Bibliometric analysis of monoclonal antibodies for atherosclerosis

ABSTRACT

Atherosclerosis (AS) is a prevalent cardiovascular disease that greatly increases mortality in the aging population and imposes a heavy burden on global healthcare systems. The purpose of this study is to examine the research structure and current trends of monoclonal antibodies (mAbs) against AS from a bibliometric perspective, since the development of these drugs is currently booming. This study collected articles and reviews on mAbs against AS from the Web of Science Core Collection, spanning from 2003 to 2022. Biblioshiny was utilized to analyze and visualize the characteristics of countries, regions, authors, institutions, and journals included in this collection. We used VOS viewer to illustrate the frequency of country co-occurrence, and CiteSpace to visualize co-cited reference, keywords co-occurrence, keywords citation bursts, keywords clustering and timeline plots. The study included 1325 publications, with the United States emerging as a leading contributor to the field. ATHEROSCLEROSIS, CIRCULATION and ARTERIOSCLEROSISTHROMBOSIS AND VASCULAR BIOLOGY are core journals that publish high-quality literature on the latest advances in the field. Noteworthy authors with numerous high-quality publications include Witztum JL and Tsimikas S. Currently, lipid metabolism and inflammation are the main research areas of interest in this field. The mAbs against AS is an evolving field, and ongoing research continues to advance our understanding. This paper provides a comprehensive overview of the current state of knowledge in this area, highlighting two primary research directions: inflammation and lipid metabolism. Additionally, the paper identifies emerging research hotspots, which will provide researchers with useful insights to guide future investigations and anticipate research directions.

KEYWORDS:

• Monoclonal antibodies
• atherosclerosis
• bibliometrics
• mabs
• CiteSpace

Introduction

Atherosclerosis (AS) is a common and severe arterial disease, which is one of the leading causes of cardiovascular mortality.¹ Millions of people worldwide suffer from atherosclerosis each year, and its incidence increases with age, reaching 50% in people between 75 and 79.² Traditionally, AS has been treated with lipid-lowering drugs and surgery such as angioplasty.^3,4 Statins serve as the cornerstone for lowering low-density lipoprotein cholesterol levels and the risk of significant adverse cardiovascular events (MACE).^5,6 However, some patients with atherosclerotic cardiovascular disease (ASCVD) need additional drugs to minimize their low-density lipoprotein (LDL) levels and MACE risk in addition to statins.⁷ In response to the imperative of discovering innovative therapeutic strategies, investigators have increasingly turned their focus to inflammatory chemokines and adhesion molecules, exemplified by interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1, and intercellular adhesion molecule (ICAM). These molecular players beckon immune cells, particularly cholesterol-laden macrophages, instigating the formation of foam cells and the accrual of arterial plaques.⁸

Monoclonal antibodies (mAbs) are highly homogeneous antibodies designed to target only one specific epitope.⁹ The use of mAbs in the treatment of cardiovascular disorders has been shown to significantly improve patient outcomes.^10,11 There are many emerging mAbs that target inflammation and lipid metabolism, which are widely recognized as key mechanisms of AS.^12,13 For example, PCSK9, a pivotal regulator of low-density lipoprotein receptor (LDLR) levels on hepatocyte surfaces, plays a crucial role in cholesterol metabolism. Monoclonal antibody drugs that target PCSK9, including alirocumab and evolocumab, effectively disrupt the PCSK9-LDLR interaction, facilitating the hepatic clearance of low-density lipoprotein cholesterol.¹⁴ These therapeutics also exhibit the capacity to reduce lipoprotein A and triglyceride levels. The ODYSSEY study substantiates that the combined use of the PCSK9 inhibitor, alirocumab, with statin therapy yields a notable 15% reduction in MACE in recent acute coronary syndrome patients.¹⁵ Findings from the FOURIER study underscores the enhanced cardiovascular risk mitigation achieved by incorporating evolocumab alongside statin therapy in ASCVD patients.^16,17 PCSK9-targeted mAbs demonstrate robust lipid-lowering efficacy whether used as monotherapy, in conjunction with statins, or for patients with suboptimal statin response.^18,19 Another promising entry into clinical lipid metabolism modulation is evinacumab, which specifically targets angiopoietin-like 3 (ANGPTL3). By inhibiting lipoprotein lipase and endothelial lipase, evinacumab effectively regulates lipid levels. In 2021, it garnered Food and Drug Administration approval for the treatment of homozygous familial hypercholesterolemia.^20,21 IL-1β has become a prominent role linked to atherosclerosis, going beyond objectives of lipid metabolism. Canakinumab, a monoclonal antibody aimed against IL-1β, has been proven in large-scale clinical trials to reduce atherosclerotic cardiovascular risk.²² These mAbs have the benefit of excellent targeting specificity and considerable efficacy, and they may be coupled with statins to block various pro-atherosclerosis pathways simultaneously.^23,24 With a wide range of prospective applications for mAbs for atherosclerosis in the future, research on the subject is far from complete, given the necessity to investigate additional targets.

Bibliometric analysis examines literature systems and literature characteristics to understand knowledge structures and explore development trends. Through quantitative analysis of the existing literature, it is possible to predict the future development direction of a research field by using an intuitive map as well as systematically analyzing the research progress of various countries, institutions, authors, and disciplines. The objective of this study was to examine the landscape of mAbs use in AS in an effort to provide new clues and ideas for future research.

Materials and methods

Data sources and search strategies

The scientific studies were downloaded from the Web of Science Core Collection (WoSCC) database on March 8, 2023 for avoiding deviation. We retrieved articles or reviews published in English from the WoSCC. A total of 1,325 publications were left after limiting the publication year from 2003 to 2022. Search session queries: TS = ((Monoclonal antibody) OR (Monoclonal antibodies)) AND ((((((((((((((TS = (Arteriosclerosis)) OR TS = (Atheromatous Plaques)) OR TS = (Atheromatous Plaque)) OR TS = (Fibroatheroma)) OR TS = (Fibroatheromas)) OR TS = (Arterial Fatty Streak)) OR TS = (Arterial Fatty Streaks)) OR TS = (Atherosclerotic Plaques)) OR TS = (Atherosclerotic Plaque)) OR TS = (Atheroma)) OR TS = (Atheromas)) OR TS = (Atheromatous Plaques)) OR TS = (Atheromatous Plaque)) OR TS = (Atherosclerosis)) OR TS = (Arteriosclerosis). The search results were exported as “Plain Text file or BibTex” and the record content was “Full Record and Cited References,” and stored in download_*.txt or download_*.bib format. After screening, we included 477 records altogether, and no duplicates were found.

Bibliometric analysis

Our bibliometric analysis followed a general to detailed path including an overview, countries/regions, authors/institutions, journals, documents/references, keywords and trends, even though the data may be enormous and complex. Data collected were later imported into Biblioshiny (R version 4.2.2; Institute for Statistics and Mathematics, Vienna, Austria; www.r-project.org), VOSviewer (1.6.18; Centre for Science and Technology Studies, Leiden University, Leiden, the The Netherlands), CiteSpace [6.1.R6; Drexel University, Philadelphia, PA, the United States of America (USA)] and Microsoft Office Excel 2021 (Redmond WA, USA) for further analysis.

Biblioshiny is primarily used to visualize the analysis of sources, authors, as well as documents.¹ A range of bibliometric indicators are analyzed through biblioshiny to assess the output of countries, authors, institutions, and journals. The number of articles is used to assess the output of countries, authors, institutions, and journals. The number of articles is used to assess productivity. Total citations are used to indicate impact in the academic community, while local citations are used to assess impact in specific fields. They are the three main dimensions for assessing the quality of research. The h-index, where the scholar has published h papers that have each been cited at least h times, is an indicator that combines productivity and impact. In addition, country/institutional collaboration plots, three field plots, and affiliation/authors’ production over time were also plotted using biblioshiny. We mapped country co-occurrence with VOSviewer, whose strength lies in knowledge mapping visualization.² CiteSpace is a JAVA application process developed by Chen for bibliometric analysis, supporting knowledge mining and data visualization.³ We used it to generate document citation and reference co-citation, keyword co-occurrence, keyword clustering, and timeline plots. Keyword bursts were also analyzed to observe trending themes across years. The yearly output and average citation graphs were produced using Microsoft Office Excel 2021.

Results

Search results

Figure 1 depicts the study’s overview. The retrieval resulted in a total of 477 publications, composed of 343 articles and 134 reviews. In Figure 2, the annual number of publications (NP) associated with the use of mAbs in the treatment of AS is presented. With slight variations depending on the year, the number of articles published annually grew from 25 in 2003 to 30 in 2022. However, there is a slight upward trend overall, and the peak was reached in 2021 (38 papers).

Figure 1. Search strategy framework flowchart.

#1 = [TS = ((Monoclonal antibody) OR (Monoclonal antibodies))].

#2 = [TS = ((((((((((((((TS = (Arteriosclerosis)) OR TS = (Atheromatous Plaques)) OR TS = (Atheromatous Plaque)) OR TS = (Fibroatheroma)) OR TS = (Fibroatheromas)) OR TS = (Arterial Fatty Streak)) OR TS = (Arterial Fatty Streaks)) OR TS = (Atherosclerotic Plaques)) OR TS = (Atherosclerotic Plaque)) OR TS = (Atheroma)) OR TS = (Atheromas)) OR TS = (Atheromatous Plaques)) OR TS = (Atheromatous Plaque)) OR TS = (Atherosclerosis)) OR TS = (Arteriosclerosis)].

#3 = [TS = ((Monoclonal antibody) OR (Monoclonal antibodies)) AND ((((((((((((((TS = (Arteriosclerosis)) OR TS = (Atheromatous Plaques)) OR TS = (Atheromatous Plaque)) OR TS = (Fibroatheroma)) OR TS = (Fibroatheromas)) OR TS = (Arterial Fatty Streak)) OR TS = (Arterial Fatty Streaks)) OR TS = (Atherosclerotic Plaques)) OR TS = (Atherosclerotic Plaque)) OR TS = (Atheroma)) OR TS = (Atheromas)) OR TS = (Atheromatous Plaques)) OR TS = (Atheromatous Plaque)) OR TS = (Atherosclerosis)) OR TS = (Arteriosclerosis)].

Figure 2. Annual output of publications and annual average article on mAbs and AS.

Countries/regions

The publications were grouped by the authors’ respective regions, and the number of publications and citations from different countries were ranked. There were 45 nations that contributed to the development and publishing of knowledge, with the USA (101), China (53), and Japan (45) being the most active. These top three countries accounted for 41.7% of the publications. In terms of citation rankings, the USA ranked first with a total of 7007 citations, accounting for 35.2% of the total number of citations, followed by Germany (2552) and Japan (2064). The top 10 prolific countries are listed in Table S1. It is clear that the USA had the most significant influence in this field.

Figure 3a displays the collaborative publications of different countries. Of the 477 collaborations, the USA was the country that initiated and participated in the most collaborations (101). The collaborations were mainly concentrated between the USA and several European countries including Germany, the Netherlands, and France. The thickest line connecting Germany and the USA signified the highest level of collaboration between these two countries. Other collaborations with significant activity included Germany and the Netherlands, the USA and Canada, Denmark, Sweden, and China. There were relatively few collaborative relationships involving other countries in this field (Figure 3b). In terms of the timing of the research, Japan, South Korea, and Greece were the first to begin research in this field, followed closely by the USA and Germany. In particular, the USA had become the central hub of research and had participated in the most collaborative studies (Figure 3c).

Figure 3. Visualization of active countries/regions analysis.

(a) Country collaboration map. The collaboration bonds between countries are represented by red lines, with thicker lines indicating stronger collaboration. (b) Network visualization of country. (c) Overlay visualization of country. (d) Corresponding author’s country. SCP, single country publications. MCP, multiple country publications

Figure 3d lists the frequency of publication. The USA accounted for the highest total, almost twice as much as China, which ranked second. The number of multiple country publications (MCP) and single country publications (SCP) was used to describe the number of collaborations between countries. MCP represents the number of papers coauthored with authors from other countries, while SCP represents the number of papers coauthored with authors from the same country. The MCP ratio represents the international collaborations. The USA had the highest percentage of MCP and SCP among the nations, considerably more than any other nation, highlighting the significance of the country’s contribution to knowledge in this area.

Authors and institutions

A total of 863 institutions were involved in the studies on AS antibody therapy, as depicted in Figure 4a. We have listed the top 10 productive institutions, with the University of California, San Diego, ranking first, followed by Sao Paulo University in Brazil and Harvard Medical School in the USA. Table S2 provides detailed information on the regional affiliations and publication output of the top 10 institutions for knowledge production related to mAbs in AS. Figure 4b displays the annual number of publications by institution. Kumamoto University, Nagoya University, and the Technical University of Munich led in mAbs research for AS, while the University of California, San Diego, started later but had consistently published articles, eventually becoming the most productive institution in the field. Figure 4c shows the collaboration status between current institutions.

Figure 4. Visualization of active institutes analysis.

(a) Most relevant affiliations in the field of mAbs in AS. The nodes’ size and darkness are proportional to the number of documents produced by the affiliation. (b) Top 10 affiliations’ production over time. (c) Collaboration network among institutions.

Figure 5a presents the top 10 corresponding authors delivering articles in this field and lists the top 10 authors by the number of published articles. The five most productive authors were Witztum JL, Tsimikas S, Li X, Ridker PM, and Soto Y. H-index and G-index are mixed quantitative indicators that take into account both the quantity and quality of academic output and are used in bibliometric evaluations to determine academic influence. According to H-index and G-index, Witztum JL was the most prominent scholar, with the highest number and quality of publications, followed by Tsimikas S (Table S3). When comparing the authors’ publishing output over time, Witztum JL and Tsimikas S had the most papers published and the longest study periods, whereas Uchida K and Weber C started their research earlier and Ridker PM and Li X contributed more significantly in the latter years. According to Figure 5b, Bobik A continued to make contributions in this field in 2021.

Figure 5. Visualization of active authors analysis.

(a) Most relevant authors. (b) Authors’ production over time. The nodes’ size and darkness are proportional to the number of documents produced by the affiliation. (c) Three-field plot.

Figure 5c uses a three-field plot diagram to illustrate the pattern of authors’ publications in different related topics and journals. The top 10 authors’ main research keywords included atherosclerosis, inflammation, antibodies, monoclonal antibodies, oxidized LDL (oxLDL), canakinumab, and hypercholesterolemia. Their research was typically published in journals such as CIRCULATION, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, ATHEROSCLEROSIS, and THE JOURNAL OF LIPID RESEARCH. Among them, CIRCULATION became the top journal in the field of cardiovascular disease and was the most frequently selected by authors.

Journal distribution

A total of 267 journals participated in publishing literature on mAbs in AS, with the specific publication and citation details of the top 10 journals listed in Table 1. Furthermore, the top-ranked journals had higher H-indexes and citation counts, indicating their leading role in directing research in this field. ATHEROSCLEROSIS had the highest publication output, followed by CIRCULATION and ATHEROSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY (Figure S1). Before 2017, CIRCULATION was the top-ranked journal in terms of output. After 2017, ATHEROSCLEROSIS saw a significant increase in output, surpassing CIRCULATION to become the most productive journal in the field (Figure S2).

Table 1. The top 10 journals with the most publications on mAbs in AS.

Rank	Journal	Publications	Total citations	H-index	IF/JCR	Category
1	Atherosclerosis	17	739	13	6.847/Q1	CARDIAC & CARDIOVASCULAR SYSTEMS
2	Circulation	13	2167	13	39.918/Q1	CARDIAC & CARDIOVASCULAR SYSTEMS
3	Arteriosclerosis Thrombosis and Vascular Biology	12	767	12	10.514/Q1	PERIPHERAL VASCULAR DISEASE
4	Journal Of Lipid Research	12	740	10	6.676/Q1	BIOCHEMISTRY & MOLECULAR BIOLOGY
5	Biochemical and Biophysical Research Communications	9	870	9	3.322/Q3	BIOCHEMISTRY & MOLECULAR BIOLOGY
6	Journal of the American College of Cardiology	9	215	9	27.203/Q1	CARDIAC & CARDIOVASCULAR SYSTEMS
7	Scientific Reports	9	175	6	4.996/Q2	MULTIDISCIPLINARY SCIENCES
8	PLoS One	7	128	5	3.752/Q2	MULTIDISCIPLINARY SCIENCES
9	Current Atherosclerosis Reports	6	253	6	5.967/Q1	PERIPHERAL VASCULAR DISEASE
10	Current Opinion in Lipidology	6	98	5	4.616/Q2	PERIPHERAL VASCULAR DISEASE

IF, impact factor. JCR, Journal Citation Reports.

Document citation and reference co-citation

We used CiteSpace to generate document citation and reference co-citation networks, respectively signify the assessment of citation levels within our collected documents and the clustering of their references. We ranked the included papers according to the citation data in the WoSCC. The top 10 papers are listed based on their citation numbers, with the top two cited papers having 496 and 470 citations, respectively. Both were authored by Ridker PM from Harvard Medical School in the USA and focused on inflammation targets in AS treatment, particularly the monoclonal antibody canakinumab that targets IL-1β²⁵ (Figure 6a). We also evaluated the impact of each paper in the field by counting its local cited numbers in the current dataset. The rank of local-cited documents is slightly different from the total cited rank. The top-ranked paper among local-cited documents is a study on the application of PCSK9 monoclonal antibody alirocumab authored by Susan Kühnast, which represents recognition of the significance and direction of the research in the field. Figures 6a,b show the top 10 globally cited documents and the top 10 locally cited documents. Table S3 lists the top 10 papers by citation number, which have milestone significance in the study of mAbs for AS. They are presented as dots in Figure S3 with authors and years of publication labeled. In Figure 7, co-cited references are visualized as nodes. The most cited reference is “Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease,” followed by “Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease,” and “Efficacy and safety of evolocumab in reducing lipids and cardiovascular events” is the third most co-cited article (Table S5).

Figure 6. Visualization of documents analysis.

(a) Most global cited documents. (b) Most local cited documents.

Figure 7. Cluster analysis of co-cited references.

Keywords and trends

Figure 8a presents a tally of the high-frequency keywords in the included literatures. “monoclonal antibody” and “atherosclerosis” were among the top two, as was to be anticipated, and other commonly used keywords were “low density lipoprotein” (75), “expression” (57), “inflammation” (51), and “cardiovascular disease” (51), all of which occurred more than 50 times (Table S6). These keywords represent the focus of research in the field and are depicted as larger circles with strong centrality (>0.1) in Figure 8a, acting as critical nodes that bridge non-adjacent keywords. Table S6 shows the details of the top 20 keywords. Keyword burst detection analysis helped identify the trend of research direction and hot spots by detecting the marked change in the frequency of occurrence of keywords. Figure 8b shows the top 25 keywords with the citation burst. Keywords describing atherosclerotic lesions, plasma, ox-LDL, etc., were replaced by more specific and in-depth mechanisms and the corresponding clinical applications of antibodies such as evolocumab and PCSK9 inhibitors. Additionally, the latest area of focus, the ANGPTL3 lipid-lowering novel target, has gradually entered the field’s view since 2019 (Figure 8b).

Figure 8. Visualization of keywords analysis.

(a) The network map of keywords. (b) Top 25 keywords with the strongest citation bursts. (c) Clusters of keywords. (d) Keyword timeline view of mAbs in AS research.

Keywords clustering shows the frequency and distribution of two keywords that appear together and form a cluster that represents the main research direction in the field (Figure 8c). These keywords form 12 clusters including “oxidative stress,” “vaccine,” “PCSK9 inhibitors,” “canakinumab,” “disease,” “extracellular matrix,” “oxidized LDL,” “monoclonal antibody,” “apoA1,” “lipoprotein lipase,” “matrix,” and “proprotein convertase subtilisin/kexin type 9.” The timeline view of keywords shows that early research was focused on pathological mechanisms such as oxidative stress and extracellular matrix in AS, and the concept of mAbs had already emerged in the early stages (2003). However, its breakthrough began with PCSK9 and canakinumab in 2012, and research focus shifted toward specific monoclonal drugs targeting specific mechanisms (Figure 8d).

Figure S4 lists the trend topic changes after analyzing the trend topics in detail. It shows that understanding of AS gradually deepened in the two directions of inflammation and lipid metabolism, and in 2015, the monoclonal antibody canakinumab began to enter the field’s view. Subsequently, many mAbs were developed, new targets were discovered, and they became research hotspots.

Discussion

To the best of our knowledge, this is the first bibliometric analysis of research on mAbs in AS. In this study, we collected literatures from the WoSCC database with keywords related to AS and mAbs in this field. Though statins are still the preferred therapeutic agents for atherosclerosis, there are certain limitations such as marginal reductions in cholesterol levels while increasing adverse reactions and statin intolerance.²⁶ The emergence of monoclonal antibodies (mAbs) holds great promise for effectively tackling the challenges in the future. Ideas regarding immunotherapy for AS have emerged since 2003 (Figure 2). Early research in this field showed a steady, slight increase in the number of publications, suggesting flourishing research on mAbs in AS. Significantly, the years 2014 and 2018 witnessed remarkable surges in both publication and citation statistics. These pivotal moments aligned with two momentous scientific occurrences. The first was that the large clinical trials showed alirocumab, a PCSK9 mAb, can effectively control blood lipids and reduce cardiovascular risk^27,28 mAbs targeting PCSK9 opened up new avenues for lipid-lowering drug development and attracting increased scientific attention. A bibliometric analysis of familial hypercholesterolemia reveals a notable peak in publications during 2016, which may also be attributed to the clinical application of alirocumab.²⁹ The other spike is that in 2017. Consistent with the publications of immunotherapy in other field hitting its peak,³⁰ a large clinical trial of canakinumab provided strong evidence for the feasibility of IL-1β as an inflammatory target in AS treatment.³¹ This study marked a seminal milestone by demonstrating, for the first time, the capacity of anti-inflammatory medications to mitigate the risk of cardiovascular disease. This novel approach stands as an independent and efficacious therapeutic avenue, distinct from lipid-lowering strategies. Importantly, this finding provided direct empirical substantiation for the inflammation hypothesis in AS. This holds particularly profound implications for ASCVD patients with elevated residual inflammation risks. These two studies were milestone events in AS treatment and, to some extent, guided the direction of future research into immunotherapy for AS.

In 2021, there was another peak in publication volume, albeit accompanied by a lower average citation rate. When delving into the underlying reasons, the awarding of the Nobel Prize in 2018 for immune checkpoint inhibition may hit a record high in this field after the 2017 surge. This led to a substantial shift in the focus of cardiovascular researchers toward antibody-based treatments. The surge of publications observed in 2021 may reflect the release of related results after a 2–3-year research period.

In this field, the USA is the most active country in publication. In parallel, it serves as a research hub in this field due to the most active international collaborations. The primary partners in collaboration with the USA are Germany, the Netherlands, and France, while fewer collaborations were found with other countries. Closer international cooperation is encouraged. Among the top 10 authors in the field of mAbs for AS, Witztum JL was found to be the most productive author, followed by Tsimikas S, who have made outstanding contributions in the field. He has researched extensively on the mechanisms of lipoprotein oxidation and oxidation-specific epitope formation, as well as inflammation-immune mechanisms of AS.^32–34 His latest research focuses on the therapeutic effects of targeting apolipoprotein apoprotein C-III in treating hyperlipidemia and AS.³⁵ Both top two authors are affiliated with the University of California, San Diego School of Medicine, which reflects this institution is very productive.

Articles related to this field are published most frequently in the ATHEROSCLEROSIS, followed by CIRCULATION and ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. The Journal Citation Reports (JCR), published annually, ranks the included journals by impact factor as a reference for evaluating the level of the journals. Among them, the top 25% (including 25%) are classified as Q1 category. It’s noteworthy that six of the top 10 journals are in the Q1 category. CIRCULATION has the highest impact factor at 39.918 and is the most highly cited journal. As a high-quality and influential journal in this field, CIRCULATION is primarily focused on the cardiovascular specialty as are the top-ranked journals. Although ATHEROSCLEROSIS and ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY published more articles, their influence is weaker than that of CIRCULATION. Of the top 10 journals, only three are general medical journals.

According to the top 10 most highly cited documents (Table S4), inflammation is evidently the hottest topic in this field, with six references related to targeting inflammation for AS treatment. Notably, four of them discussed the mechanism of IL-1β and its monoclonal antibody canakinumab.^25,36–38 Among inflammation-related targets, ICAM and TNF-α also striked the attention.^39,40 Simultaneously, the second most common targets for regulation of lipid metabolism are ANGPTL3 and adiponectin.^41,42 These findings suggest that inflammation and lipid metabolism are the two main targets for immunotherapy for AS. It supports the idea that lipid infiltration and inflammation have a role in the development of AS, and indicates a rising interest in examining how these two factors interact.⁴³ The top-cited article in the local cited documents is the study of the PCSK9 monoclonal antibody alirocumab. Although PCSK9 does not have the same comprehensive impact as well-known inflammation targets, such as IL-1β, its effects and potential are well recognized.

Co-citation analysis involves counting the frequency of cited references in a particular article to measure the connection strength and citation frequency between the references.⁴⁴ From this analysis, two distinct clusters were formed with the top three ranks of the article. One cluster centers is evolocumab, a monoclonal antibody targeting lipid metabolism, while the other is canakinumab, which targets inflammation.^45,46 These two mAbs are the most well studied drugs for the treatment of AS and represent a significant accomplishment in this field.

The analysis of high-frequency keywords reflects the research hotspots. The co-occurrence of keywords suggests that the LDL, gene expression, and inflammation are the focal points of research on immunotherapy in AS. Among these, lipid metabolism is a critical topic in the study of AS. In addition to contributing to the deposition and development of atherosclerotic plaques, high amounts of lipids also influence cellular metabolism, leading to abnormalities with the microcirculation, endothelial damage, and the onset and spread of inflammation.^47–49 The oxidative stress-induced reactive oxygen species alter LDL to create oxLDL, which is the primary cause of increased oxidative stress, inflammation, and fat deposition.^50,51 In keyword clustering, “PCSK9 inhibitors,” “Apoa I,” “lipoprotein lipase,” and “proprotein convertase subtilisin/kexin type 9” are all lipid metabolism-related. “Canakinumab” is an inflammation-inhibiting antibody, and “oxidative stress” and “oxidized LDL” are related to oxidative stress and modified lipoproteins. Notably, research on the extracellular matrix (ECM) is also one of the high-profile directions. ECM remodeling is an important pathophysiological process in AS. During lesion development, there are changes in ECM component proteoglycans-glycosaminoglycans, elastin, and collagen. These alterations reverberate through the mechanical and immunomodulatory tapestry of blood vessels, ultimately shaping the AS landscape.^52,53 Therefore, targeting ECM could be a potential direction for future immunotherapy for AS. From the perspective of keyword burst, we observed that at different time points, keywords also changed in response to shifts in research directions. For instance, the peak of research related to subtilisin/kexin type 9 occurred between 2015 and 2017, likely due to the approval of alirocumab in 2014. Keywords associated with PCSK9 inhibitors, targeting this mechanism, saw a peak starting in 2016, primarily driven by the publication of clinical trial results involving PCSK9 mAbs. This burst has endured for a longer duration and remains a research hotspot to this day, possibly owing to the positive clinical outcomes it has elicited, which has spurred further exploration into its safety, efficacy, and combination therapies. Accordingly, we also observed in Figure 8b that clinical-related keywords such as “safety,” “efficacy,” and “high cardiovascular risk” experienced a burst in 2017, coinciding with the extensive initiation of clinical trials during this phase. Furthermore, emerging hotspots in recent years include ANGPTL3, with its monoclonal antibody entering clinical trials in 2021.^20,21 In 2019, an article published in NATURE MEDICINE revealed the unique role of smooth muscle cell phenotypic transition in AS. This publication attracted some researchers to delve deeper into the study of smooth muscle cells, contributing to the research on smooth muscle cells that has continued from 2020 to the present.⁵⁴

The findings of the CANTOS trial have delivered robust evidence in support of the inflammation hypothesis. Notably, this trial does not support the inflammation hypothesis as the sole mechanism underpinning AS. Rather, it bolsters the multifaceted pathogenesis theory, which encompasses inflammation as a pivotal element. Within the landscape of AS development, inflammation intricately intertwines with lipid metabolism disturbances and other risk factors, including oxidative stress, endothelial damage, aging, and smooth muscle cell migration, collectively propelling the progression of the disease. Traditionally regarded as an irreversible condition, AS has seen a transformative revelation through the GLAGOV study.⁵⁵ This study has unveiled the potential of monoclonal antibody therapy, specifically evolocumab, to modulate plaque volume, surpassing the efficacy of statin monotherapy.⁵⁵ Such findings underscore the tremendous promise inherent in monoclonal antibody therapies. The essence of monoclonal antibody research fundamentally lies in the exploration of AS mechanisms to pinpoint critical targets. The CANTOS clinical trial represents but a nascent phase in this endeavor. With a burgeoning array of monoclonal antibody drugs targeting diverse mechanisms entering clinical trials, healthcare providers are presented with a gamut of precision treatment options.

Cutting-edge technologies like single-cell sequencing and RNA sequencing offer a promising path to identifying and analyzing distinct genetic landscapes. This will empower researchers to delineate alterations in gene expression within specific populations, allowing for the exploration of the intricate relationship between these variations and susceptibility to AS. mAbs is poised as the ideal instruments to realize this prospect.

Overall, the research direction in the field of mAbs for AS is based on targeting lipid metabolism and inflammation, with increased attention on ECM remodeling. The study’s reach includes mechanism research, novel target development, and clinical application. We envisage that advances in AS research accompanied by the emergence of targeted drugs will one day lead to the development of precision treatment.

Limitations

This study utilized the WoSCC database as the -literature data, which may have resulted in the exclusion of significant research not included in this database. The mechanical nature of the CiteSpace and VOSviewer tools employed in this paper may have led to the imprecise extraction of keywords and incomplete analysis of article content. Single research evaluations through bibliometrics are not comprehensive, and citation counts can be influenced by factors such as outdated research and publication dates. However, the impact on the overall trend of the articles is still within an acceptable range.

Conclusions

This bibliometric study shows that the research on mAbs in the area of AS provides multiple possibilities and is progressing rapidly. The USA produced the most NP and continued to make significant advances. The study identified the top researchers and institutions in this field worldwide. ATHEROSCLEROSIS had the highest publication output in this research field. Witztum JL is the most influential author. The application of mAbs in AS is a hot topic currently, and new mAbs and mechanisms by which mAbs mediate may be a key direction for future research. As a consequence, new researchers and policymakers are given a thorough understanding of the development and boundaries of the discipline.

Author contributions

JQM, KWZ and YLZ contributed equally to the article. JQM, KWZ and YLZ wrote the manuscript and analyzed data. WX and JH assisted in the design of the research and oversaw the data collection. JQM and ZQZ designed the study. XLW and ZQZ revised the manuscript and ensured correct analysis of data. XLW provided fund support for the research.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Supplementary data

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2266926.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.