## 4 _P. gingivalis_ and Systemic Diseases
### Rheumatoid Arthritis  
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder primarily affecting the synovial membranes of multiple joints. This condition leads to persistent inflammation, synovial proliferation, and ultimately the destruction of articular structures. Over time, the progressive damage to articular cartilage results in joint deformities and functional impairments, significantly reducing the patient's quality of life. While the primary pathology is localized within the synovial membranes of peripheral joints, RA can also have systemic effects, with both specific and nonspecific extra-articular manifestations that affect multiple organs and tissues. These systemic manifestations contribute to a reduction in life expectancy and exacerbate the overall burden of the disease. Rheumatoid arthritis typically presents in individuals aged between 40 and 60 years, with a higher prevalence observed in women [68].  
RA and periodontal disease share a number of common pathological mechanisms, including similar cellular involvement in the inflammatory response, parallel cytokine profiles in serum and the local microenvironment, and the activation of matrix metalloproteinases (MMPs) and other mediators that facilitate tissue breakdown. Furthermore, both conditions are characterized by osteoclast-mediated bone resorption, leading to significant skeletal damage [69].  
A pivotal process in RA pathogenesis is citrullination, a post-translational modification in which the amino acid arginine is converted to citrulline. This modification is mediated by peptidyl arginine deaminase (PAD) enzymes, which are expressed by various immune cells, including T and B lymphocytes, neutrophils, monocytes, and macrophages [70]. The excessive citrullination of proteins can result in the formation of autoantibodies that trigger the production of autoantibodies, particularly anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are central to the pathogenesis of RA. The accumulation of these citrullinated proteins, in turn, promotes an autoimmune response that exacerbates inflammation and tissue destruction [71].  
To date, _P. gingivalis_ is the only known microorganism capable of expressing peptidyl arginine deaminase (PPAD), a bacterial enzyme homologous to the human PAD enzyme [72]. The presence of _P. gingivalis_ in the oral microbiota of RA patients has been strongly correlated with the presence of anti-CCP antibodies, suggesting that this bacterium may play a pivotal role in the pathogenesis of RA [73].  
It is hypothesized that _P. gingivalis_ facilitates the accumulation of citrullinated proteins in the oral cavity, leading to the generation of autoantibodies through the activation of an aberrant immune response. In particular, the reduced immune tolerance to citrullinated proteins in RA patients may promote the formation of these autoantibodies, which in turn contribute to the systemic inflammatory burden of the disease [74].  
Moreover, the elevated production of citrullinated proteins has been associated with more severe disease manifestations, including the rapid progression of joint erosions. Consequently, the presence of anti-CCP antibodies has been shown to correlate with increased alveolar bone resorption in patients with RA, further underscoring the interconnectedness between periodontal disease and the severity of rheumatoid arthritis. Recent studies have expanded this view by identifying novel bacterial species in the oral microbiome that may synergize with _P. gingivalis_ to exacerbate citrullination and systemic autoimmunity in RA [75].  
Additionally, emerging evidence indicates that periodontal therapy can reduce systemic inflammatory markers and autoantibodies in RA patients, suggesting a therapeutic benefit in managing both conditions simultaneously [76].