The Top 100 Most Cited Articles on Hidradenitis Suppurativa

Hidradenitis Suppurativa (HS), or acne inversa, is a devastating chronic inflammatory follicular skin disease that usually starts after puberty. HS primarily affects folds of the body, including the axilla, groin, inframammary, and anogenital regions. There is an average of 7.2-year delay in HS diagnosis leading to delays in effective treatment. Substantial research has explored associations between HS and environmental factors and comorbidities. The pathophysiology of HS is not entirely elucidated, but much has been learned recently. There are multiple treatment modalities, though none are consistently curative. Currently, there are increasing number of clinical trials on HS, and with all ABSTRACT


INTRODUCTION
the research being conducted on HS, evaluating research trends using bibliometric analysis can inform future directions.
Bibliometric analysis is defined as a statistical evaluation of published scientific articles and is a tool used to evaluate research published on a certain topic. 7 This quantitative study can provide useful information about contributions made by various authors, countries, institutions, and journals which can be useful in facilitating future research collaborations. Important quantitative information can be learned to understand the progress and trends of research in the field of medicine. 8 Bibliometric analyses have been performed for rosacea, psoriasis, and melanoma. [9][10][11][12] However, HS, a devastating disease for patients, has not been studied to date. In this study, we identified and analyzed the top 100 most cited articles on HS to evaluate the characteristics of the most impactful published HS research articles.

Data Sources
A search of all databases and journals accessible within Elsevier's Scopus and Thomson Reuter's Web of Science from inception was performed on May 14th, 2020. A second search was performed on June 14th, 2020 to identify total number of publications for additional data and comparison. Document search was performed using the Boolean query "Hidradenitis Suppurativa" and "Acne Inversa" and was made without restrictions. From the search results, meta-analyses, systematic reviews, guidelines, letters, book chapters, notes, editorials, short surveys, conference papers, and news items were excluded.
The remaining original publications from the databases were combined and sorted, and the 100 most cited papers were included. (Figure 1)

Data Collection
Data extracted from Scopus included first author name and country of origin, corresponding author name and country of origin, journal name, and year of journal publication. Additional data was abstracted by five investigators (SS, DH, SG, MR, JB), which included: study design and study topic. Study design was abstracted and categorized as: "case reports/case-series," "cohort/case control/cross-sectional studies," or "randomized controlled trials (RCTs)." Study topic was categorized based on the article's main conclusion: "clinical features/diagnosis," "epidemiology," "pathogenesis/pathophysiology," or "treatment." All research topics and designs were reviewed independently by five reviewers with consensus reached for all 100 articles. The Bradford Zone comprising three zones (Zones 1, 2 and 3) was obtained as a measure of journal productivity. 13

Data Analysis
Data analysis was performed using R-Studio (R-Studio, Boston, MA) and Bibliometrix (Università degli Studi di Napoli Federico II, Naples, Italy), according to the methods described in Bibliometrix: An R-tool for comprehensive science mapping analysis. 14 Graphs and tables were created, and basic descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, Redmond, WA). Figure 1 shows the results of the queries.  (Table S1). The mean total and annual citations per article were 128.3 and 10.58, respectively. The top research topic was treatment (40%), followed by epidemiology (32%), pathogenesis/pathophysiology (20%), and clinical features/diagnosis (8%). The most frequent article design was cohort/case control/cross-sectional studies (84%), followed by RCTs (9%), case reports/caseseries (7%) ( Table 1). The top five most cited articles are listed in Table 2. Most of these articles were categorized as epidemiology and cohort/case control/crosssectional studies, for their topic and design, respectively. Furthermore, most of the top five highly cited articles were published in the Journal of the American Academy of Dermatology. The years with the highest number of top 100 articles were: 1996 (7)  The remaining 21 journals were assigned to Zone 3, which included journals with the lowest publishing productivity.

Countries and Collaborations
A total of 14 countries participated in publishing the retrieved articles. Denmark (2808) had the greatest share of citations followed by the United States (USA) (2268), the United Kingdom (1417), and France (1414) ( Table 3). For the USA, only 15.8% of the articles had co-authors from different countries, and for Denmark, only 11.8%. For the USA, approximately 84% of articles were published by domestic authors presented as percentage of single country publication (SCP). On the other hand, approximately 33% of articles produced by researchers from France (n=9) and Greece (n=3) had coauthors from different countries. For the top 10 active countries, a total of 13 (15.7%) articles were considered multiple country publication (MCP) while 69 (84.3%) of articles were considered SCP (Table 3).

Authors and Affiliations
A total of 382 authors contributed to the top 100 most cited articles on HS. Analysis of the authors regardless of their authorship order showed that Gregor B. E. Jemec from the University of Copenhagen in Denmark published the greatest number of the most cited articles (n=21), followed by Jurr Boer (n=10) from Deventer Hospital in the Netherlands, Errol P. Prens (n=9) from Erasmus Medical Center in the Netherlands, and Hessel H. van der Zee (n=8) from Erasmus Medical Center in the Netherlands. Most of the corresponding authors were from the USA (n=19) and Denmark (n=17) ( Table 3). The frequency distribution of author productivity in HS is out of 382 authors. 316 authors (82.7%) contributed to just one article. 46 authors (12%) contributed to two articles, and five authors (1.3%) contributed to three articles.     Furthermore, Jemec mentioned in his 2012 HS article that the pathogenesis of HS remains unclear; HS is a disease characterized by sebaceous gland atrophy, lymphocytic infiltration, pilosebaceous unit hyperkeratosis and formation of granulomas with hair follicle destruction. 16 A more recent article by Goldburg et al. in 2020 confirms the complexity and lack of clarity of HS pathogenesis with the addition of TNF-alpha and IL-17 as key cytokines involved. 17 Even with multiple suggestive theories for the pathogenesis of HS, without true understanding of the disease pathophysiology, research in development of diagnostic tests and treatment options may be stagnated. 18,19 After analyzing the 100 top cited articles by research topic, 40 out of 100 papers were related to treatments. Within treatments, there were 9 RCTs. The increased number of research articles regarding treatment may be associated with introduction of new pharmacotherapy options for HS. Many of the articles are focused on the new surge of biologics, such as TNF-alpha inhibitors, which have been studied in dermatological conditions with rheumatology overlap. Grant et al. had the highest cited article under treatment showing the efficacy and tolerability of infliximab as a treatment option for HS, which is a breakthrough in HS management. 20 This study provided an important landmark trial of infliximab as a treatment, which is still currently used as a medical therapy option today. Kimball et al. in 2012, the second highest cited article under treatment, conducted a phase 2 trial with 154 patients and showed promising benefits of adalimumab in moderate-tosevere HS. This led to two phase 3 trials completed in early 2014 called PIONEER I and II with bigger cohorts. The article was published in 2016 and is the second highest annually cited article. 21 Interestingly, epidemiology was a second highest study topic. The number one article was Prevalence and factors associated with hidradenitis suppurativa: Results from two case-control studies by Revuz et al. This retrospective case control study showed HS had a strong association with smoking and obesity, two important risk factors that are clinically relevant to HS management today. 22 On the other extreme, clinical features and diagnosis had the lowest articles. This may be due to the "obliteration by incorporation" phenomenon. This occurs over time because the findings may become common knowledge and as a result do not get appropriately cited. Many important articles not cited within the top 100 may have been incorporated into HS common knowledge. 12,23 Furthermore, 86 different corresponding authors from 14 countries were represented, illustrating the worldwide prevalence of HS and the collaborations around the world. Gregor B. E. Jemec from the University of Copenhagen in Denmark remains the most influential figure in the HS research landscape. Overall, the USA and Europe are leaders in HS research. The USA and Europe may be leaders in HS research because there is a higher burden of HS. HS prevalence ranges between 0.03% and 4% worldwide, but a meta-analysis by Phan et al. in 2020 shows that prevalence of HS is highest in Europe at 0.8% while the USA is at 0.2%. [24][25][26]

Limitations
The top 100 citations highlight HS research over the last 40 years, but it is important to note that many important articles exist outside of the top 100. These articles may represent growth trends in research, but this analysis may bias toward older articles that have had more time to accumulate citations. 12,27 Furthermore, although both SCOPUS and WOS were searched, their indices do not contain every article ever published. It is likewise difficult to determine whether there were articles missed due to search limitations. The total publications data from 1939-2020 capture articles outside of the top 100, but fail to recognize the influence of the studies, which the top 100 citations show.
To our knowledge, this is the first worldwide bibliometric study on HS. Our study found that HS research has experienced notable growth in the last five years. Gregor B. E. Jemec from the University of Copenhagen in Denmark is most influential because he not only started the HS Foundation in 2005, but also is the most prolific author in HS research. Moreover, the British Journal of Dermatology houses the greatest number of these top 100 articles. The clinical trials with adalimumab remain highly cited each year. The prominent focus of HS research are biological treatments and studies on the reduction of quality of life as demonstrated by the top cited articles. Given the financial, psychological and emotional burden of HS, inter-country collaboration among the top active researchers found in this study is encouraged. The quality and measurement of scientific progress is not solely based on pure number of citations. It is about the research itself in the top 100 citations that made its lasting impact on the HS research community and the patients suffering from HS.