The evolution of keyword usage can reveal the underlying structure and characteristics of the field. By analysing the occurrence frequency of keywords in different time periods, the trends in RA-related research can be obtained.[24] Keywords used at an higher frequency can represent the focus within the RA specialism and provide insight into issues which need to be addressed and determine the level of urgency. Keywords co-occurrence analysis used here employs two analytical maps, time-zones and time-lines to analyse the evolution of RA research on a macro-to-micro scale.
3.1. The evolution stages of keywords
As shown in Figure 3A, RA research can be divided into the following stages:
(1) The timespan across the time-zone was mapped from 2001-2020. This is when the literature on RA medical research was first published. "Rheumatoid arthritis" (e., purple node) is in the centre and connects to most keywords. Please see Figure 3A, which indicates that RA has attracted increasing attention for many years.
(2) There were fewer research keywords from 2003 to 2008, which suggests that there were fewer RA-related studies during this time period, and keywords appeared less frequently.
(3) In 2009, "Inflammation" first appeared as a keyword in the RA field (frequency of occurrence >15), and has become an highly central keyword (e., the purple node). Most of the keywords are connected to this word which suggests that, "inflammation" serves as a the interconnecting theme. Since 2009, the number of keywords has increased and additional keywords include: systemic lupus erythematosus, NF-κB (nf kappa b in Fig. 3A), apoptosis, etc. This suggests that in last 10 years, RA research has focused on autoimmune diseases more generally, in terms of cytokines, and damaged joints, etc.
(4) This stage ends on February 12, 2020. The research focus of 2019 can represent the more recent research interests within this field, such as the focus on TNF-ɑ, inhibition (e., inflammatory inhibition), osteoporosis, etc.
3.2. Analysis of co-occurrence cluster
Keyword co-occurrence clustering analysis is an effective way to identify the evolution of research topics because this analysis can potentially highlight knowledge links between different keywords.
From Figure 3B, we can see that the largest node is rheumatoid arthritis. Looking at the time horizontally, RA research has continued for many years without interruption. There are essentially 20 clusters, which indicates that researchers have explored many different areas in search of answers. Conversely, some clusters have had only relatively short durations, which may be because researchers have explored new research pathways and transitioned to another research topic. In addition, the map provides us with the evolutionary relationship between keywords. Using the first cluster as an example, we labelled the relationship between osteoarthritis with other keywords in Figure 3B and utilised this to generate Figure 3C.
Adalimumab has been shown to be an effective management for RA.[25] As can be seen in cluster #0 adalimumab in Figure 3C, osteoarthritis, a joint disease mainly characterized by degeneration of articular cartilage that displays similar clinical symptoms to those of RA, and has the highest frequency of co-occurrence.[26] Since 2001, there have been 207 publications about osteoarthritis in the RA research field.
One of the most influential studies is from Diarra et al. (2007), who found that inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, is able to reverse the bone-destroying pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis.[27] Their article, which has been cited 839 times, suggests that the Wnt pathway is a key regulator of joint remodelling.
According to Figure 3C, osteoarthritis in the #0 cluster is closely related to the following keywords: chronic synovitiiti, cyclooxygenase, trial, and knee osteoarthritis. In addition, the related keywords also include: double blind (cluster #14), cartilage (cluster #17), suppressed (cluster #20). After searching citation histories, we found that osteoarthritis and chronic synovitiiti appear to co-occur according to the Harald et al. (2005) article on radiosynoviorthesis (RSO). Their work states that RSO, though slightly more effective in RA, represents an effective treatment option for osteoarthritis and other disorders with concomitant synovitis.[28]
Osteoarthritis and cartilage appear together as keywords in 22 articles, of which the most highly cited publications included work from Lefèvre et al. ,[29] the work from Aida et al. on the role of interleukin-1 on altering cartilage matrix turnover,[30] and a clinical trial from Gruenwald et al. on glucosamine sulfate.[31] In particular, Gruenwald et al (2009) states osteoarthritis symptoms (e.g., morning stiffness, pain in hips and knees) were reduced at the end of the study by combining glucosamine and omega-3 fatty acids compared to glucosamine sulfate alone. These clinical results may assist drug development and highlight the need for dietary changes.