Исследования " горячих точек " и новые темы для лечения расстройства спектра нейромиелита: Отчёты по библиометрическому анализу.

1. Introduction

Neuromyelitis optica spectrum disorder (NMOSD) encompasses a range of inflammatory conditions that are characterized by recurrent episodes, with the optic nerves and spinal cord being the main sites of involvement. From a microscopic perspective, patients produce a specific autoantibody known as aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). This antibody binds to AQP4 on the astrocytic foot processes at the surface of microvessels, the spinal cord gray matter, the ocular globe, the subarachnoid space of the optic nerve, around the mesencephalic aqueduct, and the periventricular regions, forming immune complexes. This, in turn, activates the complement immune system to produce an immune response, leading to demyelination, neuronal damage, and necrosis. [ 1 , 2 ] Approximately 70% to 80% of individuals with NMOSD exhibit positive results for AQP4-IgG antibody testing. The antibody triggers the disease through various mechanisms, including inflammatory responses, amplification of immune responses, antibody-dependent cellular cytotoxicity, disruption of aquaporin function, early granulocyte recruitment, and complement-dependent cytotoxicity. Studies have shown that undiagnosed and untreated NMOSD patients are associated with disability and poor prognosis, and the degree of disability accumulates with each relapse. Therefore, preventing relapses is crucial in the disease management of NMOSD. [ 3 ] With a deeper understanding of its pathological mechanisms, the therapy for NMOSD is rapidly evolving and gradually becoming a research focus. These treatment strategies aim to control the disease, reduce relapse rates, alleviate the progression of disability, and elevate the living standards of patients by precisely regulating the relevant molecular and cellular pathways.

Bibliometrics, functioning as a thorough and unbiased approach to scientific data analysis, offers an advantageous way to delve into the knowledge architecture, developmental trajectories, hotspots, trends, and the contributions of various researchers, institutions, and countries. [ 4 ] Up to now, there has been a lack of bibliometric research in the field of treatment for NMOSD. To fill this research gap, we have conducted a bibliometric analysis and built visualization charts for the first time in this area.

2. Materials and methods

2.1. Data collection and search strategies

In this research, we gathered all publications on NMOSD therapy from the WoSCC spanning the years 2004 to 2023, with data extraction conducted on September 8, 2024. For specifics on the retrieval, filtering, and bibliometric processes, consult Appendix 1, Supplemental Digital Content, https://links.lww.com/MD/P168 and Figure 1 A. Additionally, we have archived the complete data and citation details of 3044 pertinent documents in plaintext for subsequent detailed analysis. Two researchers, Wang, and Cai, screened out irrelevant literature, with disagreements resolved through discussion.

(A) The flow diagram of literature enrollment and data screening; (B) annual output and citation counts of publications on NMOSD treatment from 2004 to 2023. NMOSD = neuromyelitis optica spectrum disorder.

2.2. Data analysis

For the management, analysis, and visualization of data, tools such as VOSviewer, Bibliometrix, CiteSpace, and Microsoft Office Excel 2019, were employed. VOSviewer and CiteSpace, which are Java-based software for bibliometric analysis and visualization, each have their unique strengths. VOSviewer boasts robust visualization features, whereas CiteSpace excels in uncovering and examining latent information within the literature. Bibliometrix, a comprehensive bibliometric research tool developed in R, facilitates the entire process from gathering data to generating visual representations. [ 5 ]

Within the scope of this research, we leveraged Excel 2019 to create bar graphs depicting the aggregate annual output of scholarly articles and their corresponding citation frequencies, as well as the publication volumes of the top 20 nations, organizations, and academic journals. Citespace was then utilized to map the collaborative networks among institutions, perform a burst detection analysis on references that are frequently co-cited, and construct chronological charts illustrating the evolution of co-cited references over time. Additionally, VOSviewer facilitated the visualization of collaborative networks between nations and researchers, the density of keyword co-occurrences, thematic clustering, and the corresponding temporal progressions. Lastly, Bibliometrix was instrumental in identifying the central journals within the field.

3. Results

3.1. Publication trends

In the period from 2004 to 2023, the volume of publications and citations both generally showed an upward trend, with 2021 marking the peak year, having published 355 papers, and the total number of citations exceeding 11,000 (Fig. 1 B). Notably, the publication output has seen a significant increase in the last 5 years, accounting for 49.5% of the total from 2004 to 2023.

3.2. Analysis of countries/regions and institutions

Figure 2 A illustrates the robust collaborative efforts among nations. Analyzing the publication output from 115 countries, the United States (US) claims the top spot with 909 publications, representing 29.86% of the total, followed by China with 539 publications (17.71%), Germany with 323 (10.61%), Japan with 300 (9.86%), and England with 241 (7.92%) (Fig. 2 B). Regarding citation frequency, the US dominates with 44,918 citations, with Germany in second place at 18,681, and England in third with 18,528. While China ranks second in terms of publication volume, it is only seventh in citation count, garnering 8435 citations.

Analysis of the countries/regions and institutions in NMOSD treatment research from 2004 to 2023. (A) The cooperation network among countries; (B) ranking of the top 20 countries/regions that have published the most articles; (C) visualization of institutional collaborations; (D) ranking of the top 20 institutions that have published the most articles. NMOSD = neuromyelitis optica spectrum disorder.

Globally, 3890 research institutions have played a pivotal role in the field of NMOSD treatment research by publishing scholarly articles, advancing our understanding of therapeutic approaches for this disease. Through the visualization of this data, we can clearly observe the collaborative networks and contributions established by these institutions within the research field. As shown in Figure 2 C, each dot in the graph represents a research institution, with the size of the dot being proportional to the number of citations it has received – the more citations, the larger the dot. As depicted in Figure 2 D, the Mayo Clinic stands out with 154 publications, becoming the leading contributor among all research institutions. It is closely followed by the University of California System, which published 133 articles, and Harvard University, which contributed 116 publications, ranking third. Among the top 20 contributing institutions, 9 are located in the US, and 7 are in Germany.

3.3. Analysis of authors

In this research area, 12,823 individuals have made contributions, with Fujihara and Paul being the most prominent, having published 76 and 71 papers, respectively (Table 1 ). Pittock leads with a total of 7626 citations, followed closely by Weinshenker with 6959, while Wingerchuk DM tops the co-citation list with 5678, highlighting their significant impact in the field of NMOSD treatment. Figure 3 A illustrates the collaboration network of key academic teams, with notable partnerships such as those between Fujihara, Paul, and Levy. Figure 3 B and C showcase inter-team collaborations, such as those between Paul and Fujihara, as well as Fujihara and Bennett.

Table 1
Ranking of the top-10 most productive authors and most co-cited authors from 2004 to 2023.
Rank Author Count Citations Rank Co-cited Author Citations 1 Fujihara 76 5312 1 Wingerchuk 2928 2 Paul 71 4873 2 Jarius 2068 3 Levy 59 3410 3 Lennon 1147 4 Pittock 52 7626 4 Pittock 1051 5 Weinshenker 51 6959 5 Kim 751 6 Nakashima 49 2923 6 Beck 693 7 Takahashi 47 1163 7 Weinshenker 585 8 Kim 45 2751 8 Cree 577 9 Wingerchuk 45 5678 9 Lucchinetti 556 10 Bennett 44 2252 10 Kitley 544

Ranking of the top-10 most productive authors and most co-cited authors from 2004 to 2023.

Analysis of the authors in NMOSD treatment research from 2004 to 2023. (A) Collaborative network map among authors; (B and C) inter-cluster cooperation network between academic teams. NMOSD = neuromyelitis optica spectrum disorder.

3.4. Analysis of journals

Academic journals are instrumental in the widespread distribution of scientific research outcomes. Among the 3044 publications analyzed, a total of 614 academic journals were identified. The top 20 journals published 1192 articles, accounting for 39.16% of the total, with these papers primarily focusing on the fields of clinical neurology and immunology (Fig. 4 A). The multiple sclerosis (MS) and related disorders led with 249 articles, followed by MS Journal at 106 and Frontiers in Neurology at 88. Among the leading 20 journals, 8 are located in the US, and 5 are situated in England; 12 of these journals are classified in Q1 by Journal Citation Reports. In terms of impact factor (IF), 5 journals have an IF exceeding 5 points. However, it is regrettable that among the top 20 journals, none have an IF surpassing 10 points. Bradford Law reveals that in any given field of study, academic journals can be categorized into 3 levels based on their significance and relevance: the core area, the secondary area, and the peripheral area. Although the number of journals in the core area is relatively small, they concentrate most of the key literature in the field. The shaded area in Figure 4 B indicates the main journals in the field of treatment for NMOSD, highlighting their central position in the discipline.

Journal analysis for research of NMOSD treatment (2004–2023). (A) Ranking of the top 20 most productive journals; (B) core sources by Bradford Law. NMOSD = neuromyelitis optica spectrum disorder.

3.5. Analysis of keyword

Keywords are instrumental in highlighting the principal subjects and key emphases within scholarly discourse. A total of 4262 author keywords were extracted from the articles. The top 5 most frequently mentioned keywords were “NMOSD (2036),” “MS (1208),” “optic neuritis (984),” “aquaporin-4 (562),” and “rituximab (263)” as detailed in Table 2 . For a more visual representation, a density map was constructed using keywords that occurred at least 25 times (Fig. 5 A). The keyword cluster network map (Fig. 5 B) delineates 3 distinct clusters. Cluster 1 (in green) encompasses 22 keywords such as MS, optic neuritis, AQP4, b cells, autoantibody, complement, demyelination, and neuroinflammation. Cluster 2 (in purple) features 23 keywords including NMOSD, transverse myelitis, myelitis, demyelinating diseases, acute disseminated encephalomyelitis, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), magnetic resonance imaging, biomarkers, cerebrospinal fluid, treatment, prognosis, etc. Cluster 3 (in blue) comprises 13 keywords like rituximab, tocilizumab, eculizumab, satralizumab, azathioprine, plasma exchange, safety, plasmapheresis, COVID-19, pregnancy, etc. Collectively, these clusters broadly signify the 3 predominant research directions and areas within this academic domain. The keyword timeline graph (Fig. 5 C) illustrates that recent periods have seen increased co-occurrence of certain keywords: tocilizumab, eculizumab, satralizumab, safety, and COVID-19.

Table 2
Top 20 keywords of this research field from 2004 to 2023.
Rank Keywords Count Rank Keywords Count 1 NMOSD 2036 11 Myelitis 166 2 MS 1208 12 Demyelinating diseases 143 3 Optic neuritis 984 13 Optical coherence tomography 112 4 AQP4 562 14 Covid-19 107 5 Rituximab 263 15 Plasma exchange 111 6 MRI 301 16 Acute disseminated encephalomyelitis 132 7 Treatment 248 17 Autoimmune diseases 91 8 Transverse myelitis 222 18 Children 110 9 Demyelination 193 19 Relapse 106 10 Myelin oligodendrocyte glycoprotein 196 20 Optic nerve 73 AQP4 = aquaporin-4, MRI = magnetic resonance imaging, MS = multiple sclerosis, NMOSD = neuromyelitis optica spectrum disorders.

Top 20 keywords of this research field from 2004 to 2023.

AQP4 = aquaporin-4, MRI = magnetic resonance imaging, MS = multiple sclerosis, NMOSD = neuromyelitis optica spectrum disorders.

Analysis of the author keywords in NMOSD treatment research from 2004 to 2023. (A) Keyword co-occurrence density map; (B) keyword clustering network graph; (C) time-zone view of keyword co-occurrence. NMOSD = neuromyelitis optica spectrum disorder.

3.6. Analysis of references

Table 3 highlights the 10 papers that have been co-cited most frequently within this research domain, each with a citation count surpassing 100 times. Prominent among them are the papers “International consensus diagnostic criteria for neuromyelitis optica spectrum disorders (415 citations)” [ 6 ] and “Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder (223 citations),” [ 7 ] which hold the top 2 spots in co-citation frequency. These influential works were authored by Wingerchuk DM in 2015 and Pittock SJ in 2019, respectively. Figure 6 A provides a visual timeline of the co-cited references in the field of NMOSD treatment, illustrating the trend of co-cited literature over time, with larger dots indicating higher frequencies of co-citation.

Table 3
Top-10 most co-cited references from 2004 to 2023.
Rank Title Author Year Journal Co-citation frequency 1 International consensus diagnostic criteria for neuromyelitis optica spectrum disorders [ 6 ] Wingerchuk 2015 Neurology 415 2 Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder [ 7 ] Pittock 2019 New England Journal of Medicine 223 3 Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomized placebo-controlled phase 2/3 trial [ 8 ] Cree 2019 Lancet 203 4 Trial of satralizumab in neuromyelitis optica spectrum disorder [ 9 ] Yamamura 2019 New England Journal of Medicine 197 5 Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria [ 10 ] Thompson 2018 Lancet Neurology 171 6 Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double-blind, multicentre, placebo-controlled phase 3 trial [ 11 ] Traboulsee 2020 Lancet Neurology 138 7 Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination [ 12 ] Ramanathan 2018 Journal of Neurology Neurosurgery And Psychiatry 124 8 MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin [ 13 ] Jarius 2016 Journal of Neuroinflammation 116 9 Revised diagnostic criteria for neuromyelitis optica [ 14 ] Wingerchuk 2006 Neurology 113 10 Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomized, double-blind, placebo-controlled trial [ 15 ] Tahara 2020 Lancet Neurology 111 MOG = myelin oligodendrocyte glycoprotein, NMO = neuromyelitis optica.

Top-10 most co-cited references from 2004 to 2023.

MOG = myelin oligodendrocyte glycoprotein, NMO = neuromyelitis optica.

Analysis of the references in NMOSD treatment research from 2004 to 2023. (A) Timeline visualization of co-cited references; (B) top 25 references with the strongest citation bursts. NMOSD = neuromyelitis optica spectrum disorder.

Citation bursts refer to the phenomenon where certain documents receive a large number of citations in a relatively short period of time. This phenomenon often signals the emergence of academic hotspots and may reveal future trends. According to the citation burst intensity, we have listed the top 25 references with the strongest citation bursts in Figure 6 B. Among them, 6 papers show a continuous citation burst, with no signs of decline, indicating that these papers have been widely noticed and frequently cited by the academic community in recent years.

4. Discussion

4.1. General information

As an autoimmune disease, NMOSD impacts the central nervous system and is characterized by a high incidence of relapses and disability. It is marked by the immune system’s erroneous assault on the spinal cord and optic nerves, which can result in debilitating symptoms like paralysis and blindness. If not treated promptly, NMOSD patients may not fully recover after acute attacks, resulting in persistent visual and motor disabilities. Therefore, early diagnosis and treatment of NMOSD are crucial. [ 16 ] Since the discovery of the highly sensitive and specific AQP4-IgG antibodies in 2004, scientists have made progress in understanding NMOSD and its treatment. [ 17 ] Based on this discovery, we have chosen 2004 as the starting point for this study. Currently, the research in the field of NMOSD treatment is increasing year by year, indicating that there may be advances in treatment methods in the future.

Our research indicates that the US is a major contributor to advancements in NMOSD treatment. Of the top 20 institutions by contribution to publications, 9 are located in the US and 7 in Germany, demonstrating the close collaboration among developed countries. Therefore, broader international cooperation is crucial for advancing the progress in the field of NMOSD treatment. We believe that with the continuous deepening of international cooperation, future research on NMOSD treatment is expected to achieve more breakthroughs. The journal MS and Related Disorders has published as many as 249 articles in the field of NMOSD treatment, ranking first among all journals. However, it is noteworthy that among the top 20 journals in this field, none has an IF exceeding 10. This phenomenon indicates to some extent that there is still room for improvement in the attention given to the NMOSD treatment field. At the same time, it also reflects the urgent need for the field to achieve some breakthroughs to enhance its overall academic influence.

4.2. Knowledge frameworks

Cluster analysis of author keywords from literature related to the treatment of NMOSD (Fig. 5 B) revealed that the current knowledge structure in this field is mainly divided into 3 distinct clusters. The first category of research topics focuses on MS, optic neuritis, and the related substances (such as AQP4, autoantibodies, and B cells), as well as the physiological processes and pathological states involved (such as demyelination and neuroinflammation). The second category of research places emphasis on neuromyelitis optica spectrum disorder (NMOSD) and related nervous system diseases. These diseases include myelitis, demyelinating diseases, etc, and also cover the diagnostic markers and prognosis of these diseases. The third category of research mainly revolves around the treatment of NMOSD, including targeted biological agents for treatment, other intervention measures, the treatment of special situations (such as pregnancy and be infected with COVID-19), and the safety of the treatment. The results of these cluster analyses generally align with the developmental progress in the field of NMOSD treatment. In the past, NMOSD was often misdiagnosed as a subtype of MS, leading many patients to receive inappropriate treatments, including drugs such as natalizumab, fingolimod, and interferon beta, which not only have no therapeutic effect on NMOSD patients but may also increase the annual relapse rate. [ 18 ] It was not until the discovery of the key biomarker AQP4 antibody that NMOSD was confirmed as an independent disease entity. [ 19 ] However, due to the limited types and side effects of immunosuppressants in the early years, preventive treatment strategies were not perfect. It was not until June 2019 that the first biological agent eculizumab was authorized by the Food and Drug Administration (FDA) for treating patients with AQP4-IgG-positive NMOSD, marking a significant advancement in treatment strategies. [ 20 ] The last 5 years have seen a steady stream of approvals for new targeted biological agents in the treatment of NMOSD. Up to the present, the FDA has approved 5 biologics specifically for AQP4-IgG-positive NMOSD individuals, and these drugs have shown significant efficacy in preventing disease relapses (Table 4 ). [ 21 ] Targeted biological agents have increased the range of treatment options available to AQP4-IgG-positive patients. The emergence of these new drugs is actively changing the relapse rate, disability rate, and mortality rate of NMOSD, bringing a more optimistic prognosis for patients.

Table 4
Summary of biologics approved for clinical use of neuromyelitis optica spectrum disorders as of October 2024.
Initial approval Product Drugs Antibody types Target Administration Mechanism of action 2019/06 FDA Soliris Eculizumab Humanized mAb Complement factor C5 Intravenous Block the terminal pathway of the complement cascade 2020/06 HC Enspryng Satralizumab Humanized mAb IL-6 receptors Subcutaneous Inhibit IL-6 signaling pathways 2020/06 FDA Uplizna Inebilizumab Humanized mAb CD19 Intravenous B-cell depletion 2022/06 PMDA Rituxan Rituximab Chimeric mAb CD20 Intravenous B-cell depletion 2023/05 EMA Ultomiris Ravulizumab Humanized mAb Complement factor C5 Intravenous Block the terminal pathway of the complement cascade EMA = European Medicines Agency, FDA = Food and Drug Administration, HC = Health Canada, IL-6 = interleukin-6, mAb = monoclonal antibody, PMDA = Pharmaceuticals and Medical Devices Agency.

Summary of biologics approved for clinical use of neuromyelitis optica spectrum disorders as of October 2024.

EMA = European Medicines Agency, FDA = Food and Drug Administration, HC = Health Canada, IL-6 = interleukin-6, mAb = monoclonal antibody, PMDA = Pharmaceuticals and Medical Devices Agency.

4.3. Hotspot

After carefully summarizing the 10 most frequently co-cited papers, we found that 5 of them focused on the efficacy, prognosis, and safety of targeted biological therapies for NMOSD, covering satralizumab, rituximab, eculizumab, and inebilizumab. [ 7 – 9 , 11 , 15 ] Another 3 papers mainly discussed the diagnostic criteria for NMOSD and MS. [ 6 , 10 , 14 ] Among the remaining 2 papers, 1 studied the clinical course, treatment plan, and prognosis of MOGAD, [ 12 ] while the other mainly explored the correlation of AQP4-IgG and MOG-IgG antibodies in neuromyelitis optica (NMO) disease (Table 3 ). [ 13 ] By conducting a comprehensive analysis of the top 10 co-cited academic papers, top 25 references with the strongest citation bursts (Fig. 6 B) and integrating the keyword timeline network graph (Fig. 5 C), it can be observed that the current research focus in the field of NMOSD treatment is on targeted biological agents. Considering the demographic characteristics of NMOSD patients, potential treatment failures, treatment preferences, safety, the severity of the disease course, and family planning, there are currently a variety of therapies available with different mechanisms of action, including B-cell depletion therapies, IL-6 receptor inhibitors, and complement inhibitors. [ 2 ]

4.3.1. B cell depletion therapies: inebilizumab and rituximab

Inebilizumab, a humanized monoclonal antibody (mAb), is designed to specifically bind to and eliminate CD19-positive B cells and their precursor subsets. A Phase III randomized controlled trial showed that patients with NMOSD who received inebilizumab experienced a significantly lower rate of relapses compared to those who took a placebo. [ 22 ] The study also showed lower expanded disability status scale scores after 3 months of treatment with inebilizumab. During a median follow-up period of 4.5 years, the drug maintained or even improved its therapeutic benefits, with the majority of relapses happening within the initial year of treatment. Additionally, no new safety issues were detected. The primary adverse effects of inebilizumab are typically experienced during the initial infusion, encompassing mild to moderate infections and infusion-related reactions. [ 23 ]

Rituximab is a mAb that is chimeric, designed to target and deplete B cells expressing the CD20 antigen. It has been shown to be clinically effective in treating NMOSD, reducing relapse rates by over 80% according to several retrospective and prospective studies. [ 24 , 25 ] Rituximab is considered to have a relatively high safety profile, although its safety may be influenced by factors such as gender, weight, age, duration of treatment, degree of disability, and history of other immunosuppressive therapies. Most adverse reactions to the drug are usually mild and related to the infusion process. [ 26 ]

4.3.2. IL-6 receptor inhibitors: satralizumab

Sartolizumab is a humanized monoclonal IgG2 antibody. Two pivotal clinical studies have confirmed that sartolizumab is effective for patients with AQP4-IgG-positive NMOSD, with clinical effects typically manifesting within 8 to 12 weeks, and can be used either as a monotherapy or in combination with other therapeutic approaches. [ 9 , 11 ] A long-term study included 111 AQP4-IgG-positive patients who were treated with sartolizumab, with a median treatment duration of 4.4 years. [ 27 ] The study results showed that over 70% of the patients did not experience relapses during the treatment period, more than 85% of the patients did not have worsening of their EDSS scores, and 90% of the patients did not suffer from severe attacks. Furthermore, no new safety concerns were identified in the study, and there were no cases of opportunistic infections reported.

4.3.3. Complement inhibitors: eculizumab and ravulizumab

Eculizumab is a humanized mAb targeting C5 to inhibit the terminal complement cascade. Initially for rheumatic diseases, it was first approved in 2007 for paroxysmal nocturnal hemoglobinuria and later for myasthenia gravis. A Phase III randomized controlled trial showed eculizumab reduced NMOSD relapse risk as monotherapy or add-on therapy. [ 28 ] Another randomized, double-blind trial involving 143 AQP4-IgG-positive NMOSD patients also confirmed that patients treated with eculizumab had a significantly lower risk of relapse compared to those receiving a placebo. [ 7 ] The safety data for eculizumab treatment in NMOSD is currently limited, mainly derived from studies of the drug’s other indications. In terms of infusion-related reactions and allergic reactions, the incidence of these adverse reactions is relatively low. Nonetheless, there have been reports of a patient who died from empyema complicated by streptococcal infection while receiving eculizumab in combination with azathioprine. [ 7 ]

Ravulizumab, a long-acting mAb that targets complement factor C5, is administered intravenously every 8 weeks and has a 4-fold longer half-life than eculizumab. It is currently approved for treating myasthenia gravis and paroxysmal nocturnal hemoglobinuria, with only the European Medicines Agency approving its use for adult patients with AQP4-IgG positivity. [ 29 ]

4.4. Emerging topics

The severity of NMOSD is closely related to the number of relapses and recovery after relapses. Therefore, timely immunotherapy and management of relapses are crucial for preserving neuronal reserve and improving the prognosis of NMOSD patients. In the acute phase of NMOSD, the main treatment methods include high-dose corticosteroids and immunoadsorption or plasma exchange (PLEX). Immunosuppressive drugs like corticosteroids, mycophenolate mofetil (MMF), and azathioprine are typically used for long-term prevention. [ 19 ] Many NMOSD patients can achieve significant functional recovery after receiving corticosteroid treatment and plasma exchange in the acute phase. Despite this, clinical relapses are inevitable in most cases, leading to cumulative neurological damage. With a deeper understanding of the pathogenesis of NMOSD, targeted biologics may provide new options for maintenance therapy for refractory patients. In addition to the 5 biologics mentioned earlier that have been approved for the treatment of NMOSD, a variety of new therapies targeting NMOSD are continuously being explored and developed. For instance, zanubrutinib, a Bruton tyrosine kinase inhibitor that has been extensively studied for its potential use in patients with MS, is currently being evaluated for its safety and efficacy in an ongoing open-label clinical trial involving patients with NMOSD. [ 30 ] Additionally, HBM9161, as a monoclonal antibody that can bind to neonatal Fc receptors and thereby promote the catabolism of IgG antibodies in the blood, a study on its combined management with methylprednisolone for NMOSD attacks is underway ( https://clinicaltrials.gov/ , ID: NCT04227470 ). [ 2 ] A multitude of innovative treatments is emerging, indicating that the range of immunotherapeutic options for NMOSD is anticipated to broaden considerably in the coming years. While the majority of treatments are designed for NMOSD patients who test positive for AQP4-IgG, there is a lack of agreement on approaches for those who are AQP4-IgG negative. This highlights the need for more research into the pathogenesis of NMOSD to develop treatment protocols, including the best order of therapies and how long they should last, based on clinical trials with larger patient groups. [ 31 ] Additionally, given the potential for increased side effects and financial strain from prolonged immunotherapy, further studies are necessary to determine the right time for patients to cease or decrease treatment.

The median age for NMOSD onset is 40, with a majority of cases occurring in women who are of childbearing age, underscoring the need to account for pregnancy when managing NMOSD. [ 32 ] Studies suggest that in managing NMOSD, immunosuppressive medications like methotrexate, MMF, cyclophosphamide, and mitoxantrone could potentially impact fertility in patients. [ 33 ] The FDA advises against the use of category D medications during gestation. In contrast, the European League Against Rheumatism views azathioprine as a relatively safe option for use during pregnancy. [ 34 ] Furthermore, the prescribing details for inebilizumab and satralizumab caution against their utilization in pregnant women and those considering conception. In contrast, the British Society for Rheumatology suggests discontinuing rituximab 6 months prior to attempting pregnancy. [ 35 ] In a cohort study, participants underwent Rituximab therapy with a median interval of 1.9 weeks following childbirth, which led to a significant reduction in relapse risk, dropping to 8.3%. [ 36 ] This finding implies that immunological interventions during gestation could potentially decrease the likelihood of relapses. Nonetheless, a counterintuitive observation is noted: the majority of individuals ceased immunotherapy prior to conception. Data from a separate study revealed that only 20.6% of patients received immunotherapy in the year prior to pregnancy. [ 37 ] In managing acute NMOSD flare-ups during pregnancy, methylprednisolone is deemed safe for short-term use. Should there be no response to steroid therapy, PLEX may be an option, albeit with more limited safety evidence. [ 38 ] Although there are worries about steroid use, particularly in the initial trimester of gestation, the latest findings indicate no heightened risk for conditions such as preeclampsia, low birth weight, or premature delivery. [ 39 ] Regarding breastfeeding safety, medications such as corticosteroids, azathioprine, PLEX, eculizumab, rituximab, and tocilizumab are deemed relatively safe, while methotrexate and MMF are contraindicated during breastfeeding. [ 40 ] Currently, the management of NMOSD in pregnant patients faces several challenges, with no universal agreement established. Yet, as NMOSD therapeutic approaches evolve and scientific inquiry progresses, there is optimism among researchers that a holistic treatment plan for pregnancy will be discovered.

Randomized controlled trials for the treatment of pediatric NMOSD are relatively fewer compared to those for pregnant patients. The current therapeutic landscape for pediatric NMOSD encompasses treatments that are used off-label, such as MMF, azathioprine, IVIG, and rituximab. [ 41 ] In 2021, satralizumab was firstly granted regulatory approval in China for subcutaneous administration to treat NMOSD in individuals aged 12 and above, who possess AQP4-IgG autoantibodies. Recently, 2 case reports collectively indicated that after pediatric NMOSD patients developed resistance to MMF, prednisone, and rituximab, their conditions were successfully alleviated following the adjustment of treatment plans to include satralizumab. [ 42 , 43 ] At present, FDA-approved therapies for childhood NMOSD are scarce, necessitating further validation through extensive cohort studies for treatment approaches in pediatric patients. As innovative treatment options arise, subsequent research endeavors should focus on refining pediatric dosing protocols to enhance treatment efficacy and reduce potential side effects.

Biomarkers play a crucial role in monitoring treatment responses and assessing long-term prognosis. Studies indicate that increased serum glial fibrillary acidic protein (sGFAP) levels suggested the presence of covert disease activity and/or compromised blood-brain barrier integrity in NMOSD. These findings underscore the significance of sGFAP and other soluble biomarkers originating from the central nervous system in detecting ongoing neurological harm and predicting the likelihood of NMOSD flare-ups. [ 44 ] New studies suggest that high serum concentrations of neurofilament light chain (sNfL) correlate with a heightened likelihood of disability worsening after NMOSD relapses, while sNfL is not as effective as sGFAP in predicting future episodes. [ 45 ] Furthermore, studies have suggested that magnetic resonance T2 relaxation time may indirectly reflect disease activity. [ 46 ] Nevertheless, the effectiveness of these biomarkers still needs to be further validated through larger patient studies. At the same time, there is a need to explore more biomarkers to improve the accuracy and reliability of monitoring.

5. Limitations

This study reveals the current state and emerging topics in the field, but it also has some limitations. Firstly, the research data is based solely on the WoSCC database. Secondly, the study only includes English-language articles. Lastly, the included literature is limited to articles and reviews, excluding letters, meeting records, editorials, case reports, retractions, and abstracts. These factors may all lead to incomplete data or selection bias.

6. Conclusions

In recent years, the field of treatment for NMOSD has made significant advancements. This study first employs bibliometric methods to comprehensively organize and analyze the literature in this area. We systematically examined key indicators such as the number of related papers, the countries and institutions of the authors, the journals in which they were published, citation patterns, and frequently cited documents. This study provides detailed statistical data and in-depth analytical discussions, clarifying the research hotspots in this field. Furthermore, we explored 3 emerging themes in the field of NMOSD, including the application of targeted biological agents, the medication use in special populations (pregnant patients and pediatric patients), as well as the research on its biomarkers, and predicted their future development trends. These research findings have certain reference value for scholars committed to the treatment research of NMOSD.

Author contributions

Conceptualization: Ben Liu.

Data curation: Juan Wang, Guangbiao Cai, Shuang Xia.

Formal analysis: Juan Wang, Shuang Xia.

Investigation: Guangbiao Cai, Jie Qin, Ben Liu.

Methodology: Juan Wang, Guangbiao Cai, Shuang Xia.

Resources: Guangbiao Cai.

Software: Shuang Xia.

Supervision: Jie Qin, Ben Liu.

Visualization: Juan Wang.

Writing – original draft: Juan Wang, Guangbiao Cai, Shuang Xia.

Writing – review & editing: Jie Qin, Ben Liu.

Supplementary Material

Abbreviations: AQP4-IgG aquaporin-4 immunoglobulin G antibodies mAb monoclonal antibody MMF mycophenolate mofetil MOGAD myelin oligodendrocyte glycoprotein antibody-associated disease MS multiple sclerosis NMOSD neuromyelitis optica spectrum disorder PLEX plasma exchange PNH paroxysmal nocturnal hemoglobinuria sGFAP serum glial fibrillary acidic protein sNfL serum concentrations of neurofilament light chain

Abbreviations:

aquaporin-4 immunoglobulin G antibodies

monoclonal antibody

mycophenolate mofetil

myelin oligodendrocyte glycoprotein antibody-associated disease

multiple sclerosis

neuromyelitis optica spectrum disorder

plasma exchange

paroxysmal nocturnal hemoglobinuria

serum glial fibrillary acidic protein

serum concentrations of neurofilament light chain

This study did not involve human or animal subjects, and therefore did not require formal ethical approval. All research activities were conducted in accordance with ethical standards for research without direct human or animal participation.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental Digital Content is available for this article.

How to cite this article: Wang J, Cai G, Xia S, Qin J, Liu B. Research hotspots and emerging topics in neuromyelitis optica spectrum disorder treatment: Insights from a bibliometric analysis. Medicine 2025;104:23(e42850).

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Juan Wang, Email: 780429021@qq.com.

Guangbiao Cai, Email: 492934800@qq.com.

Shuang Xia, Email: 1340783454@qq.com.

Jie Qin, Email: qinjie@ycsyy.com.

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