Research Hotspots in Psoriasis: A Bibliometric Study of the Top 100 Most Cited Articles

(1) Introduction: Psoriasis is a chronic, immune-mediated disease that negatively impacts patients’ quality of life and predisposes them to cardiovascular or metabolic diseases. This paper aims to summarize the knowledge structure and future directions in psoriasis research by means of bibliometrics. (2) Material and methods: The Thomson Reuters Web of Science database was interrogated using preestablished keywords. A list of the top 100 most cited articles focusing solely on psoriasis was compiled and analyzed. VOSviewer software was used to assess and visualize collaboration networks, citation, co-citation and co-wording analysis, and bibliographic coupling. (3) Results: The articles were written by 902 authors from 20 countries and were published in 31 journals. The United States was at the forefront of this field. Griffiths, CEM had the most citations, while the most prolific institution was Rockefeller University, New York City. Pathogenesis, especially key-pathogenic factors, immune pathways, and epidemiology were the most discussed topics. Work published in the last decade focused on the use of biologics. Keywords such as “quality of life”, “efficacy”, and “necrosis-factor alpha” have been widely used. (4) Conclusion: Research interest regarding psoriasis is high, leading to the rapid development of this field. Treatment modalities, especially novel-targeted therapies, immune pathways, and an integrative approach to such cases are receiving great interest and represent research hotspots in the future.


Introduction
Psoriasis is a chronic, immune-mediated disease that negatively impacts patients' quality of life (QoL). In the last published global report [1], the World Health Organization reported an increasing prevalence of psoriasis, ranging between 1.5% and 5% in developed countries [2]. Its etiopathogenesis is complex, with genetic predisposition, an altered immune response, and various triggering factors concurring in the development of this disease [3,4]. Clinically defined by cutaneous erythema, scaling, and induration, and in some cases by joint and nail involvement, this disease seems to predispose patients to a higher risk of developing cardiovascular disease, diabetes, dyslipidemia, and metabolic syndrome [5,6]. analysis, and bibliographical coupling. The counting method was set at full counting. To limit spelling differences in authors' or institutions' names an additional thesaurus file, that gives consistent labels to the same word spelled differently, was generated, and used when appropriate.

Bibliometric Analysis
Information regarding the journal, authorship, institution, publication year, and study design was extracted for the selected articles. Clarivate Journal Citation Reports was used for each journal's 2021 and 5-year impact factors. Full data regarding the selected articles were generated from the WoS database as an Excel spreadsheet and as a plain text file.
Publication-related metrics were analyzed with Microsoft Excel software. Science mapping and data visualization were performed with VOSviewer software (Version 1. 6.19-2023). VOSviewer is a graphical user interface-based free software first developed by van Eck and Waltman in 2010 [115], with the latest version launched on 23 January 2023. It allows the analysis and visualization of different collaboration patterns between research constituents.
The following performance analysis parameters were evaluated: publication-related metrics (total publications, solo-authored publications, co-authored publications) and citation-related metrics (total citations and citation rate). The citation rate was calculated by dividing the total number of citations by the number of years since publication. The bibliometric and knowledge structure of the research field is evaluated in this paper by using the following science mapping techniques: citation, co-citation, co-word, co-authorship analysis, and bibliographical coupling. The counting method was set at full counting. To limit spelling differences in authors' or institutions' names an additional thesaurus file, that gives consistent labels to the same word spelled differently, was generated, and used when appropriate.

Citation Analysis
The total citation count for the analyzed articles was 68,691, with a median of 553.5 and a mean of 686.91. Eighty-four were original articles, while sixteen were reviews. Pathogenesis and epidemiology were the topics most discussed (n = 66), followed by management (n = 45) and genetics (n = 9). Twenty-six articles focused on the use and effectiveness of novel targeted immune therapies, such as biologics, in the management of moderate-tosevere plaque psoriasis. Pustular psoriasis was addressed in two articles [45,63].
Within the top 100, the citation count ranged between 405 for "Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: Double-blind, randomized controlled trial and open-label extension study" by Gordon, K et al. [28] and 2145 for "Severe psoriasis-oral therapy with a new retinoid" by Fredriksson, T et al. [106].
The articles were published between 1969 and 2020. The oldest article was "Generalized pustular psoriasis-a clinical and epidemiological study of 104 cases" by Baker, H et al. [45], while the newest one was "Pathophysiology, clinical presentation, and treatment of psoriasis: a review" by Armstrong, AW et al. [73]. They had 421 and 420 citations, respectively. These two articles also have the lowest and highest citation rates, 8 and 211, respectively. Table 1 shows the top 100 articles and their respective citation rates. Figure 2 illustrates the distribution of the articles by decade.  33 Menter et al. [21] Journal of The American Academy of Dermatology 2008 677 48 34 Krueger et al. [18] New England Journal of Medicine 2007 617 41 35 Tsoi et al. [49] Nature Genetics 2012 661 66 36 Henseler et al. [92] Journal of The American Academy of Dermatology 1985 660 18 37 Christophers [86] Clinical And Experimental Dermatology  2001  623  30  38 Griffiths et al. [30] New England Journal of Medicine 2010 634 53 39 Lin et al. [65] Journal of Immunology 2011 627 57 40 Marrakchi et al. [63] New England Journal of Medicine 2011 610 55 41 Nograles et al. [108] British Journal of Dermatology 2008 611 44 42 Langley et al. [98] Annals of The Rheumatic Diseases 2005 607 36 43 Arican et al. [105] Mediators of Inflammation 2005 594 35 44 Sonkoly et al. [68] Plos One 2007 577 38 45 Detmar et al. [71] Journal of Experimental Medicine 1994 584 21 46 Griffiths et al. [29] Lancet 2015 592 85 47 Sano et al. [107] Nature Medicine 2005 544 32 48 Papp et al. [16] British Journal of Dermatology 2005 573 34 49 Mcinnes et al. [38] Lancet 2013 561 62 50 Hammarstrom et al. [55] Proceedings of The National Academ 1975 581 12 51 Mrowietz et al. [33] Archives of Dermatological Research 2011 550 50 52 Stern et al. [91] Journal of Investigative Dermatology 2004 558 31 53 Saurat et al. [43] British Journal of Dermatology 2008 550 39 54 Lebwohl et al. [75] New England Journal of Medicine 2015 539 77 55 Rendon et al. [94] International Journal of Molecular Sciences 2019 520 173 56 Chan et al. [53] Journal of Experimental Medicine 2006 510 32 57 Stern et al. [101] New England Journal of Medicine 1979 544 13 58 Rachakonda et al. [95] Journal of The American Academy of Dermatology 2014 535 67 59 Lebwohl [84] Lancet 2003 498 26 60 Gordon et al. [76] New England Journal of Medicine 2016 517 86 61 Gottlieb et al. [100] Nature Medicine 1995 507 19 62 Hollox et al. [90] Nature Genetics 2008 508 36 63 Michalek et al. [20] Journal of The European Academy of Dermatology and Venereology 2017 481 96 64 Pathirana et al. [46] Journal of The European Academy of Dermatology and Venereology 2009 507 39 65 Henseler et al. [34] Journal of The American Academy of Dermatology 1995 500 19 66 Wada et al. [24] Plos One 2012 492 49  68 Kagami et al. [27] Journal of Investigative Dermatology 2010 462 39 69 Blauvelt et al. [36] Journal of The American Academy of 2017 493 99 70 Takeshita et al. [87] Journal of The American Academy of 2017 472 94 71 Nickoloff et al. [99] Journal of Clinical Investigation 2004 415 23 72 Davidovici et al. [88] Journal of Investigative Dermatology 2010 477 40 73 Sommer et al. [58] Archives of Dermatological Research 2006 477 30 74 Abrams et al. [31] Journal of Clinical Investigation 1999 469 20 75 Sugiyama et al. [35] Journal of Immunology 2005 444 26 76 Ma et al. [51] Journal of Clinical Investigation 2008 451 32 77 Stern et al. [64] New England Journal of Medicine 1997 487 19 78 Mehta et al. [74] European Heart Journal 2010 488 41 79 Ellis et al. [113] New England Journal of Medicine 2001 461 22 80 Melski et al. [70] Journal of Investigative Dermatology 1977 483 11 81 Gisondi et al. [82] British Journal of Dermatology 2007 468 31 82 Kurd et al. [112] Archives of Dermatology 2010 474 40 83 Zenz et al. [97] Nature 2005 442 26 84 Hawkes et al. [93] Journal of Allergy And Clinical Immunology 2017 441 88 85 Gelfand et al. [79] Archives of Dermatology 2005 446 26 86 Krueger et al. [111] Journal of The American Academy of Dermatology 2002 431 22 87 Lebwohl et al. [19] New England Journal of Medicine 2003 449 24 88 Naldi et al. [26] Journal of Investigative Dermatology 2005 457 27 89 Gottlieb et al. [59] Journal of The American Academy of Dermatology 2004 439 24 90 Farber et al. [69] Dermatologica 1974 457 10 91 Homey et al. [114] Journal of Immunology 2000 421 19 92 Chiricozzi et al. [61] Journal of Investigative Dermatology 2011 437 40 93 Greb et al. [83] Nature Reviews Disease Primers 2016 424 71 94 Armstrong et al. [73] JAMA-Journal of The American Medical Association 2020 421 211 95 Reich et al. [37] Journal of The American Academy of Dermatology 2017 420 84 96 Nair et al. [104] American Journal of Human Genetics 2006 418 26 97 Trembath et al. [50] Human Molecular Genetics 1997 410 16 98 Gordon et al. [28] Journal of The American Academy of Dermatology 2006 405 25 99 Baker et al. [45] British Journal of Dermatology 1968 420 8 100 Nickoloff et al. [23] American Journal of Pathology 1991 406 13 Healthcare 2023, 11, x 7 of 21 Based on bibliometric algorithms that consider citation patterns, such as total citation number and the topic addressed in these papers, the analyzed articles were grouped into eight clusters. Cluster 1 is defined by 24 articles, clusters 2 and 3 by 16 articles each, cluster 4 by 15 articles, cluster 5 by 14 articles, cluster 6 by 9 articles, cluster 7 by 5 articles, and cluster 8 by a single article. The previously mentioned clusters are shown in Figure 3 as Based on bibliometric algorithms that consider citation patterns, such as total citation number and the topic addressed in these papers, the analyzed articles were grouped into eight clusters. Cluster 1 is defined by 24 articles, clusters 2 and 3 by 16 articles each, cluster 4 by 15 articles, cluster 5 by 14 articles, cluster 6 by 9 articles, cluster 7 by 5 articles, and cluster 8 by a single article. The previously mentioned clusters are shown in Figure 3 as map-based connections. Each color represents a thematic cluster, whereas each node represents an author. The size of each individual node and font size is proportional to the number of citations, both related to the completed data set and to each individual cluster. Based on bibliometric algorithms that consider citation patterns, such as total citation number and the topic addressed in these papers, the analyzed articles were grouped into eight clusters. Cluster 1 is defined by 24 articles, clusters 2 and 3 by 16 articles each, cluster 4 by 15 articles, cluster 5 by 14 articles, cluster 6 by 9 articles, cluster 7 by 5 articles, and cluster 8 by a single article. The previously mentioned clusters are shown in Figure 3 as map-based connections. Each color represents a thematic cluster, whereas each node represents an author. The size of each individual node and font size is proportional to the number of citations, both related to the completed data set and to each individual cluster.  Table 2 highlights the top 10 most cited authors. Gottlieb, A 7 4080 10 Reich, K 7 5026 The top 100 articles were published in 31 journals, which published between one and sixteen articles. New England Journal of Medicine (n = 16) published the greatest number of articles within the top 100 and had the highest number of citations (12,817). Lancet had the highest impact factor (202.73), published the third-highest number of articles (n = 10), and received the third-highest number of total citations (8966). Dermatologica had the highest average citation per publication (1301), having published 2 papers with a total of 2602 citations. Table 3 displays articles, citation count, and various journal metrics.

Co-Authorship Analysis
The 100 analyzed articles summed 902 authors, out of which 167 contributed to more than 2 papers, while 18 authored more than 5 articles. Three papers were soloauthored [84,86,111]; the highest number of contributing authors for a paper was 136 [49]. Leonardi Table 4 and Figure 5 depict the top 10 institutions, respectively, countries, that contributed to the top 100 most cited articles.
The 100 analyzed articles summed 902 authors, out of which 167 contributed to more than 2 papers, while 18 authored more than 5 articles. Three papers were solo-authored [84,86,111]; the highest number of contributing authors for a paper was 136 [49]. Leonardi and Papp first authored the highest number of papers (n = 3). Griffiths, CEM (n = 12), Krueger, JG (n = 12), Papp, K (n = 11), Krueger, GG (n = 10), and Menter, A (n = 10) contributed to the greatest number of articles. The authors who contributed to more than five papers are shown in Figure 4 as map-based connections scored by average citations.

Co-Word Analysis
A total of 471 unique keywords were identified from all articles. After removing keywords such as "psoriasis", "plaque psoriasis", "chronic plaque psoriasis", "severe plaque psoriasis", "vulgaris", "to-severe psoriasis", "psoriasis vulgaris", and "vulgaris lesions" that could affect the analysis, a minimum threshold of two occurrences was set for each keyword and the bibliometric map was generated. Based on occurrence, they were divided into 7 clusters, as follows: cluster 1 = 37 items, cluster 2 = 28 items, cluster 3 = 23 items, cluster 4 = 19 items, cluster 5 = 18 items, cluster 6 = 12 items, and cluster 7 with 8

Co-Word Analysis
A total of 471 unique keywords were identified from all articles. After removing keywords such as "psoriasis", "plaque psoriasis", "chronic plaque psoriasis", "severe plaque psoriasis", "vulgaris", "to-severe psoriasis", "psoriasis vulgaris", and "vulgaris lesions" that could affect the analysis, a minimum threshold of two occurrences was set for each keyword and the bibliometric map was generated. Based on occurrence, they were divided into 7 clusters, as follows: cluster 1 = 37 items, cluster 2 = 28 items, cluster 3 = 23 items, cluster 4 = 19 items, cluster 5 = 18 items, cluster 6 = 12 items, and cluster 7 with 8 items. Figure 6 displays them as map-based connections, while Figure 7 displays keywords occurrence density in the selected articles. A set of the 10 most used keywords was generated and presented in Table 5. Double-blind 13 4 7 Efficacy 13 4 8 Necrosis factor alpha 13 5 9 Rheumatoid arthritis 12 1 10 Safety 10 4 Figure 6. The scientometric map of the keywords from the analyzed articles. (Cluster colors are as follows: cluster 1-red, cluster 2-green, cluster 3-blue, cluster 4-yellow, cluster 5-purple, cluster 6-turquoise, cluster 7-orange) .

Bibliographical Coupling
Based on patterns of citing the same references, the 100 articles were divided into 10 clusters. Cluster 1 consists of 26 items, cluster 2 of 23 items, cluster 3 of 16 items, cluster 4 of 14 items, cluster 5 of 13 items, cluster 6 of 4 items, and clusters 7, 8, 9, and 10 of 1 item each. The map-based connections between all clusters can be found in Figure 8.

Bibliographical Coupling
Based on patterns of citing the same references, the 100 articles were divided into 10 clusters. Cluster 1 consists of 26 items, cluster 2 of 23 items, cluster 3 of 16 items, cluster 4 of 14 items, cluster 5 of 13 items, cluster 6 of 4 items, and clusters 7, 8, 9, and 10 of 1 item each. The map-based connections between all clusters can be found in Figure 8.

Co-Citation Analysis
The analyzed articles summed 3645 references. A minimum threshold of one for each reference was set The most co-cited reference was the article of Rapp, SR et al. [89], which was co-cited by 19 other articles, with 1077 links with other articles and a total link strength of 1358, followed by Fredrickson, T et al. [106], also co-cited by 19 articles, but with lower links (636) and link strength (804), and Gelfand, JM and Leonardi, CL both co-cited 15 times. Figure 9 shows the density of co-cited references. Co-citation frequency is depicted using different intensities of yellow and green. The network of references co-cited more than five times is shown in Figure 10, scored by average citations. They were divided into 4 clusters, as follows: cluster 1 = 43 items, cluster 2 = 30 items, cluster 3 = 30 items, and cluster 4 = 23 items. References located among different clusters and with the highest link strengths are circled with black.

Discussion
Psoriasis has attracted much interest in the scientific community over the years. In the face of constant evolution and novelties added to the field, it is of great use to maintain the connection to research areas of interest. Bibliometric analysis is able to handle, using quantitative methods, large amounts of literature, to avoid bias usually associated with

Discussion
Psoriasis has attracted much interest in the scientific community over the years. In the face of constant evolution and novelties added to the field, it is of great use to maintain the connection to research areas of interest. Bibliometric analysis is able to handle, using quantitative methods, large amounts of literature, to avoid bias usually associated with

Discussion
Psoriasis has attracted much interest in the scientific community over the years. In the face of constant evolution and novelties added to the field, it is of great use to maintain the connection to research areas of interest. Bibliometric analysis is able to handle, using quantitative methods, large amounts of literature, to avoid bias usually associated with qualitative-based systematic reviews, and to provide the knowledge structure and future trends of a research topic or field [116].
Among the top 100 articles reviewed, pathogenesis and epidemiology were the topics most often discussed, being the focus of 66 articles. Only 12 articles focused on the clinical and diagnostic aspects of the disease. As psoriasis remains mainly a clinical diagnosis, the emphasis is on better understanding and managing the disease. This points to the fact that the vast majority of the high-impact literature focused on understanding how and why psoriasis develops. This culminated in a trend to explore the role of different immune and inflammatory pathways since the beginning of the 2000s. As key contributors to the immunopathogenesis of psoriasis, keratinocytes provide antimicrobial peptides, such as S100A7 and LL-37, that bind to host DNA and form DNA-LL-37 complexes, which stimulate dendritic cells to produce IFN-alpha and activate myeloid dendritic cells. Activated dendritic cells produce mediators, including IL-12 and IL-23, that lead to T-cells differentiation into Type 1 [35] and Type 17 T-helper cells. Th17 cells play an important role in epithelial immune surveillance [109]. A special focus was set on key pathogenic factors of psoriasis, such as TNF-α, IL-6, IL-8, IL-17, IL-22, IL-23, and IFN-gamma, providing insightful information about disease mechanisms. [51,53,61,62,105]. Additionally, 10 papers have specifically addressed [15,17,47,49,50,56,63,68,104] the genetic basis of psoriasis, with extensive genetic testing that identified more than 50 psoriasis susceptibility loci [27,49,56]. The most important one, PSORS1 [88] is located within the major histocompatibility complex (MHC) on chromosome 6p21 and is directly linked to HLA-Cw6-allele. The gene variants of interest modulate immune pathways and processes that contribute to disease susceptibilities, such as antigen presentation, the IL-23/IL-17 axis, and the type I IFN pathway [49]. A distinctive and interesting approach to psoriasis genetics has been addressed by Sonkoly et al. [68] that identified a specific, dysregulated microRNA expression profile in psoriatic skin compared to healthy skin: miR-203 and miR-125b regulate keratinocyte proliferation and differentiation, while miR-21 inhibits T cell apoptosis. Consequently, research areas referring to therapeutical means have shifted from photochemotherapy and classical immunosuppressant therapies to novel targeted therapies in the last twenty years. Of the specific therapeutic options, this analysis identified the increasingly dominant trend in reporting the use of monoclonal antibodies, twenty-six out of forty-five articles referring to treatment options were focused only on the safety and effectiveness of such novel therapies. The significance of this trend is more accurately reflected by work published in the last decade because ten out of seventeen papers published in this timeframe were focused on treatment, out of which eight addressed specifically various monoclonal antibodies.
Even though only six articles focused specifically on disease comorbidities and four on QoL it is important to mention that these aspects have been uniformly addressed over time and mentioned in other papers, suggesting a constant focus of the research community on these topics. Treatment and management of psoriasis should not address only cutaneous manifestations, but also associated comorbidities and should aim to increase the QoL [117]. Biologics represent a cornerstone in the management of this disease because apart from alleviating skin lesions they seem to work up to a certain extent for associated comorbidities as well. Research focusing on biologics seems to steal the focus in the future as well, for further exploration.
The paper of Fredriksson et al. [106], published in 1978 in Dermatologica, was the most cited article in our analysis. It explored the effectiveness of a retinoic acid derivate in treating severe psoriasis. The study was significant at the time because apart from evaluating the effectiveness of a novel retinoid, it was the first article that introduced a currently worldwide used disease severity score, Psoriasis Area Severity Index (PASI).
PASI score is currently used in dermatology to assess disease severity and thus, allows the classification of psoriasis in mild, moderate, and severe. Further therapeutic options are selected taking into account various parameters, the PASI score being one of the strongest.
The oldest article included in this analysis, published by Baker et al. [45] focused on generalized pustular psoriasis and identified two etiologically and evolution-wise distinct subtypes of this rare form of psoriasis. The newest one, published by Armstrong et al. [73] offers a state-of-the-art review on clinical presentation, epidemiology, and therapeutic advancements. Due to the fact that the previously mentioned, most recent article included was published in 2020, ongoing research may significantly impact the top 100 articles over the next few years.
This study identified a significant difference in publication and citation patterns in the last two decades compared to before 2000, for which the articles total only 18 and 17.3% of the total citations. This can be explained by the fact that research published before the 2000s focused on pathogenesis, clinics, and conventional treatment options, thus laying the foundation for today's knowledge about psoriasis. Moreover, these last two decades represent the beginning of immunopathogenesis and biologics.
The collaboration network of authors, countries, and institutions provides an overall picture of the leading researchers in this field on different levels. The United States, Germany, Canada, and the United Kingdom are leaders in the field. Additionally, the most prolific institutions and authors originate in these countries, indicating greater research resources. Moreover, these countries possess some of the most comprehensive and betterupdated National Registries, allowing a proper evaluation and follow-up of patients suffering from this disease while also serving as comprehensive research databases. Even though the University of Manchester ranked second, its total link strength is higher than that of the institution ranked first, suggesting a higher connection to other institutions analyzed. The authors that published the most papers were Griffiths, CEM (n = 12), Krueger, JG (n = 12), Papp, K (n = 11), Krueger, GG (n = 10), and Menter, A (n = 10). On the other hand, when analyzing the authors who contributed to more than five papers based on citations link strength, Nestle, FO, Griffiths, CEM, Papp, K, and Lebwohl, M are proven to be the most influential scholars in their field.
Keywords are a hallmark of the literature, and their analysis can shed light on research and trends in a specific field. The analyzed articles summed up 471 keywords. After setting a minimum threshold of 2 occurrences for each keyword, a bibliometric map based on the 145 eligible items was created and presented in Figure 6. Seven clusters, each defining a research area, were defined. The top 10 keywords with the highest number of occurrences were "quality-of-life", "skin", "therapy", "expression", "dendritic cells", "double-blind", "efficacy", "necrosis-factor-alpha", "rheumatoid arthritis", and "safety". Figure 7 illustrates the main areas of interest based on the density of keywords in the analyzed articles, where we can observe that the research focuses on quality of life, immune pathways, and treatment safety. Reference co-citation analysis can reflect a domain's knowledge structure and indicate research hotspots. The analysis showed that the most co-cited references were the papers of Rapp, SR "Psoriasis causes as much disability as other major medical diseases" [89] and Fredrickson, T "Severe psoriasis-oral therapy with a new retinoid" [106], both co-cited 19 times and serving as an additional indicator that treatment and life-quality are main topics in the research field. The works of Rapp, SR, Fredriksson, T, Gelfand, JM, Reich, K, Schon, MP, and Lee, E which bring attention to topics such as pathogenesis and novel treatment options, have the highest link strengths and are located among different clusters, indicating that they may serve as landmarks in the field.
The limitation of this bibliometric analysis resides mainly in the fact that only fulllength English articles indexed in the WoS database have been taken into account. This has been partially addressed by not limiting article access type in any kind. Moreover, no time limit has been set when researching articles to be included in the analysis, thus a larger and more accurate overview of the research field has been obtained. To diminish the effect of time on accumulated citations, a citation rate was also calculated in order to identify articles that received a large number of citations over a short period of time. Due to the fact that bibliometric analysis covers a broad area of research, it should be taken into account that papers with the highest citations might address general topics. In order to limit this and to provide an overview of the past, present, and future of psoriasis research, we used a combination of techniques: co-citation analysis to uncover knowledge foundations, bibliographic coupling to understand the present development of themes, and co-word analysis to assess existing or future relationships among topics in psoriasis research.

Conclusions
Research interest in the scientific community regarding psoriasis is high, leading to the rapid and constant development of this field. This is the first bibliometric study focusing on psoriasis, providing an overview of the intellectual structure and scientific directions in the field, taking into account algorithms based on the top 100 most cited articles on the subject. The research focus is shifting from disease presentation. Treatment modalities, especially novel-targeted therapies, immune pathways, and an integrative, complex approach to such cases are receiving great interest and represent research hotspots in the future.