Bibliometric analysis of the Vogt‒Koyanagi‒Harada disease literature

This study conducted a bibliometric analysis of 1050 VKHD-related literature searched from the WoS database, verified by CiteSpace software (1050 unique records, 0 duplicated records and 0 invalid records). The annual publication volume is shown in Fig. 1. Among them were 966 articles (92%) and 84 reviews (8%). The annual growth rate was 9.59%, and an average of 11 articles were published each year (Fig. 1). Before 1989, few studies on VKHD had been published annually. In addition, from 1989 to 2003, the number of papers related to the VKHD globally showed a relatively stable trend. Nevertheless, since 2004, the annual publication volume of VKHD has begun to exceed 20 and has increased thereafter. The number of studies shown for 2022 is slightly lower because the data still needed to be collected as of the time of analysis.

Based on the R-language package bibliometrix, through a statistical analysis of the countries/regions included in the literature, we found that a total of 68 countries/regions have published literature on VKHD worldwide (based on the nationality of the corresponding author), and papers from the top 10 countries/regions had been cited frequently. Japan had the greatest number of articles (241 papers, 22.95%), with 5402 citations in total, while China ranked second (206 papers, 19.61%), with 3675 citations, and in third place was the United States (128 papers, 12.19%), with 3608 citations. These three countries accounted for 45.23% of the total. Countries with many published papers were also closely linked (Fig. 2; Table 1).

According to the search results, 3455 authors participated in VKHD studies, of whom the 10 most prolific are shown in Table 2. Yang P.Z. from China published 109 papers, KIJLSTRA A. from the Netherlands published 101 papers, HOU S.P. from China published 45 papers, OHNO S. from Japan published 40 papers, and RAO N.A. from the United States published 30 papers. In addition, the citation frequency of RAO N.A. was the highest (1418), and Yang P.Z., KIJLSTRA A., and OHNO S. were also cited more than 1000 times. In the top 50 cited articles (Supplementary Table 1), it is noteworthy that RAO N.A. appears as the corresponding author in a total of 6 articles, followed by Yang P.Z. (5 articles) and Tamaki K. (2 articles).

The H-index, also known as the H-factor, is a new method for evaluating academic achievement, wherein H stands for high citations. According to the H-index ranks of the authors, we find that the top five were Yang P.Z., Kijlstra A., Rao N.A., Ohno S., and Hou S.P. (Table 2). There was a close cooperative relationship among Yang P.Z., Kijlstra A. and Hou S.P. (Fig. 3, generated by Bibliometrix- Social structure), and cooperation between authors in this field is widespread.

Similar to the H-index, the impact factor (IF) is another important indicator. Supplementary Table 2 includes all the articles with an IF greater than 10. The highest IF in the list is attributed to an article published by Hou, S.P. et al. (with Yang P.Z. as the corresponding author) in NATURE GENETICS (IF = 41.307). In addition, as a corresponding author, KIJLSTRA A. has had three publications with an impact factor higher than 10.

Figure 4 shows the ranking of research institutions by the number of articles published, of which we list the top ten. This information is derived from the data analysed by the R package. According to the ranking of the number of papers issued by institution (Fig. 4a), Chongqing Medical University, where Yang P.Z. is located, ranks first, with a total of 130 papers, followed by Hokkaido University and University Eye Clinic Maastricht, with 73 and 70 papers, respectively. Since 2005, the number of papers published by Chongqing Medical University has increased dramatically. After 2014, it surpassed other institutions to become the institution with the largest annual average volume of papers (Fig. 4b). More detailed information can be found in Table 3.

Based on the retrieved results, papers on VKHD research were distributed among 261 journals. Among them, the journal with the greatest number of articles was Ocular Immunology and Inflammation, with 114, followed by the American Journal of Ophthalmology and British Journal of Ophthalmology. The journal with the highest cited frequency is the American Journal of Ophthalmology, followed by Ophthalmology, Ocul Immunol Inflamm, Br J Ophthalmol, and Invest Ophth Vis Sci. All of the abovementioned journals are ophthalmology-related journals (Table 4).

Among the top 25 keywords, the keywords with the strongest burst were optical coherence tomography, genome-wide association and antigen. The keywords with the longest duration of use were cerebrospinal fluid, antigen, and association. Among these keywords, inflammation, VKH disease, diagnosis, sunset glow fundus, and standardization had become more prevalent in recent years.

Apart from “uveitis”, “VKH syndrome”, “VKH disease”, and “disease”, which are parts of the names of VKHD itself, we can mainly divide the remaining keywords into the following two categories. The first category is keywords related to clinical diagnosis, including nomenclature, standardization, diagnosis, optical coherence tomography, sunset glow fundus, polymorphism, inflammation, and serous retinal detachment. The second category is keywords related to pathogenesis research, including antigen, genome-wide association, cerebrospinal fluid, susceptibility, allele, susceptibility loci, and cell (Fig. 5).

From January 1975 to October 2022, we searched a total of 1050 articles related to VKHD involving 261 journals. Japan published the most papers, followed by China and the United States.

According to the number of articles, we can divide the VKHD literature into three stages. The first is from 1975 to 1988. During this stage, the number of papers published was relatively low, with an annual average of 2.6 publications, reflecting the initial lack of understanding of the disease since it was officially named VKHD in 1949. At the beginning of this stage, the American Uveitis Society (AUS) developed a set of diagnostic criteria to draw attention to and help people recognize the disease [19]. Although it has some limitations as the first set of diagnostic criteria for VKHD, it still includes most of its clinical features. The second stage was from 1989 to 2003, during which 170 papers were published, with an average of 11.3 annual publications, a significant increase over the previous stage. In 2001, Read et al. proposed a more complete Revised diagnostic criteria for Vogt‒Koyanagi‒Harada disease based on AUS, which continues to be in use today [7]. In addition, OCT, an essential diagnostic tool for VKHD [20‐22], appeared in the 1990s and became of great help in research on VKHD at this stage. In the third stage, spanning 2004 to 2022, 844 articles were published, with an average of 44.4 annual publications. During this period, Japan, China, the Netherlands, Saudi Arabia, and the United States ranked among the top five in the number of publications and contributed significantly to VKHD research. As seen from the figure (Coauthorship-AND-Organizations-30), the cooperation between these five countries is also very close. In addition, at this stage, Yang et al. proposed diagnostic criteria for VKHD based on Chinese data [23]. The increase in the number of articles published in the first two stages was often accompanied by progress in VKHD clinical diagnosis. In contrast, the third stage witnessed the emergence of a substantial amount of basic research literature on molecular biology, which also constitutes the current research trend.

In 2001, the article titled “Revised diagnostic criteria for Vogt‒Koyanagi‒Harada disease: report of an international committee on nomenclature”, the most frequently cited article, was published in the American Journal of Ophthalmology. It can also be seen that the criteria proposed by this study have a high degree of recognition and authority. It is more detailed than the AUS criteria and includes two essential examinations: fluorescein angiography and ultrasonography. In addition, the diagnostic criteria allow VKHD to be divided into complete, incomplete, and probable Vogt‒Koyanagi‒Harada disease, which makes them more accurate and consistent with the clinical situation. Although this standard has been widely adopted by peers worldwide [24‐26], detailed regulations lead to more examinations, which to some extent increases the costs for patients. We can see the continuous improvement in diagnostic criteria driving VKHD research.

According to the cluster analysis, we can divide the literature searched from WoS into three categories. The first category is the essential study to explore the aetiology of VKHD, which yielded the greatest number of studies among the three categories.

The aetiology of VKHD has consistently been a focus of research attention.

As an autoimmune disease, VKHD has been the subject of ongoing immunological research regarding its pathogenesis. As early as 1982, studies found that cytotoxic T lymphocytes may be involved in the occurrence of VKHD [27]; recently, T helper 1 (Th1) cells, Th17 cells, and natural regulatory T cells (Tregs) were also found to play an important role. It is generally accepted that the immune response caused by Th1 and Th17 lymphocytes in patients with VKHD cannot be inhibited by nTreg cells, leading to autoimmune issues. In recent years, the primary purpose of this research has been to explore the influence of molecules upstream and downstream of T cells on the progression of VKHD by regulating T cells [28‐38]. Nu. C. et al. found that overexpressed kallistatin can aggravate experimental autoimmune uveitis (EAU) by accelerating the differentiation of Th17 cells [37]. Wang C et al. found a significant decrease in the levels of the immune regulatory molecule progranulin in active VKH patients. When EAU occurred in PGRN^−/− mice, Th1 and Th17 cells increased significantly, while Treg cells decreased [36].

Another research direction is to decipher the aetiology of VKHD from the perspective of genetics. In related experiments, whole blood is selected for gene sequencing to screen out susceptible genes. Some studies focused on human leukocyte antigen (HLA)-associated genes and VKH susceptibility, and HLA-DRB1, HLA-DR4/DRw53, and HLA-DR1 alleles are found to be the most susceptible gene phenotypes [39‐48]. HLA genes play leading roles in antigen presentation to T lymphocytes, but HLA-associated genes are not the real cause of the disease; they merely serve as genetic markers. Researchers have continuously reviewed the relevant research since 1980, and two related keywords (genome-wide association, susceptibility loci) in the top 25 keywords were related to genetic analysis. The periods over which these terms frequently appeared (2012–2016 and 2014–2016, respectively) overlapped with the year in which the third-generation single-molecule real-time sequencing technology emerged [49]. However, it is worth noting that almost all VKHD is sporadic and does not conform to Mendelian inheritance [1]. With improvements in gene sequencing technology, an increasing number of studies in will emerge this direction.

In addition to the study of genetic susceptibility, virus infection is another important research hotspot [32, 50‐55]. Some scholars believe that viral infection may be an important cause of VKHD. The clinical samples involved in such studies include cerebrospinal fluid aqueous humour and serum, and the types of viruses tested include herpes simplex virus (HSV), herpes zoster virus (VZV), cytomegalovirus (CMV), Epstein‒Barr virus (EBV) and human herpes virus type 6 (HHV-6) [32, 50‐52]. The research trends related to viral infection have declined in the past five years, but it is worth noting that many clinical studies and case reports in the past three years found that VKHD was associated with COVID-19 as well as with the COVID-19 vaccine [54‐61]. However, research on the basis for this hypothesis is still lacking.

The mainstream view is that these three pathogeneses are not isolated, and virus infection often acts as the trigger factor. In addition, patients with susceptibility gene alleles eventually experience attacks to target cells or target tissues under the action of different kinds of immune cells and related effector molecules, resulting in the production of VKHD.

The second cluster of studies was related to auxiliary examination and treatment. As a keyword, optical coherence tomography (OCT) had the highest strength of 7.42, frequently appearing in the related literature from 2012 to 2019. As a standard clinical examination method, different forms of OCT, such as OCT-angiography and enhanced depth imaging (EDI)-OCT, can quickly detect pathological changes in the retina and choroid and consequently be used to monitor the activity of chronic VKHD [20, 22, 62]. As a noninvasive examination with high accuracy and repeatability, OCT has been the subject of many studies for early recognition and evaluation of the prognosis of VKHD in recent years, demonstrating that it has become a popular research topic [63‐65]. OCT can effectively detect characteristic serous retinal detachment and macular oedema in VKHD. In the most cited study in this research direction, Fong et al. used EDI-OCT, found that at multiple stages, VKHD can result in permanent changes to small choroidal vessels [66].

ICGA and FFA are commonly used fundus angiography techniques in clinical practice that can detect or monitor the recurrence of VKHD early [67‐69]. The difference is that ICGA is more advantageous in choroidal angiography [69, 70]. Therefore, in the study of VKHD, a greater number of articles are written for the ICGA method than for FFA. Other auxiliary examinations include ultrabiomicroscopy [71] and in vivo confocal microscopy [72], but few studies use these kinds of examination alone as a research method.

The number of studies on VKHD treatment is relatively small. Early diagnosis and correct use of adequate systemic corticosteroids can effectively alleviate the symptoms of the disease and reduce the risk of it developing to the chronic recurrent stage [73]. Some immunosuppressive agents, such as methotrexate and cyclosporine, have been used for nearly 30 years [74, 75]. In addition, relatively newer drugs are mainly biologic agents, such as TNF-α inhibitors, infliximab, and interferon alpha-2B [9, 76‐80]. However, except for TNF-α inhibitors, very few studies have addressed the other agents. We do not seem to have made much progress in therapeutic methods for treating VKHD. Currently, the main research direction is in-depth basic research on the therapeutic mechanism of known therapeutic drugs [73, 77, 81].

The third cluster of literature is epidemiological investigations and diagnostic criteria. The authors of these studies are in countries or regions with high incidences of VKHD. Retrospective studies conducted by the authors through the case information collected in these regions over the years can often serve as an essential reference for the incidence of VKHD in those regions. As previously mentioned, the diagnostic criteria of VKHD include the American Uveitis Society (AUS) criteria [19], the Revised Diagnostic Criteria for VKH Disease [7], and the Chinese Criteria by Yang PZ [23]. In addition, the STANDARDIZATION OF UVEITIS NOMENCLATURE (SUN) WORKING GROUP has recently developed a new set of classification criteria based on a machine learning method [82]; in this method, VKHD is divided into early and late stages. The main features of the former include the following:

(1) Exudative retinal detachment with a characteristic appearance on fluorescein angiography or optical coherence tomography or (2) panuveitis with ≥ 2 of 5 neurologic symptoms/signs; the main distinguishing point of the latter included a history of early-stage VKH and either (1) sunset glow fundus or (2) uveitis and ≥ 1 of 3 cutaneous signs. However, among these standards, the one with the most far-reaching influence and that was the most frequently cited was the Revised Diagnostic Criteria for VKH Disease developed by Read et al.