In recent years, immunotherapy has become increasingly common in cancer treatment, as they have shown remarkable success in inducing durable responses in some patients (1). Monoclonal antibodies targeting immunological checkpoints, or immune checkpoint inhibitors (ICIs), represent a rapidly growing class of these agents. By targeting the T-cell cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death-ligand 1 (PD-1/PD-L1) coinhibitory receptors, ICIs, either as single agents or in combination, enhance antitumor T-cell activity, leading to unprecedented long-lasting tumor responses in patients with unresectable or advanced metastatic disease (2–6).

However, while these drugs non-specifically activate T cells, which can not only increase immune response against cancer cells, but also lead to immune-related adverse events (irAEs) that exhibit inflammatory or autoimmune-like side effects. These adverse events (AEs) are unique in comparison to conventional cancer therapies and can range from mild to severe, affecting any organ system in the body (7, 8). The incidence of irAEs depends on various factors, such as the type of ICIs used, the cancer type, and the individual patient’s characteristics. Common irAEs associated with ICIs include pneumonitis, colitis, hepatitis, endocrinopathies, and skin toxicities (9). Interestingly, specific rheumatic manifestations among irAEs have also been described, such as inflammatory arthritis, vasculitis, inflammatory myopathy, sicca syndrome, and scleroderma, etc (9). However, the prevalence and course of these rheumatic irAEs are not well-established, and detecting them during or after cancer treatment can be challenging, as they resemble conventional rheumatologic diseases (10). Clinical trials often overlook musculoskeletal/rheumatic events as a distinct organ system or report only high-grade and/or frequent adverse events occurring in at least 10% of the patients (11). Additionally, different researches might use varying terms to describe these irAEs due to their heterogeneous definitions, and real-life data suggest that they are underreported (12, 13). Also, evidence is lacking for the optimal diagnostic approach and management of these patients while allowing effective antitumor therapy to continue (9). Consequently, it is crucial to gain a comprehensive understanding of the current status, research trends and emerging topics.

Bibliometric analysis is a useful tool for achieving this goal, as it allows for the systematic and quantitative analysis of research publications in a particular field. No such studies have been published in the field of ICIs associated rheumatic irAEs. By using bibliometric analysis techniques, we aim to provide an overview of the studies and scholarly contributions, identify the most influential authors, institutions, and journals in this field and to map the most significant research topics and trends, which can contribute to the improvement of patient care and the development of safer immunotherapies. Furthermore, the results of this study can also inform policymakers and funding agencies about the most promising areas of research in the field of immunotherapy-related adverse events.

In this study, we conducted a bibliometric analysis of publications related to ICI-induced rheumatic irAEs for the first time to gain insights into the global research trends in this field. In contrast to scoping reviews and systematic reviews, bibliometric analysis provides a powerful tool for summarizing current knowledge and identifying emerging trends. After excluding 384 publications that didn’t meet our inclusion criteria, we identified 803 publications in 316 journals from 1354 institutions in 52 countries/regions. The first article was published in 2007, describing the effectiveness of CTLA-4 inhibitors in Phase I/II clinical trials. It was also observed that some patients developed arthritis, and showed improvement after treatment with Cox-2 inhibitors. A significant increase in publications related to this topic over the years was revealed, particularly since 2015, indicating the growing importance of this field of research. One possible explanation for this trend is the increasing clinical use of ICIs since the first US Food and Drug Administration (FDA) approval of ipilimumab for late-stage (metastatic) melanoma in 2011 (23). The approval of several ICIs in 2015 for various types of cancer (24) led to a surge in their use and a subsequent increase in the reports of rheumatic irAEs. As more patients were treated and more AEs were reported, the interest and awareness of this topic increased among the research community.

The distribution of contributing countries/regions and institutions showed some characteristics. The USA was the most productive country in terms of publications, followed by France and Japan. The top 10 institutions accounted for 55.9% of the papers in this field, highlighting the significant contributions made by researchers from these countries. The USA’ dominant position can be attributed to its well-established research infrastructure, long history of medical research, top-ranked institutions, and funding agencies such as the National Institutes of Health (NIH), which is one of the most important research funding agencies in the world for basic and clinical research. Most of the top 10 institutions and funding agencies are based in the USA. In addition to government fundings, pharmaceutical companies such as Bristol Myers Squibb and Merck Company also play a significant role in drug development and research. Regarding the top 10 co-cited references, six of them are from the USA, and one is a collaborative effort between the USA and the UK. USA scholars primarily publish clinical research and clinical guidelines, which enables their work to be widely disseminated and cited. China produces a considerable amount of research papers, but the citation rate is relatively low. The reasons behind this include language barriers, inadequate funding and support from the government or pharmaceutical industries, limiting large-scale clinical trials in some areas. As a result, researchers may prioritize conducting meta-analyses and case reports that have less impact on the scientific community compared to original research articles and clinical trials, thereby leading to a decreased citation rate. To address this, Chinese authorities should allocate more resources towards conducting original research articles and large-scale clinical trials to potentially increase the impact of research findings and contribute to the advancement of this research areas.

We also found that international collaboration has been increasing over time, with collaboration between the USA and France being particularly strong. This is an encouraging trend as international collaboration can lead to the sharing of knowledge and expertise, resulting in a better understanding of scientific research. China’s high publication output in the field of immunotherapy and irAEs indicates a growing interest and investment in research, which presents valuable opportunities for collaboration with researchers around the world. However, there may be limitations to China’s collaboration with other countries due to language barriers and a lack of established relationships with researchers in other countries. Additionally, China faces funding and pharmaceutical development challenges, with many local companies focusing on generic drugs rather than original products. Nonetheless, China has a large population of cancer patients, making it an attractive market for the development of new therapies. By collaborating more closely with other countries, we can effectively facilitate knowledge exchange and sharing, while simultaneously driving innovation in the healthcare industry. This can lead to a better understanding of diseases, drugs, and treatment options, ultimately resulting in improved patient care.

Our analysis further identified the top journals and institutions that have contributed to research on ICIs associated rheumatic irAEs. The top ten most central journals in this field were identified, and the institutions with the highest number of publications were also analyzed. Our findings can help researchers identify the most relevant journals and institutions to publish their research and collaborate with other researchers in this field. Additionally, researchers can subscribe to these journals to stay up-to-date with the latest developments in the field.

We also analyzed the keywords used in these publications. Analyzing the keywords used in publications can offer information about the research topics and methodologies of the publications, and analysis of keywords’ co-occurrence can often detect research hotspots and directions in the research field. By generating a network visualization map for keywords with the co-occurrence value greater than 20 times, we found that the most frequently used keywords can be broadly categorized into three sections: ICIs and their tumor indications, the mechanisms and efficacy of ICIs, and the adverse reactions caused by ICIs. As time progressed, researchers gained a deeper understanding of ICIs beyond their development as cancer treatments, with emphasis on their mechanisms, efficacy, and adverse reactions. The research hotspots included autoimmune hypophysitis, induced sarcoidosis, safety, inflammatory arthritis, and preexisting autoimmune conditions. These hotspots provide insights into the current research focus and highlight areas that require further investigation.

However, it is also important to acknowledge potential limitations and biases of our study. Firstly, this study solely relied on literature from the WoSCC database, which may have resulted in the exclusion of publications from other sources. Secondly, the study overlooked non-English articles, as it is focused only on English-language publications. These factors should be considered while interpreting the results. Another limitation of this study could be the lack of attention paid to the quality of the publications. While bibliometric methods can provide a comprehensive analysis of the literature, they do not take into account the quality of the research. Future studies could consider incorporating quality assessment tools to better understand the impact and significance of the research conducted on ICIs-associated rheumatic irAEs. Upon reviewing the literatures, we found that majority of them focused solely on describing the phenomenon of ICIs associated rheumatic irAEs, with a lack of comprehensive research on the underlying mechanisms, risk factors, and prevention strategies. We believe that delving deeper into these areas will significantly contribute to enhancing the prognosis of cancer patients. Despite these limitations, our study provides valuable insights that can significantly support researchers in their decision-making process when it comes to selecting suitable journals and institutions to publish their research or collaborate with. Additionally, this study sheds light on the current research hotspots and directions within the specific field of research being examined. These findings can contribute to enhancing the quality and impact of researchers’ work, as well as facilitating fruitful collaborations and identifying potential areas for future exploration.

Overall, our study is the first to use bibliometric methods such as CiteSpace and VOSviewer to comprehensively evaluate the current state and progress, as well as research trends and contributions in the field of ICI-induced rheumatic irAEs, which represents a new area of rheumatology that calls for urgent attention, research, and collaboration. Given the rapidly increasing use of ICIs in cancer treatment, rheumatologists can play a central role in the management of irAEs in the future, and multidisciplinary collaboration is essential to improving their recognition and outcomes. Future efforts should focus on developing classification criteria and guidelines for the diagnosis and management of rheumatic irAEs; conducting prospective studies to better estimate the incidence and prevalence of these events and understand their risk factors and patterns of onset, resolution, and persistence; investigating the immunopathogenic mechanisms involved, including the roles of different immune checkpoints, autoantibodies, and cytokines in their development and persistence; and identifying biomarkers for prediction and monitoring of these events based on their immunological and clinical features. These future directions are crucial to promoting better care for cancer patients treated with ICIs and advancing the field of rheumatology.

ICIs have emerged as a promising treatment option for various types of cancers. However, their use has been associated with various irAEs, including rheumatic irAEs, which is a growing concern now. Compared to other immune AEs, rheumatic irAEs typically involve the joints, muscles, and other connective tissues. While arthralgia and myalgia are common rheumatic irAEs reported in clinical trials, other case series and reports have described a wider spectrum of de novo rheumatic and systemic manifestations that mimic classic rheumatic diseases and can occur with ICIs (25, 26). These include polymyalgia rheumatica (PMR)-like syndromes and inflammatory arthritis syndromes, which are often encountered clinical presentations (13, 27, 28). Systemic manifestations have also been reported, including sicca syndrome, sarcoidosis, and all vessel-sized vasculitis (29–35). Interestingly, autoantibodies are often absent or at low titre in these patients (11). While these rheumatic irAEs can occur across all classes of ICI, they are most frequently and severely associated with combination treatments and may be linked with other organ-specific irAEs. Treatment of rheumatic irAEs generally depends on the CTCAE grade of the events, and may involve discontinuing ICI therapy, administering steroids or immunosuppressive agents, including biologics, and referral to a rheumatologist for specialized care (11). Careful evaluation and monitoring of treatment response and potential side effects are critical as these patients may be at higher risk for infections and other complications.

Currently, the underlying immunopathogenic mechanisms of rheumatic irAEs are not clear and several possible mechanisms have been proposed. One might involve generalized immune activation, due to checkpoint neutralization, which might result in inflammatory reactions in multiple organ systems, including the musculoskeletal system (9). It is reported that several primary immunodeficiencies associated with prominent autoimmune manifestations are linked to dysfunction or underexpression of CTLA4 (36). T cell exhaustion, which correlates with a state of low disease activity in some autoimmune diseases, such as anti-nuclear cytoplasmic antibody (ANCA)-associated vasculitis, is also a possible explanation for this mechanism (37). A study found increased production of inflammatory cytokines such as IL-17 following treatment with ICIs, as well as the effectiveness of cytokine targeting (especially by TNF inhibitors) at treating immune-related side effects further supports it (38–40). Another proposed mechanism of rheumatic irAEs is direct off-target effects of checkpoint inhibitors (9). ICIs may have off-target effects on cells other than T cells, including natural killer cells, dendritic cells, and macrophages, leading to autoimmune inflammation and rheumatic irAEs. However, the precise mechanisms by which these effects occur are not yet clear. The third proposed mechanism of rheumatic irAEs is epitope spreading (41). The diversity of T-cell receptor repertoires and the heterogeneity of tumor-associated antigens make it challenging for the immune system to recognize and eliminate tumors. However, ICIs can induce epitope spreading, which is the diversification of the epitope-specificity of T-cells. The new targets acquired by the T cells can include new antigens on self-proteins, leading to autoimmune inflammation and rheumatic irAEs (41). In addition, molecular mimicry is also suggested as a possible mechanism of ICIs-associated rheumatic irAEs. Some viral and bacterial antigens share sequence or conformational similarity with host antigens. The immune system, in response to infections, may produce antibodies and T cells that cross-react with host antigens, leading to autoimmune inflammation and rheumatic irAEs. Pre-existing asymptomatic autoimmunity is another possible mechanism involving ICIs that mediate immune activation in asymptomatic or pauci-symptomatic autoimmunity (9). However, against this argument is the fact that most patients with rheumatic irAEs test negative for serum autoantibodies. To date, rheumatic irAEs have not been thoroughly investigated for signature autoantibodies, HLA associations, or biomarkers of idiopathic disease. However, as investigations are ongoing, there is a desperate need to study immunopathogenic mechanisms for most irAEs as such investigations are far from complete.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

LZ and QZ participated in the research design. LZ and KC participated in the bibliometric analysis. GM, LZ and QZ drafted the manuscript, QZ revised and polished the manuscript. All authors contributed to the article and approved the submitted version.