We analyzed 274 publications in our study. Of the three drugs, Anakinra has been extensively studied, with 130 publications related to it between 1997 and 2021. As progresses are made in the field, Researches about the two novel inhibitors, Canakinumab and Rilonocept, will increase in a similar trend to that of Anakinra. Clinical studies on IL-1β antagonists mainly focused on rheumatoid arthritis. There were also studies associated with their applications in cardiovascular disease (atherosclerosis, heart failure, etc.) and cancer. The United States published the most articles in clinical research on IL-1β antagonists and it was the country which participated in the most collaborations. More and more countries gradually paid attention to clinical studies of IL-1β inhibitors, such as China, Italy.
IL-1β is involved in the development of many diseases, such as Atherosclerosis. It has been shown that IL-1β deficiency could slow the progression of atherosclerosis.(18) IL-1 has also been shown to be associated with joint damage due to rheumatoid arthritis.(19) In animal models of rheumatoid arthritis, IL-β was observed to promote inflammation and disease through regulation of the ERK/STAT1 pathway, which made antagonism against IL-1β one of the methods to benefit patients with rheumatoid arthritis or other Inflammatory disease. (20) Our analysis also showed that studies about rheumatoid arthritis and IL-1β dominated. The studies have gradually expanded to other diseases, such as cancer. It has been reported that IL-1β played a role in tumor invasion and angiogenesis and could inhibit the growth of breast cancer cells. (21, 22) Currently, Clinical trials associated with IL-1β have been conducted in patients with lung cancer or localized Clear Cell Renal Cell Carcinoma. (NCT03447769, NCT04028245) It is predictable that in future clinical studies, antagonism of IL-1β will receive more and more attention in cancer treatment.
As shown in the results, the United State heavily invested in and plays a major role in the clinical researches of IL-1β inhibitors. We supposed that the reason had to do with the broad scope of its collaborations and the availability of many high-level researchers. A lot of productive authors worked at U.S. institutions. In addition, the U.S. research institutions collaborated with different organizations, including academic institutions and commercial companies. As can be seen from the results, there were many collaborations in which Novartis joined. These collaborations between different types of institutions increased the vigor of research in this field.
There were 164 publications from 1997 to 2020 about Anakinra in our results. Articles about Anakinra were the most among the three drugs. Anakinra is a competitive inhibitor of IL-1. It could inhibit the binding of IL-1α and IL-1β to the receptor, thereby blocking related signaling process. (23)As researches progressed, IL-1β was found to be a more potent mediator of inflammation than IL-1α, playing an important role in a variety of inflammatory responses. (24) Therefore, Anakinra is more commonly associated with antagonism of IL-1β. The keyword network for anakinra showed that its most popular area of research was relevant to rheumatoid arthritis. However, there were also other areas such as heart failure, inflammation and etc. (NCT01542502, NCT00897715). Due to a large number of studies surrounding rheumatoid arthritis, it became one of the clinical drugs approved by the FDA for the approval of the treatment of rheumatoid arthritis.
The strategy of antagonism of IL-1β by Anakinra was to inhibit indirectly by targeting its receptor. In 2009, a human anti-il-1β monoclonal antibody, Canakinumab, developed by Novartis for immune diseases, is designed to block Il-1β signaling by directly binding IL-1β, thereby reducing its effects in the inflammatory response.(25) By 2021, there were 77 clinical research articles related to this drug. Similar to Anakinra, the United States published 39 papers, which was the most among all countries. Thuren T and Ridker PM, Libby P had the most articles. In terms of research collaborations. Since the drug was first approved for application by the US FDA and the European EMEA, relevant clinical research collaborations were also between the US and European countries, especially Switzerland, due to Canakinumab approval for the treatment of cryopyrin-associated periodic syndrome early in the drug's marketing, as well as some other immune diseases. Canakinumab is also used to treat cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, and can improve the quality of patient survival. Canakinumab has also been used in oncology treatment. Clinical trials have been conducted with the combination of Canakinumab for lung cancer treatment (NCT04905316, NCT03968419)
Rilonacept is a recombinant molecule made by Regeneron. Its structure could trap IL-1α or IL-1β and the affinity to IL-1β is stronger. (26) Only 29 clinical research papers were included in our study and their citation times are not much. This might be related to the fact that Rilonacept has not been available for a long time. Early studies of Rilonacept were conducted mainly in Europe and the United States, with the largest number of collaborations in the United States, which was similar to the situation of Canakinumab and Anakinra. It indicated that the influence of the United States in the field of antagonism of IL-1β. In the keywords network, the information was limited because of the small number of articles. Rilonacept has been used in CAPS and other autoinflammatory diseases, such as type-I diabetes. (27) (NCT00962026, NCT00288704)We can also speculate that Rilonacept has the potential to be used for clinical oncology treatment as well.
The limitation of our study was that we only analyzed the literatures in English and did not include other languages. And the sources of literatures were mainly from two databases, Pubmed and Web of Science. The literatures from other databases was not included. In the process of screening the literature, some relevant articles might be missed or other irrelevant publications may be included.