**1. Introduction**

The relationship between periodontitis and systemic disease is an important part of clinical periodontal research, which has been growing steadily since the late 1980s. Monsarrat et al., in 2016 stated that approximately a third of all recent periodontal studies address this issue [1]. Moreover, in the same year Loos published the results of a study, accrediting the fact that a total of 57 different systemic diseases are being investigated for possible links [2].

This relationship is often described as "bidirectional", but the design of many epidemiological observational studies does not allow the relationship to be firmly established and, implicitly, any identified associations will be bidirectional until clarifying data appear. At present, there is no full understanding of the importance of the multiple associations reported and especially whether they play a causal role.

Although having different etiologies, periodontal disease (PD) and rheumatoid arthritis (RA) have many common features, both being multifactorial diseases characterized by localized chronic inflammatory reactions, which are fed by an analogous set of cytokines (Tumour Necrosis Factor (TNF)-α, Interleukins (IL) 6 and 17), leading to high concentrations of inflammatory markers such as circulating C-reactive protein (CRP) [3]. In addition, bone destruction caused by proinflammatory cytokines secreted by helper T cells (TH17) is the pathological hallmark of both diseases. Furthermore, periodontitis and RA have certain risk factors in common such as environmental and genetic [4].

Rheumatoid arthritis is a chronic, autoimmune systemic inflammatory disease, characterized by an arthropathy with chronic, progressive, deforming and destructive evolution, having a major disabling character and multiple systemic manifestations that determine an important premature mortality. It affects 0.5-1.0% of the world's population, the cause however is still unclear [5]; having said all this, it is thought to be triggered by a combination of genetic and environmental factors that lead to the degradation of immune tolerance at the interface with mucosal surfaces, specifically in the lungs, intestines, and periodontium [6]. The effect is the triggering of the autoimmune response characterized by the production of rheumatoid factor (FR) and ACPA (anticitrullinated protein antibodies). Binding of ACPA to citrullinated epitopes in joints and the formation of immune complexes containing rheumatoid factor helps to form a vicious circle of tissue damage involving the activation of synovial macrophages and dendritic cells, and the release of proinflammatory cytokines and enzymes that lead to tissue degradation. At the same time, peptidilarginine deiminases (PAD) released by neutrophils during necrosis or during the production of extracellular traps citrullinate the proteins in the joints, resulting in a continuous local immune response that is self-sustaining [7].

Until a few years ago, despite these common features, it was difficult, if not impossible, to establish a potential causal link between the two diseases. The discovery and characterization of an enzyme uniquely expressed by the major pathogen in periodontal disease *Porphyromonas gingivalis*, namely peptidilarginine deiminase (called PPAD to distinguish this bacterial enzyme from human peptidilarginine deiminase - PAD), was the basis for the hypothesis that protein citrullination mediated by PPAD originating from inflamed periodontal sites may initiate a series of events that culminate in the production of anti-citrulline protein antibodies (ACPA) and ultimately in the clinical manifestation of RA [8].

The diagnosis of RA has been revolutionized by the discovery of ACPA, diseasespecific antibodies that are present in approximately 70% of patients with this pathology. These are strictly correlated with the severity of the disease and with major risk factors, genetic and environmental, suggesting a pathogenic involvement. They are also detectable in the bloodstream 10 years before the onset of clinical symptoms, suggesting that the initial loss of immune tolerance to citrullinate proteins is most likely a consequence of an inflammatory event that occurs outside the joint [9].

However, most proteins in the human body undergo certain post-translational changes, starting with proteolytic modifications, glycosylation processes or lipid changes, to modifications of residues by chemical or enzymatic means.

#### *The Complex Relationship of Periodontal Disease and Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.97172*

These changes represent, in fact, fundamental physiological processes necessary in order for the organism to function normally; however, by the generation of neo-epitopes, these changes can determine the formation of anti-modified protein antibodies (AMPA), for example ACPA, in subjects that are genetically susceptible and are subjected to certain risk factors [10].

As a chronic inflammatory disease, some of the characteristics and pathogenic processes of RA mirror those of periodontitis, both of which eventually result in the progressive destruction of bone. The profound interdependence between these two diseases is the result of common genetic and environmental risk factors, including HLA-DRB1 gene expression, smoking, and other exogenous risk factors such as nutrition, socioeconomic status, and psychological factors (stress). Despite the obvious differences in etiology, there is evidence linking the two diseases, clinically, epidemiologically, serologically and experimentally [11].
