Global research trends and priorities in the link between Toll-like receptors and rheumatoid arthritis: a bibliometric analysis from 2003 to 2023

Global research trends and priorities in the link between Toll-like receptors and rheumatoid arthritis: a bibliometric analysis from 2003 to 2023 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Global research trends and priorities in the link between Toll-like receptors and rheumatoid arthritis: a bibliometric analysis from 2003 to 2023 Yanping Zong, Hui Li, Yonglong Chang, Xiaojun Zhang, Jinchen Guo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5725138/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Rheumatoid arthritis (RA) is a widespread chronic autoimmune disease, distinguished by inflammation in the synovial membrane. Research indicates that Toll-like receptors (TLRs), which engage with internal ligands generated by the body, serve a crucial function in triggering immune reactions. These receptors are also implicated in the onset of inflammatory conditions, injuries, tumors, and are pivotal to the development of RA. This research seeks to comprehensively examine the present status and evolving trends in the study of the relationship between rheumatoid arthritis and Toll-like receptors using bibliometric methods. Methods: Research on rheumatoid arthritis and Toll-like receptors was conducted using the Web of Science Core Collection (WoSCC) database, covering the period from 2003 to 2023. Eligible articles were screened according to predefined criteria and analyzed bibliometrically using VOSviewer, CiteSpace and the R package “bibliometrix”. Results: 440 papers from 56 countries or regions, 670 institutions, and 2264 authors in the disciplines of biochemistry and molecular biology, chemistry, engineering, immunology, and materials science were included. The United States, China and the Netherlands were the primary contributors. The institution that published the most papers in the field was Radboud Univ Nijmegen from the Netherlands. Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center was the most prolific scholar. Research on TLRs and the immune-inflammatory response, interaction of TLRs with immune cells, regulation of TLRs signaling pathways, and TLRs and RA therapy in RA are hot topics in this field. The development trend is shifting from pathogenesis to targeted therapy. Conclusion: The involvement of Toll-like receptor-mediated immune inflammation in the development of rheumatoid arthritis has become a research focus of multidisciplinary interest. This article summarizes the research institutions, authors, journals, hotspots and application trends of Toll-like receptors in rheumatoid arthritis, which will help researchers to conduct further studies. Rheumatoid arthritis Toll-like receptors Bibliometric analysis Research trends Citespace VOSviewer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Key points 1. This paper is the first to use bibliometric methods to study the relationship between Toll-like receptors and rheumatoid arthritis, which fills the gaps in the field and provides a scientific basis and guidance for clinical practice and research. 2. It is found that the role of TLRs in RA involves multiple aspects. At present, the role of TLRs signaling pathway regulating immune-inflammatory response in the pathogenesis of RA has become a hot spot. In the future, exploring the relationship between TLRs and RA from multiple perspectives will help deepen our understanding of the pathogenesis of RA and provide new pathways and targets for its treatment. 1. Introduction Rheumatoid arthritis (RA) is a debilitating joint condition caused by immune system imbalance and persistent inflammation, with a global prevalence of about 0.4% to 1.3% and a high rate of disability ( 1 )， significant economic burden on patients and society ( 2 ). The main pathologic features of RA include synovial inflammation, cartilage damage, and joint destruction. In the disease state, fibroblast-like synoviocytes proliferate in the synovial lining, neovascularization occurs, and vascular opacities form, which work together with T-lymphocytes, B-lymphocytes, plasma cells, and macrophages to destroy bone and cartilage. The full pathogenesis of RA remains unclear. The condition results from the interaction of genetic predisposition and environmental factors. Smoking and infections are environmental factors clearly linked to RA development ( 3 ). The processes through which infections contribute to the progression of diseases are highly intricate, with major pathogenic factors including cells, cytokines, and signaling pathways. Cells and rheumatoid arthritis are specifically characterized by an imbalance between osteoblasts and osteoclasts, overproliferation of synovial cells, and immune cell dysfunction. Cytokines and rheumatoid arthritis are defined by inflammation driven by various inflammatory mediators, including interleukin (IL)-17, tumor necrosis factor (TNF)-α, IL-6, and IL-8, among others. Rheumatoid arthritis and its signaling pathways are marked by the involvement of nuclear transcription factor (NF)-κB signaling, Toll-like receptor pathways, and the Wnt signaling cascade ( 4 , 5 ). The Toll-like receptor (TLR) serves as a fundamental part of the immune system, essential for both innate and adaptive immune responses. TLR detects molecular patterns associated with both pathogens and tissue damage within the body. Activating the TLR signaling pathway elevates pro-inflammatory factors, modulating immune responses and potentially influencing inflammation-related conditions. Abnormal TLR expression and Inappropriate stimulation of the TLR pathway by external or internal ligands can cause autoimmune reactions and tissue damage ( 6 , 7 ). Recent research has revealed that TLRs are present in circulating mononuclear leukocytes, synovial tissue, and synovial fluid. Additionally, they are found in synovial macrophages and synovial fibroblasts in patients with RA. These components contribute to the progression of RA to varying extents ( 8 ) . The presence of endogenous TLRs, mainly TLR4 and TLR2 agonists, in RA joint tissues, which include heat shock proteins, fibrinogen, and fibronectin EDA, suggests that TLRs are engaged in the initiation and advancement of persistent inflammatory arthritis by detecting specific PAMPs ( 9 ). In addition, the pathogenesis of TLRs in RA provides new targets for the treatment of RA ( 10 ). Bibliometrics, as an interdisciplinary field, has been increasingly used in the medical field. Bibliometric analysis can not only help researchers and institutions understand their research results and impact, but also provide valuable information for policy making, academic resource allocation and research direction selection. In recent years, research on TLRs in the realm of RA has intensified, leading to notable advancements. However, as a field with considerable research value and potential, bibliometric analysis of TLRs in RA has not yet been conducted. In this research, we utilized bibliometric analysis and visualization methods to extensively review studies on TLRs in RA over the last 20 years. Our objective was to map the scientific understanding in this domain and provide new perspectives for future progress. 2. Methods 2.1 Data source and search strategy To obtain research data, a literature search was performed on July 17, 2024 in the Web of Science Core Collection (WoSCC) database. The search formula was TS=(“Rheumatoid arthritis” OR “RA”) AND TS=("Toll-like receptors “ OR “TLR”), spanning from January 1, 2003 to December 31, 2023. A total of 1,377 results were retrieved, which were subsequently evaluated by two team members utilizing established inclusion and exclusion guidelines ( Figure 1 ), and a consensus was reached with a third author to resolve disagreements, resulting in a total of 440 publications part of this research. The data concerning the titles, institutions, authors, journals, citations, references and keywords of the 440 documents were subsequently recorded in unformatted text. 2.2 Data analysis To provide an in-depth summary of the present condition and patterns in TLR studies concerning RA, we employed a variety of bibliometric visualization tools. In particular, we selected multiple software programs to examine and illustrate different facets of the research. In terms of research tools, we used R (version 4.1.2), Microsoft Excel (version 2021), the VOSviewer (version 1.6.18), CiteSpace (version 6.1), and R-bibliometrix package (version 3.0.3, http://www.bibliometrix.org). Regarding the current research status, these visualization tools were used to statistically analyze and display the publication count, annual citation rate, countries/regions, institutions, co-cited references, authors, and keywords. In terms of comprehensive analysis, we visualized the H-index of authors and journals, the proportion of corresponding authors' countries, and the international collaboration network. Finally, for scientific trend analysis, we examined knowledge structures, research clusters, and emerging research themes. 3. Results 3.1 Number of publications and citation trends We initially conducted a summary analysis of the data(Table 1, Figure 2), and the rheumatoid arthritis and Toll-like receptor-related literature totaled 440 articles written by 2,264 researchers conducted at 679 institutions across 56 countries or regions, was featured in 189 journals. We searched the literature related to rheumatoid arthritis and Toll-like receptors from 2003 to 2023. The earliest publication dating back to 2003 was by Kyburz, Diego, an academic from the University of Basel, in the journal Arthritis and Rheumatism, titled “Bacterial peptidoglycans but activate synovial fibroblasts not CpG oligodeoxynucleotides by toll-like receptor signaling”, this study reveals that bacterial PG stimulates synovial fibroblasts, partially through TLR-2, resulting in the formation of integrins, matrix metalloproteinases (MMPs), and pro-inflammatory signaling molecules. Therefore, inhibiting the TLR signaling pathway may be beneficial for alleviating both joint inflammation and injury ( 11 ). Table 1. main information Rank Main information Results Rank Main information Results 1 Timespan 2003~2023 9 Author's Keywords (DE) 752 2 Journal 189 10 Authors 2264 3 Documents 440 11 Authors of single-authored docs 12 4 Annual Growth Rate% 4.33 12 Co-Authors per doc 6.98 5 Document Average Age 10.1 13 International co-authorships% 25 6 References 18052 14 Average citations per doc 64.62 7 Keywords Plus (ID) 1377 15 Average citations per year per doc 5.55 8 Country or region 56 16 Institution 679 3. 2 Research Countries/Regions and Institutions These 440 papers come from 56 countries or regions. Figure 3A displays the distribution of these nations, with deeper blue shades representing a higher count of publications. Table 2 enumerates the leading 10 countries and organizations by publication count. The United States secured the leading spot with 97 publications, followed by China with 75, the Netherlands with 49, the United Kingdom with 41, and South Korea with 35, among other countries. The leading 10 nations by publication count are mainly located in economically developed regions such as North America, Asia and Europe, which reflects the correlation between economic development and scientific research. Using the R-bibliometrix software package, we further visualized the countries of corresponding authors of publications. As shown in Figure 3B , the United States ranked first among multiple country publications (MCPs), highlighting that international collaborations enhance the impact of publications. Subsequently, we mapped global collaboration networks ( Figure 3C ), where the thick lines indicate stronger collaborations. Consistent with our expectations, the U.S. has established strong collaborative relationships with several countries/regions, while Asian and European countries have also formed close collaborative relationships. On the institutional side, Figure 3D gives the institutional co-occurrence network. The larger the nodes, the more publications they represent, and the connections between the nodes represent cooperative ties among institutions. Table 2 presents the leading 10 organizations based on the volume of publications, with Radboud Univ Nijmegen from the Netherlands contributing the largest quantity of papers, totaling 26, in the domain, followed by Univ Zurich Hosp from Switzerland with 18 publications. Many of the leading 10 organizations in publication volume are based in the Netherlands, Switzerland, South Korea, the United States, and the United Kingdom. Figure 3E shows the number of citations for each institution, with a minimum citation threshold of 40 citations and 326 institutions meeting this criterion. Larger nodes indicate that the institution received more citations, indicating that the institution is more influential in the relevant research. Lines between nodes represent collaborative or citation relationships among organizations; the greater or denser the line, the stronger the collaboration or citation relationship.Univ Colorado Denver received the highest number of citations.In scientific research, a citation explosion reflects the fact that an institution's research has been widely noticed and cited by peers over a specific period of time. Using CiteSpace, we identified the leading 25 organizations with the most significant citation surges ( Figure 3F ). Univ Zurich was the first institution to experience a citation burst, suggesting that its research has gained a high level of scholarly recognition and attention over a given period of time, and that it has the potential to lead the way in new research directions. Radboud Univ Nijmegen has the longest duration of citation outbursts, indicating sustained attention and citations to its research, demonstrating its enduring impact and sustained contribution to a particular field. In recent years, Asian institutions such as Ajou Univ, Kyung Hee Univ, and Guangzhou Univ Chinese Med, especially Chinese institutions, have emerged as the institutions with the strongest citation outbreaks, reflecting China's rapid rise and growing academic influence in related research fields. Table 2 . Top 10 countries/regions and institutions in terms of publication volume. Rank Country Records Institutions Records 1 Usa 97 Radboud Univ Nijmegen 26 2 China 75 Univ Zurich Hosp 18 3 Netherland 49 Ajou Univ 13 4 United Kingdom 41 Northwestern Nuiv 11 5 South Korea 35 Univ London Imperial Coll Sci Technol & Med 11 6 Switzerland 31 Catholic Univ Korea 8 7 Germany 24 Karolinska Inst 8 8 Japan 20 Univ Zurich 7 9 Ireland 18 Univ Messina 7 10 Italy/Spain 15 Univ Amsterdam 7 3.3 The top-ranked journals and co-cited journals These 440 papers appeared in 189 periodicals. Using VOSviewer, we examined the active journals in the field, as shown in Figure 4A . Of these, Arthritis and Rheumatism was the most frequently issued journal with 33 articles, followed by Arthritis Research & Therapy with 28 articles. the Annals of the Rheumatic Diseases published 26 articles, which was the third most frequently published journal. This investigation examined a total of 440 articles, which received citations from 18,052 journals. Figure 4B displays the citation visualization analysis, and Table 3 lists the top 10 co-cited journals. The Journal of Immunology secured the top position with 2,112 citations, followed by Arthritis & Rheumatism with 1,492 references and the Journal of Experimental Medicine with 809 references. Other prominent journals in the top 10 include the Journal of Biological Chemistry with 805 references and Proceedings of the National Academy of Sciences of the United States of America with 732 references. Remarkably, five of the leading 10 frequently cited journals in 2024 had an impact factor of 10 or above, with Nature leading at 50.5. Figure 4C depicts the publication patterns for these top 10 journals, demonstrating a steady rise in publications over time, reflecting the increasing importance of this research area. Table 3. Top 10 journals related to influenza inflammatory response research and co-cited journals Rank Journals Counts IF (2024) Co-Cited Journals Counts IF (2024) 1 Arthritis and Rheumatism 33 4.6 Journal of Immunology 2112 3.6 2 Arthritis Research & Therapy 28 4.4 Arthritis and Rheumatism 1492 4.6 3 Annals of the Rheumatic Diseases 26 20.3 Journal of Experimental Medicine 809 12.6 4 Journal of Immunology 17 3.6 Journal of Biological Chemistry 805 4.0 5 Frontiers in Immunology 15 5.7 Proceedings of the National Academy of Sciences of the United States of America 732 9.4 6 PloS One 15 2.9 Nature 731 50.5 7 Rheumatology International 7 3.2 Arthritis & Rheumatology 709 11.4 8 Arthritis & Rheumatology 6 11.4 Annals of the Rheumatic Diseases 697 20.3 9 International Journal of Molecular Sciences 6 4.9 Arthritis Research & Therapy 585 4.4 10 Journal of Autoimmunity 6 7.9 Nature Immunology 583 27.7 3.4 Analysis of top authors and co-cited authors A combined total of 2,264 researchers have contributed to the investigation of the relationship between rheumatoid arthritis and Toll-like receptors. Figure 5A shows the collaborations between authors. It can be seen that only a few of the many researchers around the world have collaborated, and the collaborations are mostly concentrated in the same countries/regions. Table 4 displays the top 10 researchers ranked by their number of publications. At the top is Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center, with a total of 15 published works. Van Den Berg Wim B team focuses on TLRs to control inflammatory responses in arthritis by regulating inhibition of Fcγ receptor responses on macrophages ( 12 , 13 , 14 ). Prof. Gay steffen, Prof. Abdollahi-roodsaz Shahla, and Prof. Choi Sangdun tied for the second place in the number of publications with 12, including Prof. Gay steffen from the University of Zurich, who centered on the management of cellular responses to the TLR pathway by different factors and analyzed its expression, regulation and function in RA synovial fibroblasts (RASFs) ( 15 , 16 , 17 ). Prof. Abdollahi-Roodsaz Shahla from Radboud University Nijmegen Medical Center studies TLR signaling mechanisms, including the structural domain of the TLR and its exogenous and endogenous ligands. Her research also examines existing and potential therapeutic strategies aimed at targeting TLR signaling, with a specific emphasis on how TLR influences Th cell responses that could trigger autoimmunity ( 18 , 19 , 20 ). Prof. Choi Sangdun from the Department of Molecular Science and Technology, Ajou University, has made great contributions mainly in the area of TLR as an effective drug target for RA. Their group has employed a computational strategy to analyze TLR antibody-binding sites and has discovered a novel epitope at the TLR interface. This finding could direct the advancement of therapeutic antibodies and small compounds. The approach provides understanding into antibody-antigen interactions and will facilitate the creation of novel monoclonal antibodies. Integrating computational methods with experimental techniques will expedite the strategic design and creation of antibody-based treatments ( 21 , 22 , 23 ). Prof. Radstake Timothy RDJ is ranked third with 11 publications. The five scholars are from the Netherlands, Switzerland, and South Korea. In terms of authors' co-citations ( Figure 5B ), 98 authors reached the minimum citation threshold of 20 citations and were grouped into four clusters, each of which is represented by a different color to indicate a different research topic or academic field. In Table 4 , the leading 10 co-cited researchers are presented, along with the frequency of their citations. Abdollahi-roodsaz S from Division of Rheumatology, Department of Medicine, New York University School of Medicine had the most citations (166), followed by Radstake TRDJ ( 144 citations), Roelofs MF (140 citations), Akira S (120 citations), and Brentaon F (116 citations). The first to publish in the field were Gay RE, Kyburz D, and Joosten LAB as shown in Fig. 5C.Prof. Kyburz D is a consistent contributor to the field, while Prof. Van Den Berg WB and Prof. Abdollahi-roodsaz S have been leaders in the field with high annual output since 2003. This is further confirmed by the h-index positioning of the leading 10 authors( Figure 5D ). Table 4. Top 10 productive authors and co-cited authors. Rank Authors Counts Co-Cited Authors Citations 1 Van Den Berg Wim B 15 Abdollahi-roodsaz S 166 2 Gay steffen 12 Radstake TRDJ 144 3 Abdollahi-roodsaz Shahla 12 Roelofs MF 140 4 Choi Sangdun 12 Akira S 120 5 Radstake Timothy RDJ 11 Brentaon F 116 6 Gay Renate E 10 Ospelt C 113 7 Ospelt Caroline 10 Joosten LAB 108 8 Pope Richard M 9 Kawai T 98 9 Joosten Leo A B 8 Seibl R 94 10 Koenders Marije I 8 Huang QQ 87 3.5 Analysis of co-cited references and references citation bursts Co-citation, an important concept in scientific research, refers to the phenomenon that a literature is simultaneously cited by two or more academic publications, which is regarded as one of the indicators reflecting the importance of a specific research field, as it shows the influence and acceptance of a particular literature in that field. Figure 6A provides detailed information on the leading 10 co-cited publications, along with their citation totals, Radstake TRDJ et al. published a paper entitled “Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-γ” in 2004, published in the journal Arthritis & Rheumatism, tops the list with 89 citations. The research investigates the expression of TLR-2 and TLR-4 and their associations with pro-inflammatory cytokines in the synovial tissues of people with RA, OA, and healthy subjects. Our results indicate that TLR-2 and TLR-4 are identified in the synovial tissues of individuals with active disorders and are linked to the concentrations of IL-12 and IL-18. Moreover, the interplay between IL-12 and IL-18 affects T-cell IFNγ synthesis, which then influences the expression of TLR-2 and TLR-4 in the joint tissues of individuals with RA ( 24 ). Figure 6B, on the other hand, illustrates a network diagram of relationships between co-cited publications that have been cited at least 40 times. Burst analysis detects high-frequency and rapidly growing burst references by examining the temporal distribution of references, in order to reflect the leading areas and future directions of a discipline. In Figure 6C, the leading 15 citation bursts arranged by burst intensity are displayed. These citation bursts span from 2002 to 2023, with the longest lasting six years. The most recent citation burst was triggered by an article entitled “TLRs, future potential therapeutic targets for RA” by Elshabrawy HA et al. from Sam Houston State University, Published in 2017 in the journal Autoimmunity reviews. This study investigated the role of TLR in the progression of RA across different cell types, such as myeloid cells, synovial fibroblasts, T lymphocytes, osteoclast progenitors, and endothelial cells. The results indicate that TLR-induced inflammation could lead to bone erosion through osteoclast activity by connecting myeloid lineage cells with TH-17 cells in reaction to joint blood vessel formation. For identifying TLRs that impair RA patients provides a new approach to activation ( 25 ). To date, this article is still in the citation explosion phase, indicating that it has attracted widespread attention and discussion in the academic community and has had a profound impact on the development of the field. This sustained citation growth may imply the enduring importance of this research and may provide key insights and guidance for future research directions and applications in the field. Keywords encapsulate the fundamental core of a study. Keyword co-occurrence unveils research trends within a scientific domain and also provides insights into the direction of inquiry within the topic. In the “Most Frequent Words” analysis of “bibliometrix”, the most frequent keywords were toll-like receptors (95), activation (91), nf-kappa-b (65), collagen-induced arthritis (129), and collagen-induced arthritis (65), in addition to “most frequent words”. In addition to rheumatoid-arthritis (145) and experssion (129), the most frequently occurring keywords were toll-like receptors (95), activation (91), nf-kappa-b (65), collagen-induced arthritis (55), dendritic cells (55), and cells (53), inflammation (49), and synovial fibroblasts (47), as shown in Figure 7A . rheumatoid-arthritis, experssion, and toll-like receptors ranked in the top three, indicating that rheumatoid-arthritis and toll -like receptors are closely related research topics . To illustrate the research focal points more clearly, we used VOSviewer to draw the keyword co-occurrence network view on 440 documents, and grounded in the strength of keyword co-occurrence connections, we chose the 31 keywords with a frequency of >20 occurrences for visualization, and divided the network into 4 clusters ( Figure 7B ), of which the red cluster is the largest one, involving there are 14 terms including rheumatoid arthritis, expression, inflammation, activation, toll-like receptor, cells, etc. Green clustering and blue clustering involve 6 terms. The green terms include rheumatoid-arthritis, toll-like receptors, innate immunity, dendritic cells, and systemic-lupus-erythematosus, and the blue terms include arthirtis, toll-like-receptor-4, pathogenesis, cytokines, synovial tissue, fibroblast-like synoviocytes, and tumor-necrosis-factor. the yellow terminology involves five terms, including collagen- induced arthritis, synoval fibroblasts, t-cells, tnf-alpha, fibroblast-like synoviocytes. all four clusters are related to the role of TLRs in the activation of fibroblasts ( FLSs) in RA patients. We used CiteSpace to generate a keyword clustering graph and a keyword timeline graph ( Figure 7C-7D ), which highlights “positive antigen-presenting cell”, “single nucleotide polymorphism”, “pathway drive”“chronic inflammation”, “bacterial peptidoglycan”, “articular chondrocyte”, “nod receptor”, “inflammatory diseases”, “anti-inflammatory effect”, “synovial fibroblast-like phenotype” 10 keyword clusters. The clusters “nod receptor”, “inflammatory diseases”, and “anti-inflammatory effect” were the first to appear and remained the most popular in 2023. “ appeared earliest and lasted longest, and will remain a hot topic and an important area of research in 2023, suggesting that pattern recognition receptors serve a crucial function in the advancement of inflammatory mechanisms in rheumatoid joints. To achieve a more profound insight into the development of research directions and to focus on Toll-like receptors in RA, we performed a thematic evolution analysis of Keywords Plus using the R-bibliometrix software package. This analysis identified more specific research priorities, including animal model studies, expression in immune cells, immune activation, and inflammatory responses ( Figure 7E ). CiteSpace burst word analysis provides insights into the frontiers of research, shifts in research focus, and the latest hot research developments, and helps predict subsequent trends in the field. In the study of the relationship between RA and TLRs, the 15 terms with the most significant citation spikes are displayed in Figure 7F . The keyword with the strongest citation burst was “tlr2” (Strength=4.37). tlr2 belongs to one of the TLR family members, suggesting that TLR2 has a significant role in the development of RA. The keyword with the longest citation burst duration is “macrophage”, which has continued to break out for 23 years, suggesting that the modulation of immunoinflammation via the TLR signaling pathway is significant in the development of rheumatoid arthritis, and it is also a research focus and hot spot in this field. 4. Discussion As interest in the study of the relationship between rheumatoid arthritis and Toll-like receptors has increased, so has the amount of relevant literature. Unfortunately, there are no bibliometric studies in this area, which lacks a clear understanding of the overall research trends and priorities in this area. The present study utilizes bibliometric methods to analyze the relationship between rheumatoid arthritis and Toll-like receptors, which fills the gap in the field and provides an important reference and guidance for the further development of the field. General information A study of the research results in this field shows that the United States led the way with 97 publications, while China and the Netherlands ranked second and third with 75 and 49 papers, respectively. Radboud University Nijmegen from the Netherlands produced the greatest quantity of publications in this field, with 26 publications. The United States has intimate collaboration with nations such as China and the United Kingdom. In addition, the Netherlands, Sweden, Switzerland, and Germany have more extensive cooperation with other countries. However, Figures 3A and 3B show that many countries have less cooperation in this field, probably because of factors such as research methods, quality, funding, resources, and institutions. Tackling these obstacles can foster global collaboration and creativity, propel the discipline forward, and contribute to worldwide scientific advancement. In terms of authors, Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center ranked first with 15 publications.Arthritis and Rheumatism was the most frequently published journal, the Journal of Immunology was the most frequently referenced publication, while Nature held the highest impact factor. Among the top 10 most frequently co-cited journals, five had a citation impact score of 10 or above, reflecting the high caliber of research in the area. The analysis of keywords revealed that rheumatoid arthritis, expression, and toll-like receptors were the most prominent, suggesting a strong correlation between rheumatoid arthritis and toll-like receptors as key research subjects. Knowledge base The relevant literature has been analyzed to identify key papers that have made significant advances in the field, laying a strong groundwork for advancing the field. Here, we review the top 10 most referenced articles to offer an in-depth insight into the function of TLRs in RA. External and internal TLR activators have been detected within the joints of individuals with rheumatoid arthritis ( 26 ), and conducted an in-depth study. In 2003, Prof. Seibl R from the Immunology Department at Zurich University Children's Hospital explored the effect of TLR on the activation of synovial fibroblasts (SF) in RA. The study aimed to explore the role of interleukin-1β and tumor necrosis factor-α, key cytokines in RA synovium, in driving inflammation and disease progression, influence TLR gene expression when they stimulate synovial fibroblasts. The results revealed a notable increase in NF-κB activation after TLR2-specific stimulation. This implies that TLR2-dependent pathways might be involved in synoviocyte activation, potentially leading to damage of cartilage and bone in RA as a component of its pathogenesis ( 27 ). In 2004, Prof. Mitsuhiro Iwahashi and his team from Okayama University investigated TLR-2 expression on CD16+ circulating monocytes and macrophages in synovial tissue. They also examined the impact of CD16 and TLR-2 stimulation on cytokine production. Their results revealed that elevated TLR-2 levels in CD16+ circulating monocytes and macrophages within the synovial tissue may be stimulated by M-CSF and IL-10. Additionally, the generation of TNFα by these cells was found to be replicable by minor immune complexes in joints affected by rheumatoid arthritis (RA), through interactions with natural TLR ligands like Hsp60 and FcγRIIIA ( 28 ). Similarly, in 2004, at the University Medical Center Nijmegen, Professor Timothy R. D. J. examined the expression of TLR-2 and TLR-4 in synovial tissues. This research concentrated on patients with RA and OA, and healthy controls. The research revealed that TLR-2 and TLR-4 were detectable in the synovial tissues of individuals with active conditions, with their concentrations correlated with elevated levels of IL-12 and IL-18. Moreover, the simultaneous presence of IL-12 and IL-18 impacted T-cell IFNγ synthesis, This subsequently affected the levels of TLR-2 and TLR-4 in the synovial tissues of RA patients ( 29 ). Subsequently, in 2005, Professor Brentano F at University Hospital investigated the expression of TLR-3 in synovial tissues of individuals with RA and in cultured fibroblasts from the same tissue. His research focused on the impact of TLR-3 ligands on these fibroblasts. The results uncovered the existence of TLR-3 in RA synovial tissues and demonstrated that ligands like poly(I-C) and necrotic RA cells stimulated fibroblasts in vitro. Additionally, the study suggested that RNA released from injured cells might function as endogenous TLR-3 ligands, possibly elevating the levels of inflammatory genes in these fibroblasts ( 30 ). Similarly, in 2005, Prof. M. F. Roelofs at Radboud University Nijmegen Medical Centre investigated Toll-like receptors TLR-3 and TLR-7 within synovial tissues. The research also assessed the reaction of dendritic cells (DCs) from both RA patients and healthy controls to stimulation by TLR-2/3/4, and TLR-7/8, focusing on changes in cell maturation and cytokine production. The findings showed increased levels of TLR-3 and TLR-7 in rheumatoid arthritis synovium, and showed that TLR ligands induced phenotypic alterations in dendritic cells from both groups. This implies that TLRs are engaged in modulating DC activation and cytokine release, and that simultaneous activation of multiple TLRs may aid in overcoming RA tolerance ( 31 ). Kindly replace key terms in this section with appropriatesynonyms to reduce similarity and enhance originality without compromising themeaning or academic integrity:In 2007, Prof. Shahla Abdollahi-Roodsaz, examined how TLR-4 activation affects autoimmune destructive arthritis. Her study initially revealed that blocking TLR-4 could diminish the intensity of induced arthritis and decrease IL-1 levels in the affected joints. This discovery indicates that TLR-4 might be a valuable new target for managing rheumatoid arthritis ( 32 ). In 2008, Prof. Caroline Ospelt ocusing on TLRs 1-10 in both synovial and dermal fibroblasts. The study revealed that TLRs 1-6 are present in synovial fibroblasts, whereas TLRs 7-10 are absent. Additionally, elevated levels of TLR-3 and TLR-4 during the early stages of rheumatoid arthritis, along with the fibroblasts' reactions to TLR ligands in vitro, propose that the TLR signaling pathway is engaged at an early stage and is involved in continuous inflammation and joint deterioration ( 33 ). An analysis of the top 10 highly cited articles on Toll-like receptors in RA revealed that most of these articles elucidated the mode of action of TLRs in RA. Elevated levels of TLRs were noted in peripheral blood lymphocytes, synovial membranes, synovial exudates, synovial phagocytes, and synovial connective cells in individuals with RA. TLRs 2, 3, 4, 7, and 8 each played varying roles in the development of RA. Emerging topics Further analysis of keywords in the field allows us to identify current research hotspots and trends. Cluster analysis of the keywords ( Figure 6C ) showed that RA research has transitioned from examining pathological processes to exploring molecular mechanisms and from studying disease development to implementing targeted treatments. The research shows significant interdisciplinary and holistic development characteristics, and the role of TLRs is being investigated from multiple perspectives. According to the analysis of keywords and development trends ( Figure 6E-6F ), the relevant research hotspots of TLRs in RA may include: TLRs and immune-inflammatory response in RA, interaction between TLRs and immune cells in RA, and regulation of TLRs signaling pathways in RA, TLRs and RA therapy. 1. TLRs and immune-inflammatory response in RA The persistent inflammatory autoimmune disorder RA is linked to cytokines and different immune cells. In RA, activated immune cells, especially macrophages and T lymphocytes, invade the synovial tissue. This intrusion leads to the persistent generation of pro-inflammatory signaling substances and matrix-destroying enzymes, which drive inflammation and contribute to the deterioration of cartilage and bone ( 34 ). The innate immune system relies heavily on TLRs for activation when encountering pathogenic microorganisms ( 35 ). They play an important role by recognizing “self” and “non-self” components. TLRs expressed on cells specifically recognize bacterial and viral components, and activated TLRS upregulate the expression of a series of inflammation-related genes through their intracellular signaling pathways, including enhanced phagocytosis and virulence killing by phagocytes, as well as the secretion of increased quantities of pro-inflammatory cytokines and chemokines, including IL-1β, IL-6/8/12, and TNF-α, which rapidly recruit neutrophils to the immune system( 36 ). They can rapidly recruit neutrophils, monocytes-macrophages, lymphocytes, etc. to reach the infected area, and these activated natural immune cells directly or indirectly kill the pathogen. This natural immune response process is based on the recognition of invading pathogens by TLRs, which directly triggers the bactericidal action of cells or induces the secretion of various inflammatory molecules to amplify the non-specific immune response process. Acquired immune response is a specific immune response with T and B lymphocytes as effector cells, and the activation of APCs is necessary to initiate acquired immunity, and activated TLRs are able to activate APCs, which are considered to be the main bridge between natural and acquired immunity, and are able to effectively initiate and maintain the acquired immune response ( 37 ). Liu Y and colleagues showed that TLR2/TLR4 expression on macrophages facilitated the identification of endogenous ligands related to RA. This recognition triggered intracellular signaling, this leads to the activation of the NF-κB pathway and a rapid increase in the expression of pro-inflammatory genes ( 38 ). The NF-κB signaling cascade, stimulated by TLR4, propels the pro-inflammatory activities of M1 macrophages. This stimulation results in the synthesis and secretion of IL-6, TNFα, and IL-1β in both monocyte-originating and synovial phagocytes from individuals with RA. 2. Interaction of TLRs with immune cells in RA Numerous investigations reveal that abnormalities in the immune system are pivotal in the onset of RA. T cells, B cells, macrophages, and DCs are integral, and the antibodies, cytokines, and matrix metalloproteinases (MMPs) generated by these cells are vital throughout the advancement of RA. These cells produce antibodies, cytokines, and matrix metalloproteinase (MMP), which are fundamental to the progression of RA, and the disruption of T lymphocyte homeostasis contributes significantly to the pathogenesis of RA ( 39 ). B cells can act as APC to present antigens to T lymphocytes and aid in the synthesis of signaling factors and chemotactic cytokines, thereby contributing to the progression of RA ( 40 ). Activation or regulation of macrophages/monocytes implicated in RA influences the progression of RA mainly through direct cell interactions and soluble factors ( 41 ). DCs play a vital role in regulating both innate and adaptive immune responses. As the main cells responsible for presenting antigens and initiating immune responses, they have a central role in the immune system ( 42 ). TLRs are vital in the progression of RA through diverse interactions with immune cells. They promote the development of dendritic cells, which leads to an amplified secretion of signaling molecules and attractants, along with enhanced expression of accessory molecules. Furthermore, TLRs markedly affect the differentiation and functional equilibrium of Th1 and Th2 cells and can activate regulatory T cells. They also contribute to the activation of inexperienced B cells, modulating the strength and quality of memory T cell responses, and initiating CD8+ T cell responses against soluble protein antigens. Specifically, TLR4 is mainly found on the exterior of immune cells, such as dendritic cells and monocyte-macrophage lineage, neutrophils, and epithelial cells in various tissues and organs ( 43 ). Laboratory studies have shown that lipopolysaccharide stimulation of RA synoviocytes or macrophages activates TLR4-related signaling pathways, such as those related to nuclear factor-κB and MAPK. This activation triggers the release of inflammatory mediators and causes inflammation within the synovial lining. In contrast, inhibiting the TLR4 signaling pathway effectively reduces the secretion of TNF-α, IL-1, and IL-6 ( 44 ). TLR9 primarily exists on the inner membranes of various cells, encompassing immune cells like plasma cell-like dendritic cells and memory B lymphocytes, as well as non-immune cells like intestinal lining cells, alveolar lining cells, and skin cells. Studies suggest that decreasing TLR9 expression in RA model mice can mitigate the severity of rheumatoid arthritis ( 45 ). 3. Regulation of TLRs signaling pathway in RA The TLR signaling pathway involves various related proteins, including IL-1 receptor-associated kinase (IRAK), tumor necrosis factor receptor-associated factor (TRAF), and inhibitors of cytokine signaling, among others. When TLRs are activated, they can form heterodimers or homodimers and recruit MyD88 ( 46 ). The TIR structural domain of MyD88 allows it to bind to TLRs and the IL-1 receptor family. MyD88 attaches to the TIR domain situated at the carboxyl end of TLRs and attracts the cytoplasmic proteins IRAK1 and IRAK4 ( 47 ). The IRAK protein features a pivotal kinase domain and an N-terminal binding domain that facilitates the activation of MyD88. After IRAK4 activates IRAK1, it is further phosphorylated, separates from MyD88, and enters the cytosol to recruit soluble TRAF6 ( 48 ). The activation of the IRAK1/TRAF6 complex sets off a chain reaction that includes the engagement of TAK1 and its interacting binding proteins. This process ultimately activates NF-κB and MAPK. As a sequence-specific DNA-binding protein, NF-κB is crucial in controlling the production of cytokines and inflammatory agents essential to immune responses. Therefore, NF-κB is essential in various types of inflammation. Preliminary studies suggest that targeting the TLR4/NF-κB signaling pathway holds potential as a therapeutic approach for RA ( 49 ). Liu ( 50 ) et al. It was noted that purple bead skin reduces inflammation, erythema, and synovial inflammation in rheumatoid arthritis (RA) by notably blocking the TLR4/NF-κB/MAPK signaling cascade. MAPKs are vital in cellular reactions to stress and damage. The excessive activation of the p38MAPK pathway, a component of the MAPK family, leads to abnormal expression of matrix metalloproteinases (including MMP-3, and MMP-13) and increased concentrations of inflammatory cytokines (such as IL-1β, and TNF-α), and increased production of type II collagen (Col II). This heightened activation of p38MAPK, along with its impact on matrix metalloproteinase expression, inflammatory mediator levels, and type II collagen degradation, is strongly linked to the damage of articular cartilage and chondrocyte apoptosis. Studies by Sujitha et al ( 51 ). have indicated that abnormal MAPK signaling contributes to the advancement of RA. 4. TLRs and RA treatment TLRs are essential in the progression of RA and offer new targets for its treatment. For example, soluble pseudoreceptors and neutralizing antibodies can block receptor/ligand binding, thereby inhibiting the inflammatory response; inhibition of endogenous factor release and blocking the expression of TLRs are also therapeutic tools for RA; receptor dimerization is a prerequisite for the activation of TLRs, so blocking their dimerization is also a therapeutic strategy; and signaling-mediated protein molecules downstream of the signaling of TLRs can be therapeutic targets as well. Opsona created two anti-TLR2 antibodies: OPN-305 inhibits cytokine secretion, while OPN-301 blocks spontaneous cytokine production in human RA cultures in vitro and also acts as a TNF-α inhibitor ( 52 ). Wasan K M et al ( 53 ). found that the first-generation human-derived monoclonal antibody, NI-0101, binds to the ligand-determining TLR4 site binding and interfering with TLR4 dimerization, thereby inhibiting activation of the TLR4 pathway. It is presently utilized in preliminary research on acute and chronic inflammatory and autoimmune conditions. In addition, NI-0101 is currently under development for managing RA, with potential for individualized dosing ( 54 ). Zhang S et al ( 55 ). found that CU-CPT8m could effectively reduce the concentration of inflammatory agents such as IL-1β and TNF-α produced by synovial cells in osteoarthritis patients, suggesting that as a TLR8 inhibitor, the CU-CPT8m molecule has the capacity to act as an anti-inflammatory substance. Additionally, CPG-52364, a complex inhibitor, was discovered to block autoimmune disorders such as systemic lupus erythematosus and is now in phase I clinical trials. It can be seen that CU-CPT8m molecule, the complex inhibitor CPG-52364 is anticipated to be a potential contender for the specific treatment of RA ( 56 ). Hydroxychloroquine is an inhibitor of TLR7/9, which can significantly inhibit CpG-induced secretion of IL-6 and TNF-α by inhibiting TLR9-mediated B-cell function, and also antagonize TLR7 and TLR8, which are commonly utilized for the management of malaria and RA in clinical settings ( 57 ). TLRs are increasingly becoming a research hotspot in the field of RA. This transition represents a more profound grasp of RA pathogenesis and the investigation of possible treatment approaches. Historically, Studies on RA have concentrated on the clinical symptoms and pathological alterations of the condition. However, with advances in molecular biology, the emphasis of research has transitioned from the pathological scale to the molecular scale, and from understanding disease mechanisms to targeted therapy. The function of TLRs in RA studies has garnered growing interest, especially in the following areas:TLRs and immune-inflammatory responses in RA, TLRs and immune cells interaction in RA, regulation of TLRs signaling pathways in RA, TLRs and microbiome, and TLRs and immune cells in RA. TLRs and RA therapy. More innovative studies and applications are expected. Modern research is increasingly focusing on integrating multi-omics data to elucidate the role of TLRs in RA, including genomics, transcriptomics and metabolomics. Such integrated analyses can help provide a comprehensive understanding of TLRs and their impact on RA, thereby advancing personalized therapeutic approaches. 5. Limitation and outlook Visualization and analysis tools like CiteSpace and VOSviewer reveal changes in the structure and trends of TLRs in RA pathogenesis research, but also helps to identify key nodes, research hotspots, and academic collaborative networks in the field of research, which provides important clues for further studies. However, there are some limitations in this study, and one of the main problems is the limitation of data sources. As only journal articles indexed by the two major indexes, SCI and SSCI, in the core collection of Web of Science databases were used, literature from other databases were not included, which could result in an incomplete grasp of the research area. In addition, while quantitative analysis tools can provide a large amount of data, the interpretation of this data requires in-depth and comprehensive domain knowledge on the part of the researcher to avoid the effects of subjective bias. Despite these limitations, research on the mechanism of TLRs in RA has shown a continuous and dynamic trend, and its importance cannot be ignored. Therefore, future studies should aim to integrate the literature from multiple databases to obtain more comprehensive data support, and actively collaborate with scholars in related fields to obtain a more comprehensive insight into the latest developments and trends in the field of research, so as to enhance the level of objective knowledge in the field, minimize the influence of subjective bias, and promote the further development of studies in this area. 6. Conclusion At the end of our study, we found that the study of TLRs in RA has received increasing attention. As the function of TLRs in the development of RA has become more apparent, their value in diagnosis and treatment has been increasingly emphasized. Overall, the leading nations significantly advancing this field of study include the United States, China, and the Netherlands. Among the institutions publishing in this field, Radboud Univ Nijmegen from the Netherlands has the highest number of publications. Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center is the most published scholar.Arthritis and Rheumatism is the most frequently published journal. By multidimensional analysis of the keywords, we found that the role of TLRs in RA involves several aspects. The role of TLRs signaling pathway regulating immune-inflammatory response in the pathogenesis of RA has become a hot topic at present. In the future, exploring the relationship between TLRs and RA from multiple perspectives will enhance our comprehension of the mechanisms underlying RA and offer new opportunities and targets for its management. Declarations Availability of data and materials All data generated or analyzed during this study are included in this published article and its supplementary information files. No datasets were generated or analysed during the current study. Funding Anhui University of Chinese Medicine High-level Talent Support Program(2022rcyb025) Author contributions YPZ, HL: Analyzing data and writing the initial draft. YLC: Reading references. XJZ and JCG: Conceptualization - review & editing. All authors approved the final version of the manuscript for submission and publication. Ethics approval and consent to participate Not applicable. Consent for publication All authors approved the final version of the manuscript for submission and publication. Competing interests The authors affirm that the study was carried out without any commercial or financial ties that could be perceived as a possible conflict of interest. References Luo X, Cui J, Long X, et al. TLRs play crucial roles in regulating RA synoviocyte[J]. 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Clinical Immunology, 2018, 195: 1-7. doi:10.1016/j.clim.2018.07.003 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5725138","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":396160911,"identity":"9dfae0cc-4af6-4e8b-a0eb-6c70ac44d75d","order_by":0,"name":"Yanping Zong","email":"","orcid":"","institution":"Anhui University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yanping","middleName":"","lastName":"Zong","suffix":""},{"id":396160912,"identity":"aaab4cc2-e476-4b63-94bf-15f40f773630","order_by":1,"name":"Hui Li","email":"","orcid":"","institution":"Anhui University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Li","suffix":""},{"id":396160913,"identity":"aceb70d3-c2f1-4f26-8322-681273889359","order_by":2,"name":"Yonglong Chang","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Yonglong","middleName":"","lastName":"Chang","suffix":""},{"id":396160914,"identity":"d21e08fa-a125-46a6-9e43-e0a93463214e","order_by":3,"name":"Xiaojun Zhang","email":"","orcid":"","institution":"Anhui University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Zhang","suffix":""},{"id":396160915,"identity":"73b08e74-3fe1-4f37-b184-d3e74fd49174","order_by":4,"name":"Jinchen Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABG0lEQVRIiWNgGAWjYJACgwQGBiBibHzwwcCGwQAiyEyMFuZmwxkVaQwGbERoAQGgFvY2aZ4zhwlrkY9IPlDwcIddHr90Y5s0b9t5eXP55qcbGCqsExvYzx7ApsXwRlqCQeKZ5GLJOQebLee23Tbc2cZmdoPhTHpiA09eAlYtM3IMDBLbDiRuuJHYeONt223GDcd42G4wth1ObJDgMcCrZf8NoBretnP2EC3/cGuRl4DZIpHYJMlzBsgAa2nArcWA5xnQL23JiTNuJIICOTl5w7E0sxsJx9KN23hysNvSnnzM8GebXWL/jPSHwKi0s91w+PCzGx9qrGX72c9gt+UAAxsWCVBQsWFTD7KlgYH5AQ65UTAKRsEoGAUQAAAtAGwsK50BbgAAAABJRU5ErkJggg==","orcid":"","institution":"Anhui University of Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jinchen","middleName":"","lastName":"Guo","suffix":""}],"badges":[],"createdAt":"2024-12-28 08:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5725138/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5725138/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72790870,"identity":"d6562cf6-a3ac-4c29-8fae-7a54884a1ffc","added_by":"auto","created_at":"2025-01-02 08:20:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":147975,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart for inclusion and exclusion of publications.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/3dfd4da5e4d8769556d301f1.png"},{"id":72790875,"identity":"c1d59609-f3a5-4f73-974a-923693748437","added_by":"auto","created_at":"2025-01-02 08:20:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97140,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverview of research.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/9614ece2db567e79f2260c6b.png"},{"id":72790872,"identity":"b4e0cabe-1c5d-4912-8332-a42efb724027","added_by":"auto","created_at":"2025-01-02 08:20:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":418599,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Geographical distribution map of total publications by country/region. (B) Distribution map of corresponding authors' affiliated countries/regions. (C) Cooperation among countries network map. (D) Institutional co-occurrence network map. (E) Institution co-occurrence network diagram based on citation counts. (F) Top 25 institutions with the strongest citation bursts.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/c2e01bf0b725a37b78f37d03.png"},{"id":72792119,"identity":"c291853e-0f6f-49b7-84ce-9db911de3e18","added_by":"auto","created_at":"2025-01-02 08:28:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":222909,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Top 10 journals by number of publications. (B) Co-cited journal network map. (C) Trends in the growth of publications in the top 10 journals by volume.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/e928623e03d65c1a7fa0c756.png"},{"id":72792116,"identity":"b4d7d464-3806-4805-b385-3d5751e3cff8","added_by":"auto","created_at":"2025-01-02 08:28:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":215875,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Author co-occurrence network map. (B) Author co-citation network map. (C) Publication trajectories of the top 10 published authors over time. (D) Top 10 authors based on H-index.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/8c2064fd5a9175e690324993.png"},{"id":72792114,"identity":"4320ea13-d1bb-4fc1-b342-823c2385c66b","added_by":"auto","created_at":"2025-01-02 08:28:44","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":418376,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Top 10 co-cited publications. (B) Network of co-cited publications cited at least 40 times. (C) Top 15 articles by citation burst strength.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/7d276e96cdfded8a81e5357e.png"},{"id":72790882,"identity":"d9137005-dea8-4388-99b2-719e6f1eaf68","added_by":"auto","created_at":"2025-01-02 08:20:44","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":433126,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Top 10 most frequent keywords plus. (B) Keyword co-occurrence network diagram generated by VOSviewer. (C) Keywords cluster map. (D) Keywords cluster timeline map. (E) Research trend evolution map based on keywords plus. (F) Top 15 keywords with the strongest citation bursts.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/67e098438cd8d8ea94a92e36.png"},{"id":72806422,"identity":"8241e02b-e235-408c-8672-642c8dfe2d23","added_by":"auto","created_at":"2025-01-02 10:24:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2866859,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5725138/v1/d2231349-cc90-4a51-bff4-8cb4bf709ab5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Global research trends and priorities in the link between Toll-like receptors and rheumatoid arthritis: a bibliometric analysis from 2003 to 2023","fulltext":[{"header":"Key points","content":"\u003cp\u003e1. This paper is the first to use bibliometric methods to study the relationship between Toll-like receptors and rheumatoid arthritis, which fills the gaps in the field and provides a scientific basis and guidance for clinical practice and research.\u003c/p\u003e\n\u003cp\u003e2. It is found that the role of TLRs in RA involves multiple aspects. At present, the role of TLRs signaling pathway regulating immune-inflammatory response in the pathogenesis of RA has become a hot spot. In the future, exploring the relationship between TLRs and RA from multiple perspectives will help deepen our understanding of the pathogenesis of RA and provide new pathways and targets for its treatment.\u0026nbsp;\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eRheumatoid arthritis (RA) is a debilitating joint condition caused by immune system imbalance and persistent inflammation, with a global prevalence of about 0.4% to 1.3% and a high rate of disability \u0026nbsp; (\u003csup\u003e1\u003c/sup\u003e)，\u0026nbsp;significant economic burden on patients and society\u0026nbsp;(\u003csup\u003e2\u003c/sup\u003e).\u0026nbsp;The main pathologic features of RA include synovial inflammation, cartilage damage, and joint destruction. In the disease state, fibroblast-like synoviocytes proliferate in the synovial lining, neovascularization occurs, and vascular opacities form, which work together with T-lymphocytes, B-lymphocytes, plasma cells, and macrophages to destroy bone and cartilage. The full pathogenesis of RA remains unclear. The condition results from the interaction of genetic predisposition and environmental factors. Smoking and infections are environmental factors clearly linked to RA development (\u003csup\u003e3\u003c/sup\u003e). The processes through which infections contribute to the progression of diseases are highly intricate, with major pathogenic factors including cells, cytokines, and signaling pathways. Cells and rheumatoid arthritis are specifically characterized by an imbalance between osteoblasts and osteoclasts, overproliferation of synovial cells, and immune cell dysfunction. Cytokines and rheumatoid arthritis are defined by inflammation driven by various inflammatory mediators, including interleukin (IL)-17, tumor necrosis factor (TNF)-α, IL-6, and IL-8, among others. Rheumatoid arthritis and its signaling pathways are marked by the involvement of nuclear transcription factor (NF)-κB signaling, Toll-like receptor pathways, and the Wnt signaling cascade (\u003csup\u003e4\u003c/sup\u003e,\u003csup\u003e5\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003eThe Toll-like receptor (TLR) serves as a fundamental part of the immune system, essential for both innate and adaptive immune responses. TLR detects molecular patterns associated with both pathogens and tissue damage within the body. Activating the TLR signaling pathway elevates pro-inflammatory factors, modulating immune responses and potentially influencing inflammation-related conditions. Abnormal TLR expression and Inappropriate stimulation of the TLR pathway by external or internal ligands can cause autoimmune reactions and tissue damage (\u003csup\u003e6\u003c/sup\u003e,\u003csup\u003e7\u003c/sup\u003e). Recent research has revealed that TLRs are present in circulating mononuclear leukocytes, synovial tissue, and synovial fluid. Additionally, they are found in synovial macrophages and synovial fibroblasts in patients with RA. These components contribute to the progression of RA to varying extents (\u003csup\u003e8\u003c/sup\u003e) . The presence of endogenous TLRs, mainly TLR4 and TLR2 agonists, in RA joint tissues, which include heat shock proteins, fibrinogen, and fibronectin EDA, suggests that TLRs are engaged in the initiation and advancement of persistent inflammatory arthritis by detecting specific PAMPs (\u003csup\u003e9\u003c/sup\u003e). In addition, the pathogenesis of TLRs in RA provides new targets for the treatment of RA (\u003csup\u003e10\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003eBibliometrics, as an interdisciplinary field, has been increasingly used in the medical field. Bibliometric analysis can not only help researchers and institutions understand their research results and impact, but also provide valuable information for policy making, academic resource allocation and research direction selection. In recent years, research on TLRs in the realm of RA has intensified, leading to notable advancements. However, as a field with considerable research value and potential, bibliometric analysis of TLRs in RA has not yet been conducted. In this research, we utilized bibliometric analysis and visualization methods to extensively review studies on TLRs in RA over the last 20 years. Our objective was to map the scientific understanding in this domain and provide new perspectives for future progress.\u003c/p\u003e"},{"header":"2. Methods ","content":"\u003cp\u003e\u003cstrong\u003e2.1 Data source and\u0026nbsp;search strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo obtain research data, a literature search was performed on July 17, 2024 in the Web of Science Core Collection (WoSCC) database. The search formula was TS=(\u0026ldquo;Rheumatoid arthritis\u0026rdquo; OR \u0026ldquo;RA\u0026rdquo;) AND TS=(\u0026quot;Toll-like receptors \u0026ldquo; OR \u0026ldquo;TLR\u0026rdquo;), spanning from January 1, 2003 to December 31, 2023. A total of 1,377 results were retrieved, which were subsequently evaluated by two team members utilizing established inclusion and exclusion guidelines (\u003cstrong\u003eFigure 1\u003c/strong\u003e), and a consensus was reached with a third author to resolve disagreements, resulting in a total of 440 publications part of this research. The data concerning the titles, institutions, authors, journals, citations, references and keywords of the 440 documents were subsequently recorded in unformatted text.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Data analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo provide an in-depth summary of the present condition and patterns in TLR studies concerning RA, we employed a variety of bibliometric visualization tools. In particular, we selected multiple software programs to examine and illustrate different facets of the research. In terms of research tools, we used R (version 4.1.2), Microsoft Excel (version 2021), the VOSviewer (version 1.6.18), CiteSpace (version 6.1), and R-bibliometrix package (version 3.0.3, http://www.bibliometrix.org). Regarding the current research status, these visualization tools were used to statistically analyze and display the publication count, annual citation rate, countries/regions, institutions, co-cited references, authors, and keywords. In terms of comprehensive analysis, we visualized the H-index of authors and journals, the proportion of corresponding authors\u0026apos; countries, and the international collaboration network. Finally, for scientific trend analysis, we examined knowledge structures, research clusters, and emerging research themes.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Number of\u0026nbsp;publications and\u0026nbsp;citation trends\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe initially conducted a summary analysis of the data(Table 1, Figure 2), and the rheumatoid arthritis and Toll-like receptor-related literature totaled 440 articles written by 2,264 researchers conducted at 679 institutions across 56 countries or regions, was featured in 189 journals. We searched the literature related to rheumatoid arthritis and Toll-like receptors from 2003 to 2023. The earliest publication dating back to 2003 was by Kyburz, Diego, an academic from the University of Basel, in the journal Arthritis and Rheumatism, titled \u0026ldquo;Bacterial peptidoglycans but activate synovial fibroblasts not CpG oligodeoxynucleotides by toll-like receptor signaling\u0026rdquo;, this study reveals that bacterial PG stimulates synovial fibroblasts, partially through TLR-2, resulting in the formation of integrins, matrix metalloproteinases (MMPs), and pro-inflammatory signaling molecules. Therefore, inhibiting the TLR signaling pathway may be beneficial for alleviating both joint inflammation and injury (\u003csup\u003e11\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;main information\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRank\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain information\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRank\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain information\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTimespan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2003~2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAuthor\u0026apos;s Keywords (DE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e752\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eJournal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAuthors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2264\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDocuments\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e440\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAuthors of single-authored docs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAnnual Growth Rate%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eCo-Authors per doc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDocument Average Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eInternational co-authorships%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eReferences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAverage citations per doc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e64.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eKeywords Plus (ID)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1377\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAverage citations per year per doc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCountry or region\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eInstitution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e679\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3. 2 Research Countries/Regions and Institutions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese 440 papers come from 56 countries or regions. \u003cstrong\u003eFigure 3A\u003c/strong\u003e displays the distribution of these nations, with deeper blue shades representing a higher count of publications.\u003cstrong\u003e\u0026nbsp;Table 2\u003c/strong\u003e enumerates the leading 10 countries and organizations by publication count. The United States secured the leading spot with 97 publications, followed by China with 75, the Netherlands with 49, the United Kingdom with 41, and South Korea with 35, among other countries. The leading 10 nations by publication count are mainly located in economically developed regions such as North America, Asia and Europe, which reflects the correlation between economic development and scientific research. Using the R-bibliometrix software package, we further visualized the countries of corresponding authors of publications. As shown in \u003cstrong\u003eFigure 3B\u003c/strong\u003e, the United States ranked first among multiple country publications (MCPs), highlighting that international collaborations enhance the impact of publications. Subsequently, we mapped global collaboration networks (\u003cstrong\u003eFigure 3C\u003c/strong\u003e), where the thick lines indicate stronger collaborations. Consistent with our expectations, the U.S. has established strong collaborative relationships with several countries/regions, while Asian and European countries have also formed close collaborative relationships.\u003c/p\u003e\n\u003cp\u003eOn the institutional side, \u003cstrong\u003eFigure 3D\u003c/strong\u003e gives the institutional co-occurrence network. The larger the nodes, the more publications they represent, and the connections between the nodes represent cooperative ties among institutions.\u003cstrong\u003e\u0026nbsp;Table 2\u003c/strong\u003e presents the leading 10 organizations based on the volume of publications, with Radboud Univ Nijmegen from the Netherlands contributing the largest quantity of papers, totaling 26, in the domain, followed by Univ Zurich Hosp from Switzerland with 18 publications. Many of the leading 10 organizations in publication volume are based in the Netherlands, Switzerland, South Korea, the United States, and the United Kingdom. \u003cstrong\u003eFigure 3E\u003c/strong\u003e shows the number of citations for each institution, with a minimum citation threshold of 40 citations and 326 institutions meeting this criterion. Larger nodes indicate that the institution received more citations, indicating that the institution is more influential in the relevant research. Lines between nodes represent collaborative or citation relationships among organizations; the greater or denser the line, the stronger the collaboration or citation relationship.Univ Colorado Denver received the highest number of citations.In scientific research, a citation explosion reflects the fact that an institution\u0026apos;s research has been widely noticed and cited by peers over a specific period of time. Using CiteSpace, we identified the leading 25 organizations with the most significant citation surges (\u003cstrong\u003eFigure 3F\u003c/strong\u003e). Univ Zurich was the first institution to experience a citation burst, suggesting that its research has gained a high level of scholarly recognition and attention over a given period of time, and that it has the potential to lead the way in new research directions. Radboud Univ Nijmegen has the longest duration of citation outbursts, indicating sustained attention and citations to its research, demonstrating its enduring impact and sustained contribution to a particular field. In recent years, Asian institutions such as Ajou Univ, Kyung Hee Univ, and Guangzhou Univ Chinese Med, especially Chinese institutions, have emerged as the institutions with the strongest citation outbreaks, reflecting China\u0026apos;s rapid rise and growing academic influence in related research fields.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e.\u0026nbsp;\u003cstrong\u003eTop 10 countries/regions and institutions in terms of publication volume.\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRank\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecords\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInstitutions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecords\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eUsa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eRadboud Univ Nijmegen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eUniv Zurich Hosp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNetherland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eAjou Univ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNorthwestern Nuiv\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eSouth Korea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eUniv London Imperial Coll Sci Technol \u0026amp; Med\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eSwitzerland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eCatholic Univ Korea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eKarolinska Inst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eUniv Zurich\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eIreland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;Univ Messina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eItaly/Spain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eUniv Amsterdam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.3\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe top-ranked journals and co-cited journals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese 440 papers appeared in 189 periodicals. Using VOSviewer, we examined the active journals in the field, as shown in \u003cstrong\u003eFigure 4A\u003c/strong\u003e. Of these, Arthritis and Rheumatism was the most frequently issued journal with 33 articles, followed by Arthritis Research \u0026amp; Therapy with 28 articles. the Annals of the Rheumatic Diseases published 26 articles, which was the third most frequently published journal. This investigation examined a total of 440 articles, which received citations from 18,052 journals. \u003cstrong\u003eFigure 4B\u0026nbsp;\u003c/strong\u003edisplays the citation visualization analysis, and \u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003elists the top 10 co-cited journals. The Journal of Immunology secured the top position with 2,112 citations, followed by Arthritis \u0026amp; Rheumatism with 1,492 references and the Journal of Experimental Medicine with 809 references. Other prominent journals in the top 10 include the Journal of Biological Chemistry with 805 references and Proceedings of the National Academy of Sciences of the United States of America with 732 references. Remarkably, five of the leading 10 frequently cited journals in 2024 had an impact factor of 10 or above, with Nature leading at 50.5. \u003cstrong\u003eFigure 4C\u003c/strong\u003e depicts the publication patterns for these top 10 journals, demonstrating a steady rise in publications over time, reflecting the increasing importance of this research area.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3. Top 10 journals related to influenza inflammatory response research and co-cited journals\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRank\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJournals\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCounts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIF (2024)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCo-Cited Journals\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCounts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIF (2024)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eArthritis and Rheumatism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eJournal of Immunology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e2112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eArthritis Research\u0026nbsp;\u0026amp; Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eArthritis and Rheumatism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e1492\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eAnnals of the Rheumatic Diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eJournal of Experimental Medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e809\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eJournal of Immunology\u003ca href=\"https://sci.justscience.cn/details.html?sci=1\u0026id=394\"\u003e\u0026nbsp;\u003c/a\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eJournal of Biological Chemistry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eFrontiers in Immunology\u003ca href=\"https://sci.justscience.cn/details.html?sci=1\u0026id=394\"\u003e\u0026nbsp;\u003c/a\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eProceedings of the National Academy of Sciences of the United States of America\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e732\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePloS One\u003ca href=\"https://sci.justscience.cn/details.html?sci=1\u0026id=394\"\u003e\u0026nbsp;\u003c/a\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eNature\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e731\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e50.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eRheumatology International\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eArthritis\u0026nbsp;\u0026amp; Rheumatology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e709\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eArthritis\u0026nbsp;\u0026amp; Rheumatology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eAnnals of the Rheumatic Diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e697\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eInternational Journal of Molecular Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eArthritis Research\u0026nbsp;\u0026amp; Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eJournal of Autoimmunity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 149px;\"\u003e\n \u003cp\u003eNature Immunology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e27.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Analysis of top authors and co-cited authors\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA combined total of 2,264 researchers have contributed to the investigation of the relationship between rheumatoid arthritis and Toll-like receptors. Figure 5A shows the collaborations between authors. It can be seen that only a few of the many researchers around the world have collaborated, and the collaborations are mostly concentrated in the same countries/regions. Table 4 displays the top 10 researchers ranked by their number of publications. At the top is Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center, with a total of 15 published works. Van Den Berg Wim B team focuses on TLRs to control inflammatory responses in arthritis by regulating inhibition of Fc\u0026gamma; receptor responses on macrophages (\u003csup\u003e12\u003c/sup\u003e,\u003csup\u003e13\u003c/sup\u003e,\u003csup\u003e14\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003eProf. Gay steffen, Prof. Abdollahi-roodsaz Shahla, and Prof. Choi Sangdun tied for the second place in the number of publications with 12, including Prof. Gay steffen from the University of Zurich, who centered on the management of cellular responses to the TLR pathway by different factors and analyzed its expression, regulation and function in RA synovial fibroblasts (RASFs) (\u003csup\u003e15\u003c/sup\u003e,\u003csup\u003e16\u003c/sup\u003e,\u003csup\u003e17\u003c/sup\u003e). Prof. Abdollahi-Roodsaz Shahla from Radboud University Nijmegen Medical Center studies TLR signaling mechanisms, including the structural domain of the TLR and its exogenous and endogenous ligands. Her research also examines existing and potential therapeutic strategies aimed at targeting TLR signaling, with a specific emphasis on how TLR influences Th cell responses that could trigger autoimmunity (\u003csup\u003e18\u003c/sup\u003e,\u003csup\u003e19\u003c/sup\u003e,\u003csup\u003e20\u003c/sup\u003e). Prof. Choi Sangdun from the Department of Molecular Science and Technology, Ajou University, has made great contributions mainly in the area of TLR as an effective drug target for RA. Their group has employed a computational strategy to analyze TLR antibody-binding sites and has discovered a novel epitope at the TLR interface. This finding could direct the advancement of therapeutic antibodies and small compounds. The approach provides understanding into antibody-antigen interactions and will facilitate the creation of novel monoclonal antibodies. Integrating computational methods with experimental techniques will expedite the strategic design and creation of antibody-based treatments (\u003csup\u003e21\u003c/sup\u003e,\u003csup\u003e22\u003c/sup\u003e,\u003csup\u003e23\u003c/sup\u003e). Prof. Radstake Timothy RDJ is ranked third with 11 publications. The five scholars are from the Netherlands, Switzerland, and South Korea.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; In terms of authors\u0026apos; co-citations (\u003cstrong\u003eFigure 5B\u003c/strong\u003e), 98 authors reached the minimum citation threshold of 20 citations and were grouped into four clusters, each of which is represented by a different color to indicate a different research topic or academic field. In \u003cstrong\u003eTable 4\u003c/strong\u003e, the leading 10 co-cited researchers are presented, along with the frequency of their citations. Abdollahi-roodsaz S from Division of Rheumatology, Department of Medicine, New York University School of Medicine had the most citations (166), followed by Radstake TRDJ ( 144 citations), Roelofs MF (140 citations), Akira S (120 citations), and Brentaon F (116 citations). The first to publish in the field were Gay RE, Kyburz D, and Joosten LAB as shown in Fig. 5C.Prof. Kyburz D is a consistent contributor to the field, while Prof. Van Den Berg WB and Prof. Abdollahi-roodsaz S have been leaders in the field with high annual output since 2003. This is further confirmed by the h-index positioning of the leading 10 authors(\u003cstrong\u003eFigure 5D\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTop 10 productive authors and co-cited authors.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRank\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCounts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCo-Cited Authors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCitations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eVan Den Berg Wim B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eAbdollahi-roodsaz S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e166\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eGay steffen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eRadstake TRDJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eAbdollahi-roodsaz Shahla\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eRoelofs MF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eChoi Sangdun\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eAkira S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eRadstake Timothy RDJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eBrentaon F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eGay Renate E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eOspelt C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eOspelt Caroline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eJoosten LAB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003ePope Richard M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eKawai T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eJoosten Leo A B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eSeibl R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eKoenders Marije I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eHuang QQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Analysis of co-cited references and references citation bursts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCo-citation, an important concept in scientific research, refers to the phenomenon that a literature is simultaneously cited by two or more academic publications, which is regarded as one of the indicators reflecting the importance of a specific research field, as it shows the influence and acceptance of a particular literature in that field. Figure 6A provides detailed information on the leading 10 co-cited publications, along with their citation totals, Radstake TRDJ et al. published a paper entitled \u0026ldquo;Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-\u0026gamma;\u0026rdquo; in 2004, published in the journal Arthritis \u0026amp; Rheumatism, tops the list with 89 citations. The research investigates the expression of TLR-2 and TLR-4 and their associations with pro-inflammatory cytokines in the synovial tissues of people with RA, OA, and healthy subjects. Our results indicate that TLR-2 and TLR-4 are identified in the synovial tissues of individuals with active disorders and are linked to the concentrations of IL-12 and IL-18. Moreover, the interplay between IL-12 and IL-18 affects T-cell IFN\u0026gamma; synthesis, which then influences the expression of TLR-2 and TLR-4 in the joint tissues of individuals with RA (\u003csup\u003e24\u003c/sup\u003e).\u0026nbsp;Figure 6B, on the other hand, illustrates a network diagram of relationships between co-cited publications that have been cited at least 40 times.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBurst analysis detects high-frequency and rapidly growing burst references by examining the temporal distribution of references, in order to reflect the leading areas and future directions of a discipline. In Figure 6C, the leading 15 citation bursts arranged by burst intensity are displayed. These citation bursts span from 2002 to 2023, with the longest lasting six years. The most recent citation burst was triggered by an article entitled \u0026ldquo;TLRs, future potential therapeutic targets for RA\u0026rdquo; by Elshabrawy HA et al. from Sam Houston State University, Published in 2017 in the journal Autoimmunity reviews. \u0026nbsp;This study investigated the role of TLR in the progression of RA across different cell types, such as myeloid cells, synovial fibroblasts, T lymphocytes, osteoclast progenitors, and endothelial cells. The results indicate that TLR-induced inflammation could lead to bone erosion through osteoclast activity by connecting myeloid lineage cells with TH-17 cells in reaction to joint blood vessel formation. For identifying TLRs that impair RA patients provides a new approach to activation (\u003csup\u003e25\u003c/sup\u003e). To date, this article is still in the citation explosion phase, indicating that it has attracted widespread attention and discussion in the academic community and has had a profound impact on the development of the field. This sustained citation growth may imply the enduring importance of this research and may provide key insights and guidance for future research directions and applications in the field.\u003c/p\u003e\n\u003cp\u003eKeywords encapsulate the fundamental core of a study. Keyword co-occurrence unveils research trends within a scientific domain and also provides insights into the direction of inquiry within the topic. In the \u0026ldquo;Most Frequent Words\u0026rdquo; analysis of \u0026ldquo;bibliometrix\u0026rdquo;, the most frequent keywords were toll-like receptors (95), activation (91), nf-kappa-b (65), collagen-induced arthritis (129), and collagen-induced arthritis (65), in addition to \u0026ldquo;most frequent words\u0026rdquo;. In addition to rheumatoid-arthritis (145) and experssion (129), the most frequently occurring keywords were toll-like receptors (95), activation (91), nf-kappa-b (65), collagen-induced arthritis (55), dendritic cells (55), and cells (53), inflammation (49), and synovial fibroblasts (47), as shown in \u003cstrong\u003eFigure 7A\u003c/strong\u003e. rheumatoid-arthritis, experssion, and toll-like receptors ranked in the top three, indicating that rheumatoid-arthritis and toll -like receptors are closely related research topics .\u003c/p\u003e\n\u003cp\u003eTo illustrate the research focal points more clearly,\u0026nbsp;we used VOSviewer to draw the keyword co-occurrence network view on 440 documents, and grounded in the strength of keyword co-occurrence connections, we chose the 31 keywords with a frequency of \u0026gt;20 occurrences for visualization, and divided the network into 4 clusters (\u003cstrong\u003eFigure 7B\u003c/strong\u003e), of which the red cluster is the largest one, involving there are 14 terms including rheumatoid arthritis, expression, inflammation, activation, toll-like receptor, cells, etc. Green clustering and blue clustering involve 6 terms. The green terms include rheumatoid-arthritis, toll-like receptors, innate immunity, dendritic cells, and systemic-lupus-erythematosus, and the blue terms include arthirtis, toll-like-receptor-4, pathogenesis, cytokines, synovial tissue, fibroblast-like synoviocytes, and tumor-necrosis-factor. the yellow terminology involves five terms, including collagen- induced arthritis, synoval fibroblasts, t-cells, tnf-alpha, fibroblast-like synoviocytes. all four clusters are related to the role of TLRs in the activation of fibroblasts ( FLSs) in RA patients.\u003c/p\u003e\n\u003cp\u003eWe used CiteSpace to generate a keyword clustering graph and a keyword timeline graph (\u003cstrong\u003eFigure 7C-7D\u003c/strong\u003e), which highlights \u0026ldquo;positive antigen-presenting cell\u0026rdquo;, \u0026ldquo;single nucleotide polymorphism\u0026rdquo;, \u0026ldquo;pathway drive\u0026rdquo;\u0026ldquo;chronic inflammation\u0026rdquo;, \u0026ldquo;bacterial peptidoglycan\u0026rdquo;, \u0026ldquo;articular chondrocyte\u0026rdquo;, \u0026ldquo;nod receptor\u0026rdquo;, \u0026ldquo;inflammatory diseases\u0026rdquo;, \u0026ldquo;anti-inflammatory effect\u0026rdquo;,\u0026nbsp;\u0026ldquo;synovial fibroblast-like phenotype\u0026rdquo; 10 keyword clusters. The clusters \u0026ldquo;nod receptor\u0026rdquo;, \u0026ldquo;inflammatory diseases\u0026rdquo;, and \u0026ldquo;anti-inflammatory effect\u0026rdquo; were the first to appear and remained the most popular in 2023. \u0026ldquo; appeared earliest and lasted longest, and will remain a hot topic and an important area of research in 2023, suggesting that pattern recognition receptors serve a crucial function in the advancement of inflammatory mechanisms in rheumatoid joints.\u003c/p\u003e\n\u003cp\u003eTo achieve a more profound insight into the development of research directions and to focus on Toll-like receptors in RA, we performed a thematic evolution analysis of Keywords Plus using the R-bibliometrix software package. This analysis identified more specific research priorities, including animal model studies, expression in immune cells, immune activation, and inflammatory responses (\u003cstrong\u003eFigure 7E\u003c/strong\u003e). CiteSpace burst word analysis provides insights into the frontiers of research, shifts in research focus, and the latest hot research developments, and helps predict subsequent trends in the field. In the study of the relationship between RA and TLRs, the 15 terms with the most significant citation spikes are displayed in \u003cstrong\u003eFigure 7F\u003c/strong\u003e. The keyword with the strongest citation burst was \u0026ldquo;tlr2\u0026rdquo; (Strength=4.37). tlr2 belongs to one of the TLR family members, suggesting that TLR2 has a significant role in the development of RA. The keyword with the longest citation burst duration is \u0026ldquo;macrophage\u0026rdquo;, which has continued to break out for 23 years, suggesting that the modulation of immunoinflammation via the TLR signaling pathway is significant in the development of rheumatoid arthritis, and it is also a research focus and hot spot in this field.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAs interest in the study of the relationship between rheumatoid arthritis and Toll-like receptors has increased, so has the amount of relevant literature. Unfortunately, there are no bibliometric studies in this area, which lacks a clear understanding of the overall research trends and priorities in this area. The present study utilizes bibliometric methods to analyze the relationship between rheumatoid arthritis and Toll-like receptors, which fills the gap in the field and provides an important reference and guidance for the further development of the field.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA study of the research results in this field shows that\u0026nbsp;the United States\u0026nbsp;led the way with 97 publications, while China and the Netherlands ranked second and third with 75 and 49 papers, respectively. Radboud University Nijmegen from the Netherlands produced the greatest quantity of publications in this field, with 26 publications.\u0026nbsp;The United States has intimate collaboration with nations such as China and the United Kingdom. In addition, the Netherlands, Sweden, Switzerland, and Germany have more extensive cooperation with other countries. However, Figures 3A and 3B show that many countries have less cooperation in this field, probably because of factors such as research methods, quality, funding, resources, and institutions. Tackling these obstacles can foster global collaboration and creativity, propel the discipline forward, and contribute to worldwide scientific advancement.\u003c/p\u003e\n\u003cp\u003eIn terms of authors, Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center ranked first with 15 publications.Arthritis and Rheumatism was the most frequently published journal, the Journal of Immunology was the most frequently referenced publication, while Nature held the highest impact factor. Among the top 10 most frequently co-cited journals, five had a citation impact score of 10 or above, reflecting the high caliber of research in the area. The analysis of keywords revealed that rheumatoid arthritis, expression, and toll-like receptors were the most prominent, suggesting a strong correlation between rheumatoid arthritis and toll-like receptors as key research subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKnowledge base\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relevant literature has been analyzed to identify key papers that have made significant advances in the field, laying a strong groundwork for advancing the field. Here, we review the top 10 most referenced articles to offer an in-depth insight into the function of TLRs in RA.\u003c/p\u003e\n\u003cp\u003eExternal and internal TLR activators have been detected within the joints of individuals with rheumatoid arthritis (\u003csup\u003e26\u003c/sup\u003e), and conducted an in-depth study. In 2003, Prof. Seibl R from the Immunology Department at Zurich University Children's Hospital explored the effect of TLR on the activation of synovial fibroblasts (SF) in RA. The study aimed to explore the role of interleukin-1β and tumor necrosis factor-α, key cytokines in RA synovium, in driving inflammation and disease progression, influence TLR gene expression when they stimulate synovial fibroblasts. The results revealed a notable increase in NF-κB activation after TLR2-specific stimulation. This implies that TLR2-dependent pathways might be involved in synoviocyte activation, potentially leading to damage of cartilage and bone in RA as a component of its pathogenesis (\u003csup\u003e27\u003c/sup\u003e). In 2004, Prof. Mitsuhiro Iwahashi and his team from Okayama University investigated TLR-2 expression on CD16+ circulating monocytes and macrophages in synovial tissue. They also examined the impact of CD16 and TLR-2 stimulation on cytokine production. Their results revealed that elevated TLR-2 levels in CD16+ circulating monocytes and macrophages within the synovial tissue may be stimulated by M-CSF and IL-10. Additionally, the generation of TNFα by these cells was found to be replicable by minor immune complexes in joints affected by rheumatoid arthritis (RA), through interactions with natural TLR ligands like Hsp60 and FcγRIIIA (\u003csup\u003e28\u003c/sup\u003e). Similarly, in 2004, at the University Medical Center Nijmegen, Professor Timothy R. D. J. examined the expression of TLR-2 and TLR-4 in synovial tissues. This research concentrated on patients with RA and OA, and healthy controls. The research revealed that TLR-2 and TLR-4 were detectable in the synovial tissues of individuals with active conditions, with their concentrations correlated with elevated levels of IL-12 and IL-18. Moreover, the simultaneous presence of IL-12 and IL-18 impacted T-cell IFNγ synthesis, This subsequently affected the levels of TLR-2 and TLR-4 in the synovial tissues of RA patients (\u003csup\u003e29\u003c/sup\u003e). Subsequently, in 2005, Professor Brentano F at University Hospital investigated the expression of TLR-3 in synovial tissues of individuals with RA and in cultured fibroblasts from the same tissue. His research focused on the impact of TLR-3 ligands on these fibroblasts. The results uncovered the existence of TLR-3 in RA synovial tissues and demonstrated that ligands like poly(I-C) and necrotic RA cells stimulated fibroblasts in vitro. Additionally, the study suggested that RNA released from injured cells might function as endogenous TLR-3 ligands, possibly elevating the levels of inflammatory genes in these fibroblasts (\u003csup\u003e30\u003c/sup\u003e). Similarly, in 2005, Prof. M. F. Roelofs at Radboud University Nijmegen Medical Centre investigated Toll-like receptors TLR-3 and TLR-7 within synovial tissues. The research also assessed the reaction of dendritic cells (DCs) from both RA patients and healthy controls to stimulation by TLR-2/3/4, and TLR-7/8, focusing on changes in cell maturation and cytokine production. The findings showed increased levels of TLR-3 and TLR-7 in rheumatoid arthritis synovium, and showed that TLR ligands induced phenotypic alterations in dendritic cells from both groups. This implies that TLRs are engaged in\u0026nbsp;modulating DC activation and cytokine release, and that simultaneous activation of multiple TLRs may aid in overcoming RA tolerance (\u003csup\u003e31\u003c/sup\u003e). Kindly replace key terms in this section with appropriatesynonyms to reduce similarity and enhance originality without compromising themeaning or academic integrity:In 2007, Prof. Shahla Abdollahi-Roodsaz, examined how TLR-4 activation affects autoimmune destructive arthritis. Her study initially revealed that blocking TLR-4 could diminish the intensity of induced arthritis and decrease IL-1 levels in the affected joints. This discovery indicates that TLR-4 might be a valuable new target for managing rheumatoid arthritis (\u003csup\u003e32\u003c/sup\u003e). In 2008, Prof. Caroline Ospelt ocusing on TLRs 1-10 in both synovial and dermal fibroblasts. The study revealed that TLRs 1-6 are present in synovial fibroblasts, whereas TLRs 7-10 are absent. Additionally, elevated levels of TLR-3 and TLR-4 during the early stages of rheumatoid arthritis, along with the fibroblasts' reactions to TLR ligands in vitro, propose that the TLR signaling pathway is engaged at an early stage and is involved in continuous inflammation and joint deterioration (\u003csup\u003e33\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003eAn analysis of the top 10 highly cited articles on Toll-like receptors in RA revealed that most of these articles elucidated the mode of action of TLRs in RA. Elevated levels of TLRs were noted in peripheral blood lymphocytes, synovial membranes, synovial exudates, synovial phagocytes, and synovial connective cells in individuals with RA. TLRs 2, 3, 4, 7, and 8 each played varying roles in the development of RA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmerging topics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFurther analysis of keywords in the field allows us to identify current research hotspots and trends. Cluster analysis of the keywords (\u003cstrong\u003eFigure 6C\u003c/strong\u003e) showed that RA research has transitioned from examining pathological processes to exploring molecular mechanisms and from studying disease development to implementing targeted treatments. The research shows significant interdisciplinary and holistic development characteristics, and the role of TLRs is being investigated from multiple perspectives. According to the analysis of keywords and development trends (\u003cstrong\u003eFigure 6E-6F\u003c/strong\u003e), the relevant research hotspots of TLRs in RA may include: TLRs and immune-inflammatory response in RA, interaction between TLRs and immune cells in RA, and regulation of TLRs signaling pathways in RA, TLRs and RA therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1. TLRs and immune-inflammatory response in RA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe persistent inflammatory autoimmune disorder RA is linked to cytokines and different immune cells. In RA, activated immune cells, especially macrophages and T lymphocytes, invade the synovial tissue. This intrusion leads to the persistent generation of pro-inflammatory signaling substances and matrix-destroying enzymes, which drive inflammation and contribute to the deterioration of cartilage and bone (\u003csup\u003e34\u003c/sup\u003e). The innate immune system relies heavily on TLRs for activation when encountering pathogenic microorganisms (\u003csup\u003e35\u003c/sup\u003e). They play an important role by recognizing “self” and “non-self” components. TLRs expressed on cells specifically recognize bacterial and viral components, and activated TLRS upregulate the expression of a series of inflammation-related genes through their intracellular signaling pathways, including enhanced phagocytosis and virulence killing by phagocytes, as well as the secretion of increased quantities of pro-inflammatory cytokines and chemokines, including IL-1β, IL-6/8/12, and TNF-α, which rapidly recruit neutrophils to the immune system(\u003csup\u003e36\u003c/sup\u003e). They can rapidly recruit neutrophils, monocytes-macrophages, lymphocytes, etc. to reach the infected area, and these activated natural immune cells directly or indirectly kill the pathogen. This natural immune response process is based on the recognition of invading pathogens by TLRs, which directly triggers the bactericidal action of cells or induces the secretion of various inflammatory molecules to amplify the non-specific immune response process. Acquired immune response is a specific immune response with T and B lymphocytes as effector cells, and the activation of APCs is necessary to initiate acquired immunity, and activated TLRs are able to activate APCs, which are considered to be the main bridge between natural and acquired immunity, and are able to effectively initiate and maintain the acquired immune response (\u003csup\u003e37\u003c/sup\u003e). Liu Y and colleagues showed that TLR2/TLR4 expression on macrophages facilitated the identification of endogenous ligands related to RA. This recognition triggered intracellular signaling, this leads to the activation of the NF-κB pathway and a rapid increase in the expression of pro-inflammatory genes (\u003csup\u003e38\u003c/sup\u003e). The NF-κB signaling cascade, stimulated by TLR4, propels the pro-inflammatory activities of M1 macrophages. This stimulation results in the synthesis and secretion of IL-6, TNFα, and IL-1β in both monocyte-originating and synovial phagocytes from individuals with RA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Interaction of TLRs with immune cells in RA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNumerous investigations reveal that abnormalities in the immune system are pivotal in the onset of RA. T cells, B cells, macrophages, and DCs are integral, and the antibodies, cytokines, and matrix metalloproteinases (MMPs) generated by these cells are vital throughout the advancement of RA. These cells produce antibodies, cytokines, and matrix metalloproteinase (MMP), which are fundamental to the progression of RA, and the disruption of T lymphocyte homeostasis contributes significantly to the pathogenesis of RA (\u003csup\u003e39\u003c/sup\u003e). B cells can act as APC to present antigens to T lymphocytes and aid in the synthesis of signaling factors and chemotactic cytokines, thereby contributing to the progression of RA (\u003csup\u003e40\u003c/sup\u003e). Activation or regulation of macrophages/monocytes implicated in RA influences the progression of RA mainly through direct cell interactions and soluble factors (\u003csup\u003e41\u003c/sup\u003e). DCs play a vital role in regulating both innate and adaptive immune responses. As the main cells responsible for presenting antigens and initiating immune responses, they have a central role in the immune system (\u003csup\u003e42\u003c/sup\u003e). TLRs are vital in the progression of RA through diverse interactions with immune cells. They promote the development of dendritic cells, which leads to an amplified secretion of signaling molecules and attractants, along with enhanced expression of accessory molecules. Furthermore, TLRs markedly affect the differentiation and functional equilibrium of Th1 and Th2 cells and can activate regulatory T cells. They also contribute to the activation of inexperienced B cells, modulating the strength and quality of memory T cell responses, and initiating CD8+ T cell responses against soluble protein antigens. Specifically, TLR4 is mainly found on the exterior of immune cells, such as dendritic cells and monocyte-macrophage lineage, neutrophils, and epithelial cells in various tissues and organs (\u003csup\u003e43\u003c/sup\u003e). Laboratory studies have shown that lipopolysaccharide stimulation of RA synoviocytes or macrophages activates TLR4-related signaling pathways, such as those related to nuclear factor-κB and MAPK. This activation triggers the release of inflammatory mediators and causes inflammation within the synovial lining. In contrast, inhibiting the TLR4 signaling pathway effectively reduces the secretion of TNF-α, IL-1, and IL-6 (\u003csup\u003e44\u003c/sup\u003e). TLR9 primarily exists on the inner membranes of various cells, encompassing immune cells like plasma cell-like dendritic cells and memory B lymphocytes, as well as non-immune cells like intestinal lining cells, alveolar lining cells, and skin cells. Studies suggest that decreasing TLR9 expression in RA model mice can mitigate the severity of rheumatoid arthritis (\u003csup\u003e45\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Regulation of TLRs signaling pathway in RA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe TLR signaling pathway involves various related proteins, including IL-1 receptor-associated kinase (IRAK), tumor necrosis factor receptor-associated factor (TRAF), and inhibitors of cytokine signaling, among others. When TLRs are activated, they can form heterodimers or homodimers and recruit MyD88 (\u003csup\u003e46\u003c/sup\u003e). The TIR structural domain of MyD88 allows it to bind to TLRs and the IL-1 receptor family. MyD88 attaches to the TIR domain situated at the carboxyl end of TLRs and attracts the cytoplasmic proteins IRAK1 and IRAK4 (\u003csup\u003e47\u003c/sup\u003e). The IRAK protein features a pivotal kinase domain and an N-terminal binding domain that facilitates the activation of MyD88. After IRAK4 activates IRAK1, it is further phosphorylated, separates from MyD88, and enters the cytosol to recruit soluble TRAF6 (\u003csup\u003e48\u003c/sup\u003e). The activation of the IRAK1/TRAF6 complex sets off a chain reaction that includes the engagement of TAK1 and its interacting binding proteins. This process ultimately activates NF-κB and MAPK. As a sequence-specific DNA-binding protein, NF-κB is crucial in controlling the production of cytokines and inflammatory agents essential to immune responses. Therefore, NF-κB is essential in various types of inflammation. Preliminary studies suggest that targeting the TLR4/NF-κB signaling pathway holds potential as a therapeutic approach for RA (\u003csup\u003e49\u003c/sup\u003e). Liu (\u003csup\u003e50\u003c/sup\u003e) et al. It was noted that purple bead skin reduces inflammation, erythema, and synovial inflammation in rheumatoid arthritis (RA) by notably blocking the TLR4/NF-κB/MAPK signaling cascade. MAPKs are vital in cellular reactions to stress and damage. The excessive activation of the p38MAPK pathway, a component of the MAPK family, leads to abnormal expression of matrix metalloproteinases (including MMP-3, and MMP-13) and increased concentrations of inflammatory cytokines (such as IL-1β, and TNF-α), and increased production of type II collagen (Col II). This heightened activation of p38MAPK, along with its impact on matrix metalloproteinase expression, inflammatory mediator levels, and type II collagen degradation, is strongly linked to the damage of articular cartilage and chondrocyte apoptosis. Studies by Sujitha et al (\u003csup\u003e51\u003c/sup\u003e). have indicated that abnormal MAPK signaling contributes to the advancement of RA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. TLRs and RA treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTLRs are essential in the progression of RA and offer new targets for its treatment. For example, soluble pseudoreceptors and neutralizing antibodies can block receptor/ligand binding, thereby inhibiting the inflammatory response; inhibition of endogenous factor release and blocking the expression of TLRs are also therapeutic tools for RA; receptor dimerization is a prerequisite for the activation of TLRs, so blocking their dimerization is also a therapeutic strategy; and signaling-mediated protein molecules downstream of the signaling of TLRs can be therapeutic targets as well. Opsona created two anti-TLR2 antibodies: OPN-305 inhibits cytokine secretion, while OPN-301 blocks spontaneous cytokine production in human RA cultures in vitro and also acts as a TNF-α inhibitor (\u003csup\u003e52\u003c/sup\u003e). Wasan K M et al (\u003csup\u003e53\u003c/sup\u003e). found that the first-generation human-derived monoclonal antibody, NI-0101, binds to the ligand-determining TLR4 site binding and interfering with TLR4 dimerization, thereby inhibiting activation of the TLR4 pathway. It is presently utilized in preliminary research on acute and chronic inflammatory and autoimmune conditions. In addition, NI-0101 is currently under development for managing RA, with potential for individualized dosing (\u003csup\u003e54\u003c/sup\u003e). Zhang S et al (\u003csup\u003e55\u003c/sup\u003e). found that CU-CPT8m could effectively reduce the concentration of inflammatory agents such as IL-1β and TNF-α produced by synovial cells in osteoarthritis patients, suggesting that as a TLR8 inhibitor, the CU-CPT8m molecule has the capacity to act as an anti-inflammatory substance. Additionally, CPG-52364, a complex inhibitor, was discovered to block autoimmune disorders such as systemic lupus erythematosus and is now in phase I clinical trials. It can be seen that CU-CPT8m molecule, the complex inhibitor CPG-52364 is anticipated to be a potential contender for the specific treatment of RA (\u003csup\u003e56\u003c/sup\u003e). Hydroxychloroquine is an inhibitor of TLR7/9, which can significantly inhibit CpG-induced secretion of IL-6 and TNF-α by inhibiting TLR9-mediated B-cell function, and also antagonize TLR7 and TLR8, which are commonly utilized for the management of malaria and RA in clinical settings (\u003csup\u003e57\u003c/sup\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTLRs are increasingly becoming a research hotspot in the field of RA. This transition represents a more profound grasp of RA pathogenesis and the investigation of possible treatment approaches. Historically, Studies on RA have concentrated on the clinical symptoms and pathological alterations of the condition. However, with advances in molecular biology, the emphasis of research has transitioned from the pathological scale to the molecular scale, and from understanding disease mechanisms to targeted therapy. The function of TLRs in RA studies has garnered growing interest, especially in the following areas:TLRs and immune-inflammatory responses in RA, TLRs and immune cells interaction in RA, regulation of TLRs signaling pathways in RA, TLRs and microbiome, and TLRs and immune cells in RA. TLRs and RA therapy. More innovative studies and applications are expected. Modern research is increasingly focusing on integrating multi-omics data to elucidate the role of TLRs in RA, including genomics, transcriptomics and metabolomics. Such integrated analyses can help provide a comprehensive understanding of TLRs and their impact on RA, thereby advancing personalized therapeutic approaches.\u003c/p\u003e\n\n\n"},{"header":"5. Limitation and outlook","content":"\u003cp\u003eVisualization and analysis tools like CiteSpace and VOSviewer reveal changes in the structure and trends of TLRs in RA pathogenesis research, but also helps to identify key nodes, research hotspots, and academic collaborative networks in the field of research, which provides important clues for further studies. However, there are some limitations in this study, and one of the main problems is the limitation of data sources. As only journal articles indexed by the two major indexes, SCI and SSCI, in the core collection of Web of Science databases were used, literature from other databases were not included, which could result in an incomplete grasp of the research area. In addition, while quantitative analysis tools can provide a large amount of data, the interpretation of this data requires in-depth and comprehensive domain knowledge on the part of the researcher to avoid the effects of subjective bias.\u003c/p\u003e\u003cp\u003eDespite these limitations, research on the mechanism of TLRs in RA has shown a continuous and dynamic trend, and its importance cannot be ignored. Therefore, future studies should aim to integrate the literature from multiple databases to obtain more comprehensive data support, and actively collaborate with scholars in related fields to obtain a more comprehensive insight into the latest developments and trends in the field of research, so as to enhance the level of objective knowledge in the field, minimize the influence of subjective bias, and promote the further development of studies in this area.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eAt the end of our study, we found that the study of TLRs in RA has received increasing attention. As the function of TLRs in the development of RA has become more apparent, their value in diagnosis and treatment has been increasingly emphasized. Overall, the leading nations significantly advancing this field of study include the United States, China, and the Netherlands. Among the institutions publishing in this field, Radboud Univ Nijmegen from the Netherlands has the highest number of publications. Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center is the most published scholar.Arthritis and Rheumatism is the most frequently published journal. By multidimensional analysis of the keywords, we found that the role of TLRs in RA involves several aspects. The role of TLRs signaling pathway regulating immune-inflammatory response in the pathogenesis of RA has become a hot topic at present. In the future, exploring the relationship between TLRs and RA from multiple perspectives will enhance our comprehension of the mechanisms underlying RA and offer new opportunities and targets for its management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files. No datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnhui University of Chinese Medicine High-level Talent Support Program(2022rcyb025)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYPZ, HL: Analyzing data and writing the initial draft. YLC: Reading references. XJZ and JCG: Conceptualization - review \u0026amp; editing. All authors approved the final version of the manuscript for submission and publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors approved the final version of the manuscript for submission and publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm that the study was carried out without any commercial or financial ties that could be perceived as a\u0026nbsp;possible conflict of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLuo X, Cui J, Long X, et al. TLRs play crucial roles in regulating RA synoviocyte[J]. 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Clinical Immunology, 2018, 195: 1-7. doi:10.1016/j.clim.2018.07.003\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rheumatoid arthritis, Toll-like receptors, Bibliometric analysis, Research trends, Citespace, VOSviewer","lastPublishedDoi":"10.21203/rs.3.rs-5725138/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5725138/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eRheumatoid arthritis (RA) is a widespread chronic autoimmune disease, distinguished by inflammation in the synovial membrane. Research indicates that Toll-like receptors (TLRs), which engage with internal ligands generated by the body, serve a crucial function in triggering immune reactions. These receptors are also implicated in the onset of inflammatory conditions, injuries, tumors, and are pivotal to the development of RA. This research seeks to comprehensively examine the present status and evolving trends in the study of the relationship between rheumatoid arthritis and Toll-like receptors using bibliometric methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eResearch on rheumatoid arthritis and Toll-like receptors was conducted using the Web of Science Core Collection (WoSCC) database, covering the period from 2003 to 2023. Eligible articles were screened according to predefined criteria and analyzed bibliometrically using VOSviewer, CiteSpace and the R package “bibliometrix”.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e440 papers from 56 countries or regions, 670 institutions, and 2264 authors in the disciplines of biochemistry and molecular biology, chemistry, engineering, immunology, and materials science were included. The United States, China and the Netherlands were the primary contributors. The institution that published the most papers in the field was Radboud Univ Nijmegen from the Netherlands. Prof. Van Den Berg Wim B from Radboud University Nijmegen Medical Center was the most prolific scholar. Research on TLRs and the immune-inflammatory response, interaction of TLRs with immune cells, regulation of TLRs signaling pathways, and TLRs and RA therapy in RA are hot topics in this field. The development trend is shifting from pathogenesis to targeted therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe involvement of Toll-like receptor-mediated immune inflammation in the development of rheumatoid arthritis has become a research focus of multidisciplinary interest. This article summarizes the research institutions, authors, journals, hotspots and application trends of Toll-like receptors in rheumatoid arthritis, which will help researchers to conduct further studies.\u003c/p\u003e","manuscriptTitle":"Global research trends and priorities in the link between Toll-like receptors and rheumatoid arthritis: a bibliometric analysis from 2003 to 2023","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-02 08:20:39","doi":"10.21203/rs.3.rs-5725138/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"44057277-2ce9-4a6a-9731-d53f9ab060b5","owner":[],"postedDate":"January 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-02T10:23:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-02 08:20:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5725138","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5725138","identity":"rs-5725138","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}