A Bibliometric Analysis of Atopic Dermatitis Research over the Past Three Decades and Future Perspectives

Atopic dermatitis (AD) has been increasing in prevalence over the past few decades; however, AD has never been analyzed using a bibliometric approach. We searched for AD studies in the dermatology and allergy category of the Web of Science and SCOPUS databases using the keywords “atopic dermatitis”, “eczema”, and “atopy”. In total, 53,460 documents were retrieved. We analyzed annual publication trends and performed keyword and co-authorship network analyses. The annual number of AD publications has increased over the years. Asthma, food allergies, the skin barrier, IgE, and epidemiology have received extensive attention. The keywords ‘allergic rhinitis’, ‘child(ren)’, ‘quality of life’, and ‘probiotics’ have become more commonly used in recent years. AD research has been led by only a few countries, such as the USA, Germany, and the UK, and longstanding research topics such as asthma, allergy, and the immune system continue to be important. We suggest that global collaborations, research in developing countries, and research that is more holistic (thus exploring how genes, the immune system, the environment, and the microbiome together impact AD) are necessary.


Introduction
Atopic dermatitis (AD) is a chronic skin disease characterized by severe pruritus, recurrent eczema, sleep disruption, and skin manifestations (erythema, edema, papulation, oozing and crusting, excoriation, lichenification, and dryness). AD primarily affects infants and young children, and the prevalence (15-20% in children and 1-3% in adults) and recurrence rates are high [1]. AD reduces the quality of life [2], promotes suicidal ideation [3], and imposes significant economic burdens on patients and healthcare systems [4]. Patients with AD are hypersensitive to skin irritations, certain foods, and aero-allergens. They often develop other atopic disorders such as asthma or allergic rhinitis (the "atopic march" phenomenon [5,6]). Genetic variations, an impaired skin barrier, excessive inflammation, and allergic responses involving T-helper type 2 cytokines (e.g., interleukin [IL]-4 and IL-13), immunoglobulin E (IgE), and eosinophils have been proposed to contribute to AD pathogenesis [7]. Thus, the clinical evaluation and management of AD remain challenging [8]. Recently developed drugs (dupilumab, oluminant, and rinvoq), a growing interest in patient quality of life, and new potential therapeutic targets (such as the gut and skin microbiomes [9][10][11][12][13][14]) have motivated researchers to intensify their current approaches and explore new areas of AD research.
To achieve this goal, we strongly believe that bibliometric analysis is useful for tracking the rise and fall of research topics over time and for evaluating the impacts of publications, research affiliations, and journals. A bibliometric analysis provides an overview of a large number of publications, allows for the quantitative assessment of past research, and can be used to predict future research trends [15][16][17]). Bibliometric analysis has been used to estimate research trends in various research fields, including dermatology [17].
Bibliometrics can be utilized to analyze publication trends by country and institution and to identify the main keywords and organizations associated with AD research. However, to the best of our knowledge, AD research has not been analyzed using a bibliometric approach that lacks restrictions on research subjects (see Zhong et al. 2011 [18] for a bibliometric analysis of AD treated via Traditional Chinese Medicine).
We aimed to analyze publication and citation trends by year, country, journal, and organization; to assess trends in the most frequently studied topics; and to identify keyword and organization clusters by performing network analyses. We identified the most productive countries, affiliations, and journals and the 30 top-cited publications to highlight the progress made and the landmark studies. This will guide future research on AD.

Data Search and Analysis
We retrieved publications from the Web of Science and SCOPUS on 2 July 2021 using search topics including atopic dermatitis, eczema, and atopy. The retrieval strategies were TS = ("atopic dermatit*" OR atopy OR "atopic eczema") for the Web of Science and TITLE-ABS-KEY ("atopic dermatit*" OR "atopic eczema" OR atopy) for SCOPUS. No date range limits were applied, but we restricted our search to articles written in English. The exclusion criteria were (1) articles not retrieved from the Web of Science or SCOPUS, (2) conference and meeting abstracts, (3) corrigendum documents, and (4) retracted publications. We merged the datasets from the Web of Science and SCOPUS and removed duplicates using the mergeDbSources function of R. All articles were evaluated by ISL.
Biblioshiny (https://www.bibliometrix.org/Biblioshiny.html, accessed on 5 July 2021) and the 'bibliometrix' R package [19] were used for the analysis of annual publication productivity (total number of publications per year), the total number of publications from each country and affiliation, the total number of citations for each article, and keyword frequency. The keyword frequency analysis was conducted for all three decades combined (1990-2020), and for each decade separately (1990-1999, 2000-2009, and 2010-2020), to identify trends in keywords over time.
We also performed a network analysis of keywords and a co-authorship-based network analysis of countries, using VOSviewer software (version 1.6.16; Centre for Science and Technology Studies, Leiden University of Leiden, Leiden, the Netherlands). Network analyses were conducted using a modularity-based clustering method. The parameters for analyses were as follows: unit of analysis = country or author keywords; fractional counting of keywords and affiliations; "layout attraction" = 3; and clustering resolution = 0.5. The minimum number of keyword occurrences was set to 5, and we excluded the keywords 'atopic dermatitis', 'eczema', 'atopic eczema', and 'atopy' from analysis. Countries that published more than five articles were included in co-authorship network analysis. All nodes were weighted by occurrence and the number of documents, respectively, to aid visualization. The total link strength and normalized citation of each country were explored to determine the influence of that country on AD research.
The 10 countries with the highest total numbers of publications were the USA, Germany, the UK, Japan, South Korea, China, France, Italy, the Netherlands, and Australia ( Table 2). The total number of publications by affiliation (institution, hospital, or university) revealed that Northwestern University, the Karolinska Institute, the University of Copenhagen, the Technical University of Munich, Yonsei University, the University of California San Francisco, Seoul National University, Harvard University, the University of Munich, and the University of Helsinki were the most productive institutions; these are located in the USA, Sweden, Denmark, Germany, and Finland ( Table 3).
The Journal of Allergy and Clinical Immunology, Allergy, Journal of Investigative and Clinical Dentistry, British Journal of Dermatology, Clinical & Experimental Allergy, International Journal of Advanced Biotechnology and Research, Journal of the American Academy of Child and Adolescent Psychiatry, Acta Dermato-Venereologica, Pediatric Allergy and Immunology, and Contact Dermatitis were the top 10 journals in terms of AD articles published (Table 4).

Co-Authorship Network Analysis
Of the 103 countries, 38 were included in the co-authorship analysis, and four clusters were identified (Figure 4 and Table 6). Cluster 1 included 18 countries, almost all of which are European (e.g., Germany, the UK, Italy, France, and the Netherlands; red cluster in Figure 4). Co-authorship connections were also found between European countries and Singapore, Austria, or New Zealand (Cluster 1). Cluster 2 contained 12 countries in the Americas (including the USA, Brazil, and Mexico), Canada, and East Asia (Japan, China, Hong Kong, and South Korea; green cluster in Figure 4). Cluster 3 included Turkey, Greece, and India (blue cluster in Figure 4). Cluster 4 included Switzerland and the Czech Republic (yellow cluster in Figure 4). Cluster 5 included Australia and Thailand (purple cluster in Figure 4).
Germany, the USA, the UK, Sweden, and the Netherlands exhibited the greatest normalized citation scores (326, 311, 249, 151, and 144, respectively) and total link strengths (in a slightly different order), suggesting that these countries exert the most influence on AD research in terms of both impactful papers and global collaborations that have been in operation for decades.

Discussion
Analysis of the 53,460 articles collected from the Web of Science and SCOPUS databases showed that the number of publications on AD has increased since 1990. The citation and keyword frequency analyses revealed that research topics such as asthma, food allergies, the skin barrier, IgE, and epidemiology have received extensive attention. The rankings of the keywords 'contact dermatitis', 'cytokines', 'IgE', 'prevention', and 'risk factor' decreased gradually over time, while the keywords 'allergic rhinitis', 'child(ren)', 'quality of life', and 'probiotics' have become more popular. We identified five main AD-related topics (inflammation and allergy, the skin barrier, allergens, contact dermatitis, and non-skin diseases). The USA, Germany, the UK, Japan, and South Korea were the top five most productive countries in the field of AD research. The USA, Germany, the UK, Sweden, and the Netherlands exerted the greatest influence on AD research.
The most cited article (published in 2006) addressed the prevalence of eczema in childhood [33]. That study conducted a cross-sectional questionnaire survey in 193,404 children from 37 countries (aged 6-7 years) and 304,679 children from 56 countries (aged 13-14 years). The top citation rate suggests that researchers are very interested in the different prevalences of eczema worldwide; geographical variation may be important in terms of the development of asthma and allergies. The cited authors found that the prevalences of eczema symptoms in both groups increased over time in most regions but decreased in some. An understanding of the factors promoting the decreases might allow the effective prevention and treatment of allergic diseases. The fourth most-cited article dealt with the skin microbiome [20], suggesting that microbial factors may contribute to AD development. Indeed, recent studies have suggested that an impaired skin microbiome can affect both the skin barrier [12] and the immune environment [14], eventually causing AD development and worsening the symptoms [13].

Sustainable and Newly Highlighted Research Themes
AD is frequently associated with respiratory allergic diseases, such as asthma and allergic rhinitis. The term "atopic march", which refers to the progression of symptoms from AD to asthma to allergic rhinitis during childhood, emphasizes the strong association between AD and respiratory allergy. While the preventative effects of treating atopic march are controversial, IgE-associated allergic reactions are regarded as a key mechanism of AD, and our keyword frequency analysis emphasized the significance of the keywords 'asthma', 'allergy', and 'IgE' (the ranking of the latter decreased over time, but it still remains in the most recent top five). As AD is a chronic and recurrent disease, managing quality of life has become a major concern when treating AD patients. In contrast, the keywords 'contact dermatitis' and 'cytokine' dropped in the rankings, which might reflect the reduced interest of AD researchers in contact dermatitis. However, as AD patients may have an increased risk of contact sensitization, and contact dermatitis is more severe in patients with than without AD [35,36], studies that focus on the weak, sensitized skin of AD patients remain meritorious. We performed citation and keyword frequency analyses to identify topics that have recently received significant attention. These topics included the microbiome and probiotics. The roles played by the microbiological environments of the skin and other organs (e.g., the gut) remain poorly understood, as do the effects of probiotics [9]. As patients are now increasingly exposed to commercial probiotics, any abnormal changes in the composition or functions of the AD microbiome require attention, as do any effect of probiotics on AD. Such work might yield new treatments for AD.

Insufficient Global Collaborative Research Network
The co-authorship network analysis identified five clusters of countries. The UK, Germany, the USA, the Netherlands, and Sweden were influential research hubs; these countries scored highest in terms of total link strength. On the other hand, Japan and South Korea were both very productive, but the citation scores were rather low, suggesting that research quality requires improvement. The clusters consisted mainly of neighboring countries or those on the same continent, indicating that there are only a few intercontinental global collaborations in AD research. Building an international network to strengthen the research community, and enhance research quality and diversity, could be valuable.

Future Directions
It is important to note that although AD is a worldwide disease, research thereon has mostly been performed in a few developed countries and may not be transferable to AD patients in developing countries. Thus, AD patients in developing countries might not benefit from the research findings, even though studies have shown an increasing prevalence of AD in such countries [33,37]. For example, the mechanisms and risk factors in developing countries could be different to those in developed countries. Therefore, it is necessary to train healthcare providers and improve patient access to healthcare resources, as well as to facilitate AD research, in developing countries.
In addition to skin barrier impairments in the context of food and skin contact, AD is also related to environmental factors (e.g., climate, UV light exposure, temperature, and air pollution), diet, and the gut and skin microbiomes [38]. We suggest that collaborations among epidemiologists, basic scientists, clinical researchers, microbiologists, and pharmaceutical industrialists, and the establishment of international research networks, will improve our knowledge of the causes of AD and enable us to treat AD more effectively in the future.

Limitations
This study had several limitations. The quality of the publications was not considered, and all authors were treated equally regardless of their contribution to the work (e.g., first, corresponding, or co-author). Finally, some institutes might have close relationships (e.g., the Karolinska Institute and Karolinska University Hospital), although we changed or combined organization names to account for this.

Conclusions
In conclusion, the countries leading AD research have been the USA, Germany, the UK, Japan, South Korea, Sweden, and the Netherlands. The most prevalent research themes have been 'asthma', 'allergy', 'child(ren)', 'IgE', '(allergic) rhinitis', 'epidemiology', 'food allergy', '(allergic) contact dermatitis', 'psoriasis', 'cytokines', and 'pruritus (itch)'. Five research topic clusters were identified (inflammation and allergy, skin barrier, allergens, contact dermatitis, and non-skin diseases). Our analyses identified global temporal trends and the current status of AD research and suggest possible future research hotspots. For example, the lack of international research networks and interdisciplinary studies, and the few publications from developing countries, are limitations of AD research. We suggest that global collaborations, research in developing countries, and research on multiple factors (genes, the immune system, the environment, and the microbiome) are required in the field of AD research.