3.1 Quantitative analysis of the publications
According to our search strategy, there were 9341 publications on cellular therapies for RA in the past 21 years, including 6275 "articles" and 3066 "reviews". The 9341 papers used in this study were from 44914 authors at 8015 institutions in 107 countries, published in 1735 journals, and cited 332584 citations from 19120 journals. In terms of the number of articles issued each year, the overall fluctuations throughout the period were relatively flat(Figure 2).From 2003 to 2009, the number of publications on cell therapy applied to RA showed an increasing trend, with the number of publications in 2009 about twice that of 2003; from 2010 to 2022, the number of publications on cell therapy applied to RA fluctuates, but the overall trend is increasing and the number of publications per year will reach at least 444, which suggests that many scholars are interested in the treatment of RA with cell therapy. This indicates the continued interest of many scholars in cell therapy for the treatment of RA.
3.2 Journals and co-cited academic journals
We found 9341 articles related to RA in cell therapy published in 1735 academic journals(Table 1).Arthritis research & therapy (299,2.23%), an international, open-access, peer-reviewed journal established in 1999, has the highest number of outputs and tends to publish original articles in the field of arthritis research and its treatment. This journal focuses on several factors associated with rheumatic autoimmune diseases, with an emphasis on the immune processes of inflammation, injury, and repair. This was followed by Frontiers in Immunology (257,4.06%),Arthritis and Rheumatism (240,0.85%),Annals of The Rheumatic Diseases (194,1.27%) and Rheumatology(180,2.12%). The top five impact factors among the 32 journals in rheumatology are Lancet, Nature, Annals of The Rheumatic Diseases, Arthritis Research & Therapy, and Osteoarthritis and Cartilage, Among the top 15 journals, Annals of The Rheumatic Disease has the highest impact factor (IF: 27.4), the official journal of the European League Against Rheumatic Diseases, dedicated to promoting the highest level of scientific communication and education, and the third highest impact factor among 32 journals in the field of rheumatology. This was followed by Autoimmunity Reviews with an IF of 13.6.
The purpose of the co-citation analysis is to capture the high-frequency cited papers in the field and the journals that publish them, intending to measure the degree of relationship between articles. The size of a journal's impact depends on its co-citation frequency, reflecting the journal's influence in a particular field of study. As shown in Table 1, Annals of The Rheumatic Diseases (24232) was the most frequently cited journal, followed by Journal of Immunology (22125) and Arthritis and Rheumatism (22026) .Among the top 15 journals, Lancet has the highest IF (168.9), and it is not only the world's leading independent general medical journal, but it also has the highest impact factor among 32 journals in the field of rheumatology. The second is the New England Journal of Medicine, with an IF of 158.5, the world's longest continuously published medical journal, is a refereed medical journal and general medical journal founded by the Massachusetts Medical Society in 1811, often ranked as the world's highest impact factor journal in the field of medicine, with a very rigorous review process, mainly providing important, unpublished research results, clinical findings, and ideas.
Table 1
Top 15 journals and co-citations of cell therapy in RA
| No. | Journal | Count(%) | IF(2023) | JCR | Co-cited journal | Citations | IF(2023) | JCR |
| 1 | Arthritis research & therapy | 299(2.23%) | 4.9 | Q1 | Annals of the rheumatic diseases | 24232 | 27.4 | Q1 |
| 2 | Frontiers in immunology | 257(4.06%) | 7.3 | Q1 | Journal of immunology | 22125 | 4.4 | Q2 |
| 3 | Arthritis and rheumatism | 240(0.85%) | 0 | Not included | Arthritis and rheumatism | 22026 | 0 | Not included |
| 4 | Annals of the rheumatic diseases | 194(1.27%) | 27.4 | Q1 | Arthritis & Rheumatology | 15304 | 13.3 | Q1 |
| 5 | Rheumatology | 180(2.12%) | 5.5 | Q1 | New england journal of medicine | 11710 | 158.5 | Q1 |
| 6 | Clinical and experimental rheumatology | 137(4.32%) | 3.7 | Q2 | Blood | 11181 | 20.3 | Q1 |
| 7 | Autoimmunity reviews | 133(1.85%) | 13.6 | Q1 | Arthritis research & therapy | 10274 | 4.9 | Q1 |
| 8 | Plos one | 128(3.41%) | 3.7 | Q2 | Journal of rheumatology | 10027 | 3.9 | Q2 |
| 9 | Journal of rheumatology | 116(2.42%) | 3.9 | Q2 | Journal of Experimental Medicine | 9943 | 15.3 | Q1 |
| 10 | International journal of molecular sciences | 113(4.00%) | 5.6 | Q1 | Proceedings of the National Academy of Sciences of the United States of America | 9411 | 11.1 | Q1 |
| 11 | Journal of immunology | 107(1.35%) | 4.4 | Q2 | Rheumatology | 9245 | 5.5 | Q1 |
| 12 | International immunopharmacology | 107(4.77%) | 5.6 | Q1 | Nature | 7837 | 64.8 | Q1 |
| 13 | Clinical rheumatology | 94(5.10%) | 3.4 | Q3 | Journal of clinical investigation | 7524 | 15.9 | Q1 |
| 14 | Rheumatology international | 94(5.04%) | 4.0 | Q3 | Lancet | 7257 | 168.9 | Q1 |
| 15 | Clinical and experimental immunology | 92(2.43%) | 0 | Q2 | Journal of biological chemistry | 6495 | 4.8 | Q2 |
IF, Impact Factor; JCR, Journal Citation Reports
We screened 44 journals based on the minimum number of relevant publications equal to 30, and the journal network was mapped by VOSviewer for journal mapping (Fig. 3A). Figure 3A shows the relationship between the individual journals. Figure 3A shows that Arthritis Research and Therapy has active citation relationships with Frontiers in immunology and Arthritis and rheumatism with Blood. The co-citation mapping of journals was performed by VOSviewer, setting the threshold of the minimum number of journal co-citations to 1959, leaving 44 journals for co-citation analysis of cited journals, and the final co-citation relationship mapping was presented in Fig. 3B. Journal of Immunology Research has positive co-citation with Annals of the Rheumatic Diseases and New England Journal of medicine.
3.3 Geography and author distribution
To understand which countries contribute most to research in the field of cell therapy RA, this paper analyzes the volume of publications from 107 countries. The results are visualized by VOSviewer for countries with more than or equal to 88 posts and are shown in Fig. 4. The larger the circle node in the figure, the more the number of articles issued; the node connecting line represents the association strength, the thicker the line indicates the more the number of articles issued by two countries in cooperation; the node color represents different clusters. As can be seen from the figure, the distribution of publications in this field is very uneven in terms of countries, and the top effect is very significant, with most of the papers being authored by scholars from a few countries.
In addition to the number of papers published, the number of citations of a country's published papers reflects its contribution to the field. Table 2 shows the top 10 countries in terms of papers published and the number of citations to their articles. The United States published the most papers and was cited more frequently, with upwards of 24,000 citations. The second highest number of publications is from China. In contrast, although a certain number of papers have been published by Chinese scholars on this topic, Chinese articles in the field have not received many citations. Although the ranking order in Fig. 4 and Table 2 do not precisely match, the countries/regions in Table 2 all appear in Fig. 4. This means that the countries most involved in this topic are also the main drivers of this topic.
These articles come from 107 countries and 8015 institutions. As shown in Table 2, the most important number of publications came from the United States (2736, 1.59%) and China (1435, 4.12%), followed by England (924, 1.33%), Japan (719, 2.74%) and Germany (706, 1.58%). Several countries and institutions, such as the England (0.18), United States (0.16), Germany (0.11), Stanford University (0.12), and Harvard University (0.10), have a high centrality, representing them as more representative of this research theme.
Table 2
Top 10 countries and institutions for cell therapy in RA
| Rank | Country | Count(%) | Centrality | Total Citations | Institution | Count(%) | Centrality | Total Citations |
| 1 | USA | 2736(1.59%) | 0.16 | 172551 | University of Amsterdam(Netherlands) | 131(1.68%) | 0.03 | 7771 |
| 2 | CHINA | 1435(4.12%) | 0.02 | 34825 | Harvard University (USA) | 112(1.08%) | 0.10 | 10374 |
| 3 | ENGLAND | 924(1.33%) | 0.18 | 69550 | Karolinska Institutet (Sweden) | 109(1.70%) | 0.05 | 6427 |
| 4 | JAPAN | 719(2.74%) | 0.09 | 26211 | Stanford University (USA) | 107(0.97) | 0.12 | 11031 |
| 5 | GERMANY | 706(1.58%) | 0.11 | 44647 | University of Leeds(UK) | 98(1.54) | 0.03 | 6376 |
| 6 | ITALY | 683(2.16%) | 0.07 | 31563 | University of Calif San Diego(USA) | 91(0.88%) | 0.01 | 10359 |
| 7 | NETHERLANDS | 523(1.78%) | 0.05 | 29422 | Harvard Medical School(USA) | 86(4.33%) | 0.05 | 1984 |
| 8 | FRANCE | 467(1.46%) | 0.07 | 31896 | University of Pennsylvania(USA) | 79(0.77%) | 0.01 | 10321 |
| 9 | SPAIN | 331(2.02%) | 0.04 | 16380 | University of Glasgow (UK) | 67(0.99%) | 0.05 | 6790 |
| 10 | AUSTRALIA | 261(1.61%) | 0.02 | 16237 | Johns Hopkins University (USA) | 65(0.61%) | 0.09 | 3626 |
Figure 5 shows the top 20 countries with the most published articles (corresponding authors' countries). The United States produced the most results within this field, participating in the writing of 2143 papers. China is second only to the United States in terms of the number of papers published, with 1318 papers. All countries participated in international collaborative research to a greater or lesser extent, with 438, 184, and 221 papers from the United States, China, and the United Kingdom, respectively, being joint publications from multiple countries. The 20 countries in Fig. 6 have formed a network of international cooperation, a phenomenon that shows that although international cooperation is infrequent in each country, there is a sense of international cooperation.
An analysis of the authors of the literature reveals the representative scholars and core research teams in the research area. Table 3 shows the highly productive authors with more than or equal to 27 publications in this field. Among the highly productive authors, the most prolific posters are Emery and Tak. A total of 48 publications from 2003 to August 2023, which received 5181 citations, with an average of about 108 citations per article; In second place is Tak, with 46 articles, 3238 citations, and about 70 citations per article. Professors Emery and Tak are very interested in research on immunotherapy for rheumatoid arthritis, with a high number of publications and citations, and are highly cited researchers on cell therapy for RA。Tak belongs to the Department of Rheumatology and Clinical Immunology at the Amsterdam Rheumatology and Immunology Center in the Netherlands and has studied cell therapy in the treatment of RA.
Table 3
Most important authors in the cell therapy and RA big data research field
| Rank | Author | Publications | Citations | Average Citation/Publication |
| 1 | Emery, P. | 48 | 5181 | 107.94 |
| 2 | Tak, P. P. | 46 | 3238 | 70.39 |
| 3 | Doerner,T. | 35 | 2684 | 76.69 |
| 4 | Isaacs, J. D. | 31 | 2060 | 66.45 |
| 5 | Vital,E.M. | 27 | 1209 | 44.78 |
Figure 6 shows the nine affiliations with the highest number of publications on cellular therapies applied to RA. The Udice French Research Universities is involved in 663 publications on this topic and has a clear advantage in terms of the total number. Université Paris Cité came in second with 473 articles. Assistance Publique Hôpitaux Paris, Harvard University were all involved in the publication of at least 390 papers. The affiliations in Fig. 6 include the France, United States, and the United Kingdom. Except for France, these affiliations are the top-ranked countries in Fig. 5. This means that France scientists have been extensively involved in the investigation of this topic, even though they have published few papers as corresponding authors.
3.4. Literature analysis
3.4.1 Co-cited references
Over the past two decades, there are 332,584 co-cited references on research on cell therapy in RA. Of the top 10 co-cited references (Table 4), all references were co-cited at least 231 times. In 1988, Arnett Fc et al. published the most co-cited study that proposed new classification criteria for RA in both traditional and tree-like formats, which laid the foundation for therapeutic research in RA 11. Four of these 10 total cited papers were published in the New England Journal of Medicine. We selected references with co-citations greater than or equal to 147 to construct the co-citation network graph (Fig. 7). According to Fig. 7, "Arnett Fc, 1988, Arthritis Rheum " shows active co-citation relationships with "Edwards Jcw, 2004, New Engl J Med", "Mcinnes Ib, 2011, New Engl J Med " and "Firestein Gs, 2003, Nature", among others.
Table 4
top 10 co-cited references for cell therapy in RA studies
| Rank | Co-cited reference | Citations |
| 1 | Arnett Fc, 1988, Arthritis Rheum, V31, P315 11 | 633 |
| 2 | Edwards Jcw, 2004, New Engl J Med, V350, P257212 | 540 |
| 3 | Mcinnes Ib, 2011, New Engl J Med, V365, P220513 | 365 |
| 4 | Firestein Gs, 2003, Nature, V423, P35614 | 352 |
| 5 | Cohen Sb, 2006, Arthritis Rheum-us, V54, P279315 | 322 |
| 6 | Prevoo ml,1995, Arthritis Rheum,V38,p4416 | 294 |
| 7 | Lipsky Pe, 2000, New Engl J Med, V343, P159417 | 269 |
| 8 | Ehrenstein Mr, 2004, J Exp Med, V200, P27718 | 266 |
| 9 | Bongartz t, 2006, Jama-j Am Med Assoc, V295, P227519 | 258 |
| 10 | Mcinnes ib,2007,Nat Rev immunol,V7,P42920 | 254 |
3.4.2 Burst citation of literature
Burst-cited references are those that are frequently cited by scholars in a particular field over some time. In our study, CiteSpace identified 15 references with strong citation bursts (Fig. 8). As shown in Fig. 8, the blue line is the timeline, and the blue timeline shows a red segment representing a strong citation burst, which can also indicate the start year, end year, and duration of the reference of the strong citation burst21. Burst citation references appeared as early as 2004 and as late as 2012. The reference with the strongest citation burst (intensity = 79.44) was titled "Observations on the efficacy of rituximab b-cell targeted therapy for RA" by Edwards, et al. The years of the citation burst were 2004 to 2012. The study conducted by Edwards, J. C. et al. provides clear evidence that a single short course of rituximab is clinically significant in patients with active RA and has attracted the most scholarly citations. The second strongest citation burst (intensity = 70.19) was for a reference titled "Pathogenesis of RA" published in the New england journal of medicine by McInnes, I. B et al. The citation burst years was 2013 to 2022. This reference, with an impact factor of 158.5 and 2232 citations to date, summarizes the key mechanistic issues of RA. Table 5 summarizes the main studies of the 15 references in the order of the literature in Fig. 8.
Table 5
The main studies of the 15 references that cite strong bursts
| Rank | Strength | Main research content |
| 1 | 79.44 | Proven selective depletion of b cells with rituximab leads to sustained clinical improvement in RA patients 12 |
| 2 | 54.25 | To determine the efficacy and safety of rituximab in combination with methotrexate (MTX) in patients with active RA who are not responding to anti-tumor necrosis factor (anti-TNF) therapy and to investigate the pharmacokinetics and pharmacodynamics of rituximab in this population 15 |
| 3 | 42.72 | Effect of infliximab and methotrexate therapy on joint and clinical benefits in patients with RA 17 |
| 4 | 39.66 | Study the efficacy and safety of different doses of rituximab plus MTX (with or without glucocorticoids) in patients with active RA who are resistant to DMARDs, including biologics 22 |
| 5 | 38.61 | The extent to which anti-TNF antibody therapy may increase the risk of serious infections and malignancies in patients with RA by conducting a meta-analysis to derive estimates of sparse harmful events that occurred in randomized trials of anti-TNF therapy 19 |
| 6 | 70.19 | To study the pathogenesis of RA, such as how it leads to joint localization, the causes of persistent synovial inflammation, what drives local destruction leading to joint dysfunction, and the mechanisms by which RA causes systemic disease 13 |
| 7 | 54.92 | RA epidemiology, pathophysiology, diagnosis, and treatment 1 |
| 8 | 48.67 | To obtain optimal results with synthetic and biological disease-mitigating antirheumatic drugs for RA, the recommendations of the European League Against Rheumatism (EULAR) were updated in 2016 23 |
| 9 | 45.53 | RA-related disability can be prevented with sequential drug therapy, such as early treatment with methotrexate plus glucocorticoids, followed by other DMARDs (e.g. TNF, IL-6, etc.) 24 |
| 10 | 42.91 | Immunopathogenesis of RA, expressing a bold vision for the future of RA therapeutics 25 |
| 11 | 39.92 | Etiological insights from the treatment of RA: studies of the mode of action of specific immune-targeted drugs reveal which immune pathways drive joint inflammation and associated comorbidities 26 |
| 12 | 38.75 | Provides an updated summary of the EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs, focusing on treatment goals, treatment options, medication use, combination therapy, follow-up management, and patient education(2019)27 |
| 13 | 38.67 | Updates the 2010 European League Against Rheumatism (EULAR) recommendations on the use of synthetic and biologic disease-modifying antirheumatic drugs (sDMARD and bDMARD, respectively) for the treatment of rheumatoid arthritis (RA) (2013)28 |
| 14 | 37.2 | Rheumatoid arthritis pathogenesis involves autoantibodies, T cells and inflammatory cytokines. Modern pharmacological treatments include DMARDs, biologic DMARDs, and targeted synthetic DMARDs aimed at slowing disease progression and joint damage29 |
| 15 | 36.81 | Inflammatory cell status in synovial tissue of rheumatoid arthritis joints was investigated by integrating single-cell transcriptomics and mass spectrometry cytometry. Different types of inflammatory cells have different functions and phenotypes in synovial tissue, and the status of these cells can be used as an indicator of disease activity30 |
3.5. Keyword/Terms Analysis
Keywords condense the core and essence of a paper, and keyword co-occurrence analysis is not only the most effective way to discover the research hotspots in a scientific field but also the most effective way to understand the direction of investigation of issues of concern in a topic. We used VOSviewer to plot the keyword co-occurrence network view for 9341 documents and selected 50 key keywords with a frequency greater than or equal to 201 for visualization, and the results are shown in Fig. 9. The larger the circle node in the graph, the more the keyword appears, and the more it represents the hotspot of the field; the node connecting line represents the association strength, and the thicker the line indicates that the two appear together in the same literature more often; the node color represents different clusters (research topics). The statistical analysis of the words in different parts of the paper gives a concept of the different research directions of the topic.
Table 6
The research themes for cell therapy studies in RA
| Theme | Colour | More frequent keyword | Prevailing sub-categories |
| monoclonal antibody therapy | Red | Rituximab (406), autoimmune disease (370), autoimmunity (323), systemic lupus erythematosus(244),multiple sclerosis(138),cancer(134), immunotherapy (124),cytokine(110), inflammatory bowel disease(109), immunosuppression(88),b cell (67) | Rituximab is a chimeric mouse-human monoclonal antibody against the CD20 molecule expressed on the surface of human B cells. It is the first monoclonal antibody drug targeting B cells in RA and is a B cell depletion therapy3 |
| Tumour necrosis factor-alpha inhibitor therapy | Blue | infliximab (159), psoriasis (146), tnf-alpha (121), etanercept (112), Abatacept (109), tocilizumab (99), psoriatic arthritis(97), Adalimumab (89), ankylosing spondylitis(66) | infliximab, etanercept, tocilizumab and Adalimumab belong to the group of tumour necrosis factor-alpha inhibitors31. currently used clinically for the treatment of RA, ankylosing spondylitis and psoriatic arthritis |
| Gene and Mesenchymal Stem Cell Therapy | Yellow | Inflammation (646), Arthritis (243), osteoarthritis (128), Atherosclerosis (94), gene therapy (84), mesenchymal stem cells (81), immunomodulation (80), osteoporosis (68) | Gene therapy has been shown to be effective in experimental models for the treatment of RA with OA, but it is not yet well established in clinical trials32;MSC therapy for RA is a promising approach 33 |
| Targeted Immune Cell and Cytokine Therapy | Green | cytokines (297), b cells (154), treatment (118), biologics (112), t cells (99), biomarkers (81), Autoantibodies (67) | Cytokine targeting has been shown to be an effective treatment for rheumatoid arthritis34, The two main categories of targeted immune cells are b cells and t cells. |
| traditional therapy and novel therapies | Violet | rheumatoid arthritis (2300), methotrexate (323), Apoptosis (131), collagen-induced arthritis (126), Angiogenesis (106), regulatory t cells (106), fibroblast-like synoviocytes (69) | Methotrexate has been used in the treatment of RA for about 40 years and remains part of the global standard of care for RA to this day 35 |
Numbers in parenthesis present the number of papers in which an author keyword occurred