellular epitopes of AQP4 on the astrocyte plasma membrane, particularly in the case of AQP4-IgG seropositive in NMOSD (Tuller et al. 2016). In the process of ADCC, the Fc region of AQP4-IgG interacts with Fcγ receptors on effector leukocytes, leading to the activation and degranulation of neutrophils, macrophages, and natural killer cells (Ratelade and Verkman 2012). This cascade leads to localized cellular injury and tissue damage (Ratelade et al. 2013; Duan et al. 2019; Kim et al. 2024). Second, complement-dependent cytotoxicity is an innate immune system in part of the complement system, and its overactivation or misdirected activation can be deleterious (Xu et al. 2025). In NMOSD, C1q binding to the Fc region of AQP4-IgG initiates activation of the classical complement pathway, amplifying the inflammatory reaction by producing proinflammatory (C3a, C4a, and C5a), and this cascade culminates in the generation of the membrane attack complex (MAC), which inserts into the target cell membrane, forming pores that compromise membrane integrity, ultimately resulting in target cell lysis and prompting the infiltration and activation of monocytes, neutrophils, and eosinophils (such as inflammatory cells) (Phuan et al. 2012; Tradtrantip et al. 2021; Nishiyama et al. 2024). AQP4-IgG activated astrocytes therefore induce prominent microglia activation (Fukuda and Badaut 2012). This results in the activated pro-inflammatory cytokine as well as including TNF-A, IL-1beta, and IL-6 (Yick et al. 2023). Subsequently, NMO is characterized pathologically by significant astrocyte injuries, initiating secondary responses, such as demyelination, oligodendrocyte, and neuronal loss (Siriratnam et al. 2023).
Figure 1. B-cell initiation by helper T-cell produces a plasma cell that generates an NMO-specific antibody termed as aquaporin 4 IgG (AQP4-IgG). This antibody crosses the blood-brain barrier (BBB) and binds to Aquaporin 4, activating the complement and classical complement cascade that causes astrocyte injury. Neutrophils, monocytes, and eosinophils (such as inflammatory cells) enter the BBB, followed by recruitment and activation. Secondary responses involve oligodendrocyte loss, demyelination, and neuron loss.
Eculizumab is a monoclonal IgG2 antibody that functions by selectively inhibiting the terminal complement protein C5. This inhibition prevents the cleavage of C5 into C5a and C5b, complements involved in the formation of the membrane attack complex (Levy et al. 2021; Wallach et al. 2021). It downregulates the adaptive and innate immune response through C5a in the periphery, and C5b on astrocytes in the CNS (Holmøy et al. 2021; Wingerchuk and Lucchinetti 2022). Eculizumab was approved by the US Food and Drug Administration in 2019 and is administered via intravenous injection (weekly for the first four doses, followed by every 2 weeks thereafter) (Giglhuber and Berthele 2020). The effectiveness of Eculizumab is particularly pronounced in lowering the relapse rate among individuals with detectable AQP4-IgG antibodies (Davis 2008; Frampton 2020). However, this treatment increases the risk of infection, particularly for meningococcal infections, necessitating vaccination or prophylactic antibiotics before administration, which causes headache and nausea (Sudhakar et al. 2023).
Satralizumab is an immunoglobulin G2 monoclonal antibody that inhibits relapses in NMO disorders by inhibiting intracellular interleukin-6 (IL-6) signaling (Wingerchuk and Lucchinetti 2022). The mechanism of action of Satralizumab involves inhibition of IL-6-mediated autoimmune responses through blocking IL-6 receptor binding and subsequent interference with IL-6 signaling pathways associated with inflammation (Giglhuber and Berthele 2022). It received approval from the food and drug administration in 2020 and is administered via subcutaneous injection; it is initially administered three times at 2 week intervals, followed by maintenance doses every 4 weeks, allowing patients to self-administer the drug at home (Heo 2020). Satralizumab is reported to be significantly effective in patients exhibiting several relapses that are seropositive for the AQP4-IgG antibody (Yamamura et al. 2019; Fung and Shirley 2023). Some of the most observed adverse reactions include headaches, joint pain, and infusion-related reactions (Sudhakar et al. 2023).
Rituximab is a chimeric monoclonal/recombinant antibody and a type of “target” anticancer drug. It selectively binds to the CD20 antigen primarily expressed on the surface of memory B cells, which is widely distributed among B cell precursors to mature B cell stages but is not present on stem and plasma cells (Papadopoulos et al. 2014; Wingerchuk and Lucchinetti 2022; Demuth et al. 2023). It shows promising effects in treating autoimmune disorders primarily by targeting the CNS, where antibody-associated humoral immunity is the main pathological mechanism. Rituximab induces B cell depletion by triggering antibody-dependent cellular cytotoxicity, which is executed by natural killer cells. Complement-dependent cytotoxicity occurs and activates neutrophils, causing macrophage phagocytosis (Yong and Burton 2023). Current therapy using this drug reportedly exhibits the longest-lasting therapeutic effects and is more effective in approximately 70% of patients in reducing the relapse rate during the treatment period in comparison with azathioprine or mycophenolate; it also improved disability stabilization in 93% of patients (Kim et al. 2013). The most common side effects of rituximab are acute injection-related reactions that occur during drug administration, which are mild; however, hypotension, rash, and acute respiratory dyspnea syndrome can occur, in some severe cases, which can be a risk factor for severe opportunistic infections. In addition, it causes a risk of neutropenia and increased liver enzymes (Tahara et al. 2020; Shi et al. 2022).
Inebilizumab is similar to rituximab and, achieves relapse prevention in CNS disorders by depleting CD-19 expressing B cells through the action of its afucosylated monoclonal antibody (Yong and Burton 2023). It is administered via intravenous injection (initially at 2 week intervals and then every 6 months) for maintenance. Commonly observed adverse reactions include urinary tract infections, joint pain, lower back pain, and headaches (Tullman et al. 2021; Nie and Blair 2022).
Azathioprine is metabolized in the body into thiopurine nucleotides, which interfere with DNA synthesis and block de novo synthesis of purines, inhibiting humoral and cell-mediated immunity, thereby reducing lymphocyte levels and monocyte counts (Wingerchuk and Lucchinetti 2022). It is administered at a dosage of 2.0-3.0 mg/kg per day, with a therapeutic effect that may take several months to manifest (Kessler et al. 2016). Therefore, concurrent use of oral steroid preparations for approximately 6 months is necessary. Retrospective studies in patients with CNS disorders have reported a 70-89% reduction in relapse rates, with 38% of patients experiencing no relapse over a span of 2 years (Chan and Lee 2021). However, 38-46% of patients ultimately discontinued the medication because of side effects or inadequate therapeutic effects. Despite being relatively cost-effective compared to mycophenolate mofetil and rituximab, azathioprine exhibits a lower relapse prevention effect and cause adverse effects such as leukopenia, hemolytic anemia, gastrointestinal symptoms, hepatic dysfunction, and opportunistic infections. We have summarized NMO targeted drugs in Table 1.
Table 1 . An overview of NMO target treatments.
| Drug | Function | Reference |
|---|---|---|
| Eculizumab | Complement cascade blocking and suppressing relapses in NMO disorders of the central nervous system | Holmøy et al. 2021; Levy et al. 2021; Wallach et al. 2021 |
| Satralizumab | Interleukin 6 receptor inhibitor, reduces relapses in adults with aquaporin 4 autoantibody seropositive NMOSD | Fujihara et al. 2020; Wingerchuk and Lucchinetti 2022 |
| Rituximab | Monoclonal antibody against the CD20 antigen, which leads to B-cell depletion due to complement cytotoxicity and phagocytosis, and reduceds relapse in NMOSD | Papadopoulos et al. 2014; Wingerchuk and Lucchinetti 2022; Demuth et al. 2023 |
| Inebilizumab | Monoclonal antibody against the CD19 antigen, which depletes circulating B cells, suppressing inflammatory NMOSD attacks and reducing relapses in NMOSD | Yong and Burton 2023 |
| Azathioprine | Immunosuppressive medication to prevent relapses | Wingerchuk and Lucchinetti 2022 |
Most commonly reported clinical trials involve the preemptive administration of chemical or antibody-based agents for NMO therapies. Although many trials with these agents have been applied for NMO treatment, failures accompanied by immune suppression, headache, hypertension, and hematologic abnormalities have led to the development of new NMO-targeted therapies (Patejdl et al. 2016; Masters-Israilov and Robbins 2017; Waliszewska-Prosół et al. 2021). Recently, clinical trials have been initiated to investigate cell transplantation using hematopoietic or mesenchymal stem cells as a potential strategy to overcome the limitations of NMO treatment (Ramírez Camacho et al. 1988; Burt et al. 2019; Burton et al. 2021). While several therapeutic strategies for NMO treatment have been suggested, developing predictive biomarkers to guide or monitor the application of NMO treatment is important. In addition, unveiling molecular mechanisms during disease progression is particularly important when considering and monitoring patients with NMO. Although functional validation of NMO-specific biomarkers requires robust biopharmaceutical research, this can lead to the development of novel therapies to improve treatment for patients with NMO.
The authors declare that they have no conflict of interest.
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (2022R1C1C1002933), Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2024-00440787), and the research grant of the Chungbuk National University in 2022. The figure was created in BioRender.com.
Table 1 An overview of NMO target treatments
| Drug | Function | Reference |
|---|---|---|
| Eculizumab | Complement cascade blocking and suppressing relapses in NMO disorders of the central nervous system | Holmøy et al. 2021; Levy et al. 2021; Wallach et al. 2021 |
| Satralizumab | Interleukin 6 receptor inhibitor, reduces relapses in adults with aquaporin 4 autoantibody seropositive NMOSD | Fujihara et al. 2020; Wingerchuk and Lucchinetti 2022 |
| Rituximab | Monoclonal antibody against the CD20 antigen, which leads to B-cell depletion due to complement cytotoxicity and phagocytosis, and reduceds relapse in NMOSD | Papadopoulos et al. 2014; Wingerchuk and Lucchinetti 2022; Demuth et al. 2023 |
| Inebilizumab | Monoclonal antibody against the CD19 antigen, which depletes circulating B cells, suppressing inflammatory NMOSD attacks and reducing relapses in NMOSD | Yong and Burton 2023 |
| Azathioprine | Immunosuppressive medication to prevent relapses | Wingerchuk and Lucchinetti 2022 |
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