Adult-onset Still Disease (AoSD) is a systemic autoinflammatory disease. In 1971, Bywaters analyzed the clinical and laboratory characteristics of 14 adult patients. He found that these characteristics were very similar to systemic-onset juvenile idiopathic arthritis (SoJIA), a condition also known as Still disease. From these observations, he named the disease AoSD (1).

The incidence of AoSD is low. Furthermore, at present, there is no unified understanding of the incidence and prevalence of the disease in different populations in the world. A French study showed that the incidence of AoSD is about 0.16 per 1,00,000 people (2). In Japan, the incidence of AoSD in men and women is 0.22–0.34 per 1,00,000 patients, respectively (3). Additionally, AoSD can occur in any age group and race; however, it is more prevalent in young (15–25 years) and middle-aged (36–46 years) people.

The main characteristics of AoSD include recurrent fever, joint pain or arthritis, skin lesions, hepatosplenomegaly, enlarged lymph nodes, abnormal liver function, increased peripheral blood leukocytes, a high neutrophil ratio, increased C-reactive protein, an enhanced erythrocyte sedimentation rate, and a high concentration of serum ferritin.

Multiple factors such as heredity, infection, and immune dysfunction may be related to the pathogenesis of AoSD; however, the exact mechanism or causes remain unknown. The human leukocyte antigen (HLA) genotype is closely related to the pathogenesis of several diseases. Furthermore, HLA-Bw35, HLA-B17, HLA-B18, HLA-B35, HLA-DR4, HLA-DRw6, etc., are thought to be closely related to the onset of several diseases (4–8). Additionally, interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A, and macrophage migration inhibitory factors are hypothesized to affect disease susceptibility (9–12). Given that similar symptoms of infection such as a sore throat appear before the onset of AoSD, we hypothesize that infectious factors are involved in the onset of the disease. In agreement with this hypothesis, the incidence of AoSD is related to a variety of viruses and pathogenic bacteria (13, 14).

Both the innate and adaptive arms of the host immune response are involved in the pathogenesis of AoSD, of which macrophages, neutrophils, and serum cytokines play a key role. Inflammasome activation, like NLRP3 inflammasome (NOD-, LRR-and pyrin domain-containing 3), by pathogen-associated molecular patterns and damage-associated molecular patterns (15, 16) increase interleukin-1β (IL-1β) and interleukin-18 (IL-18) levels by cysteine-containing aspartate proteolytic enzyme-1 (caspase-1) (17–19). This leads to the dysregulation of IL-6, IL-8, interleukin-17, and Tumor Necrosis Factor alpha (TNF-α) levels (20–22) and results in the induction of cytokine storm and, thus, contribute to AoSD pathogenesis.

Bibliometrics is a comprehensive knowledge system that integrates mathematics, statistics, and linguistics. It is widely used to explore development trends and research frontiers in various fields (23). However, there is no bibliometric study for AoSD. Therefore, we conducted a bibliometric study to evaluate all available evidence for AoSD. Here, we aim to provide an up-to-date overview of the status of AoSD with the help of a variety of bibliometric tools.

This study uses a variety of bibliometric software and tools to analyze the published research article on AoSD based on the WoSCC database. Studies have shown that the earliest retrospective article was published in 1976 (28).

By 2020, the annual number of publications and citations of AoSD-related research showed an overall upward trend, thus highlighting the rapid development of AoSD studies and sustained interest in its research. However, as an orphan disease, AoSD has a low incidence in the population with the prevalence rate estimated to be one case per million people in Europe and 10 cases per million people in Japan (2, 3). This low incidence has translated into fewer published studies relative to other rheumatic diseases. From 1976 to 2020, a total of AoSD 2,199 articles were published indicating the growing importance of AoSD research in spite of its low incidence. In addition, compared with other rare immune-related diseases such as Primary Combined Immune Deficiency (26), Chediak-Higashi Syndrome (29), and Chronic Primary Granulomatous Disease (30), which publications were 866, 1,252, and 1,425, respectively. The result indicates that AoSD may attract more interest than these rare diseases in terms of publications. However, compared with common rheumatic immune diseases such as rheumatoid arthritis (more than 190,000 articles) and systemic lupus erythematosus (more than 80,000 articles), the publication count of papers on AoSD is still significantly insufficient.

Through the comprehensive and systematic summary of the research topics, trends, and global research on the impact of AoSD, scholars can quickly and preliminarily understand the current state of AoSD research. The H-index reflects the academic achievements of countries, institutions, or individuals in a certain field. The higher the H-index, the greater the academic influence. From the perspective of regional distribution, the United States is the global leader in terms of both the number of published article and H-index in AoSD-related research. Specifically, AoSD research originating in the United States has significantly contributed to the field. However, in the current study, further analysis of research institutions and individuals revealed that France and Italy may have superior contributing roles to global AoSD research. This is especially valid when assessing the Top 10 authors by the number of publications and citations. Further, these data indicated that no American scholars were found in the Top 10, and French and Italian scholars occupy the majority.

Keyword cluster analysis can highlight current research hotspots. In agreement with the research direction of highly cited articles and co-cited references, our data indicate that the research hotspots of AoSD are mainly related to the identification and diagnosis of the disease. These hotspots may be attributed to the fact that as an orphan disease, the pathogenesis of AoSD is not clear, and multiple factors including heredity, infection, and immune dysfunction may contribute to AoSD development. As an immune-related disease, AoSD is difficult to distinguish from juvenile rheumatoid arthritis and rheumatoid arthritis (RA) in the initial clinical diagnosis.

Additionally, multiple difficulties exist in the diagnosis of AoSD resulting in a lack of a unifying clinical diagnostic gold standard. Traditionally, the diagnostic criteria for AoSD have mainly been based on four main symptoms including fever, arthritis or joint pain, rash, and increased white blood cell and neutrophil counts (14). Fautrel proposed a new diagnostic classification criterion in 2002. His set of eight diagnostic classification criteria included spiking fever ≥39°C, arthralgia, maculopapular rash, transient erythema, pharyngitis, leukocyte count ≥10,000/mm³, polymorphonuclear count ≥80%, and glycosylated ferritin ≤20%. Of these criteria, maculopapular rash and leukocyte count ≥10,000/mm³ are considered to be secondary, and the remaining six signs are considered to be the primary criteria. Using these parameters, a positive AoSD diagnosis would be defined as a patient presenting with four primary criteria, or three primary criteria +2 secondary criteria. Studies have shown that these diagnostic criteria have a higher sensitivity relative to traditional diagnostic strategies (31). Because the symptoms of AoSD are diverse and systemic, it is necessary to differentiate AoSD from a variety of other diseases such as infections, malignancies, and other chronic rheumatism during diagnosis. These newly proposed criteria may assist with this. There are still a variety of diagnostic and classification criteria (32), but most of the criteria are exclusionary diagnosis. Even after the diagnosis is made, the changes of the disease should be observed at any time during treatment and follow-up. Since the research on AoSD is relatively short and many contents are not yet perfect, developing a diagnostic standard with higher specificity is still a hotspot and difficulty in future research.

Previously, non-steroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying antirheumatic drugs have been used for the treatment of AoSD; however, their curative effect is poor. Further, in ~40% of cases, patient symptoms remain unaffected by traditional treatment (33, 34). Common anti-rheumatic immune drugs such as interferon-γ, etanercept and anakinra are also widely used clinically (35). The activation of innate immunity and the dysregulation of cytokines are important mechanisms contributing to the pathogenesis of AoSD. IL-1β, IL-18, IL-6, and TNF-α are elevated in the serum, skin lesions, and synovial membrane of AoSD patients. The targeted therapy for these factors has been successfully applied in other models of chronic rheumatic disease and may provide a reference for the treatment of AoSD. Many studies have shown that biological agents have good safety and effectiveness in the treatment of refractory AoSD, but the sample size of clinical trials is obviously inadequate (20, 36, 37).

We found that research on targeted therapy for AoSD has been on the rise. As early as 2007, Efthimiou suggested that recent advances in basic immunology have improved our ability to hinder the pathogenic mechanisms associated with AoSD, and discussed the impact of targeted anti-inflammatory cytokine-based targeted therapies on AoSD (14, 38, 39). An increasing number of clinical trials have demonstrated that targeting these proinflammatory cytokines may be effective in controlling AoSD (40). Antagonists of IL-1β and its receptor have been successfully used to treat AoSD (41). Three anti-IL-1β biologics, namely, anakinra, canakinumab, and rilonacept, which are used to control AoSD, are currently available on the market. In the results of this study, Anakinra is one of the current research hotspots, and the publications of papers mentioning AoSD with Anakinra as 227 on WOS data. To our knowledge, a randomized, double-blind, placebo-controlled, multicenter, phase III study to assess the efficacy and safety of anakinra in the treatment of AoSD (https://clinicaltrials.gov/ct2/show/study/NCT03265132), just concluded the update in June 2021, and no relevant literature has been published. In addition, systematic reviews are indicating that the use of IL-1β inhibitors in AoSD has led us to a new era of targeted therapy for AoSD (42). Whilst TNF-α inhibitors, as the first biological agent for the treatment of AoSD, have a good curative effect in chronic inflammatory joint diseases (especially RA), the curative effect in the treatment of AoSD is poor (43). Therefore, we believe that as molecular biology progresses, targeted therapy will play a more beneficial role in AoSD.

Due to the rarity of AoSD, many clinical studies are limited by small sample sizes and are thus underpowered. Furthermore, because of the varying clinical designs among different studies an accurate consensus is difficult to conclude. These are significant obstacles that need to be overcome to improve the credibility of published AoSD studies in the future.

Analysis of AoSD article by Citespace and Vosviewer has some limitations. The first is the deadline for article retrieval by 2020, but as WoSCC continues to update, the number of articles retrieved in this study may be slightly different from the actual number of relevant articles. The Second, due to the possible time lag, the importance of some studies, especially some newly published article, may not be given sufficient attention at present. Finally, the use of single database WOSCC is also a limitation. However, its use can be further substantiated, as it provides more accurate document type labeling than other databases such as Scopus (44). And this research based on bibliometrics still well demonstrates the research hotspot and development trend of AoSD, especially providing reference for young scholars in scientific decision-making.

This study analyzed AoSD research published from 1976 to 2020. Furthermore, we summarized the regional distribution, journal category, article citation, main cooperative groups, and keyword clustering related to AoSD research. As an understudied, orphan disease, the mechanisms and pathogenesis of AoSD still need to be elucidated. The development of targeted AoSD therapy is a relatively effective and safe. However, existing clinical research samples sizes are small and prone to Type I or Type II errors. It is necessary to further expand the clinical sample size and clarify the safety and effectiveness of biological agents. This study provides key insights into current AoSD research and can be used as a useful resource for researchers in the field to identify hotspots and trends.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

BX and BB conceived the study. BX, JW, and XM collected the data. BB re-examined the data. BB and XM analyzed the data. BX wrote the manuscript. JW, BB, and XM reviewed and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.