Rheumatoid arthritis (RA), an autoimmune disease that affects ∼1% of the human population, is driven by autoantibodies that target modified self-epitopes, whereas ∼11% of the global adult population are affected by severe chronic periodontitis, a disease in which the commensal microflora on the tooth surface is replaced by a dysbiotic consortium of bacteria that promote the chronic inflammatory destruction of periodontal tissue. Despite differences in aetiology, RA and periodontitis are similar in terms of pathogenesis; both diseases involve chronic inflammation fuelled by pro-inflammatory cytokines, connective tissue breakdown and bone erosion. The two diseases also share risk factors such as smoking and ageing, and have strong epidemiological, serological and clinical associations. In light of the ground-breaking discovery that Porphyromonas gingivalis, a pivotal periodontal pathogen, is the only human pathogen known to express peptidylarginine deiminase, an enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies, a new paradigm is emerging. In this Review, the clinical and experimental evidence supporting this paradigm is discussed and the potential mechanisms involved in linking periodontitis to RA are presented.

The case for periodontitis in the pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects joints. The several mechanisms involved in the development of the disease are not completely understood. It has been proposed that different environmental factors, such as cigarette smoking, occupational and atmospheric agents act as trigger stimuli for the development of RA in genetically predisposed individuals, leading to synovial hyperplasia and bone destruction. The initial disease stage of RA is associated with alteration of innate and adaptive immune system with consequent production of autoantibodies, targeting various molecules including modified self-epitopes. In the following stages of the disease, both the innate (e.g. dendritic cells, macrophages and neutrophils) and adaptive immune cells (e.g. B and T lymphocytes) contribute to the amplification and perpetuation of the chronic inflammatory state. The recognition of key cells, mediators and mechanisms implicated in the pathogenesis of RA could provide the basis for the development of new and precise disease-modifying anti-rheumatic drugs. Therefore, we reviewed the literature of the last year in order to find the new insights in RA pathogenesis.

One year in review 2018: pathogenesis of rheumatoid arthritis.

Periodontitis is characterized by a chronic inflammation produced in response to a disease-associated multispecies bacterial community in the subgingival region. Although the inflammatory processes occur locally in the oral cavity, several studies have determined that inflammatory mediators produced during periodontitis, as well as subgingival species and bacterial components, can disseminate from the oral cavity, contributing therefore, to various extraoral diseases like cancer. Interestingly, carcinogenesis associated with periodontal species has been observed in both the oral cavity and in extra oral sites. In this review, several studies were summarized showing a strong association between orodigestive cancers and poor oral health, presence of periodontitis-associated bacteria, tooth loss, and clinical signs of periodontitis. Proinflammatory pathways were also summarized. Such pathways are activated either by mono- or polymicrobial infections, resulting in an increase in the expression of proinflammatory molecules such as IL-6, IL-8, IL-1β, and TNF-α. In addition, it has been shown that several periodontitis-associated species induce the expression of genes related to cell proliferation, cell cycle, apoptosis, transport, and immune and inflammatory responses. Intriguingly, many of these pathways are linked to carcinogenesis. Among them, the activation of Toll-like receptors (TLRs) and antiapoptotic pathways (such as the PI3K/Akt, JAK/STAT, and MAPK pathways), the reduction of proapoptotic protein expression, the increase in cell migration and invasion, and the enhancement in metastasis are addressed. Considering that periodontitis is a polymicrobial disease, it is likely that mixed species promote carcinogenesis both in the oral cavity and in extra oral tissues and probably—as observed in periodontitis—synergistic and/or antagonistic interactions occur between microbes in the community. To date, a good amount of studies has allowed us to understand how monospecies infections activate pathways involved in tumorigenesis; however, more studies are needed to determine the combined effect of oral species in carcinogenesis.

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Chronic Inflammation as a Link between Periodontitis and Carcinogenesis.

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features. RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction. PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues. Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors. Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD. Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA. However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD. This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases. In addition, the current available treatments targeting both RA and PD were revised.

https://www.mdpi.com/1422-0067/20/18/4541/pdf

Linkage of Periodontitis and Rheumatoid Arthritis: Current Evidence and Potential Biological Interactions.

A high prevalence of periodontitis has been reported in rheumatoid arthritis (RA) patients, although the strength of this association, its temporal link and the possible relationship between the severity of periodontitis and RA disease activity remain unclear. The objective of this work was to investigate whether periodontitis is associated with RA and whether periodontitis severity is linked to RA disease activity. This case–control study included 187 patients diagnosed with RA and 157 control patients without inflammatory joint disease. RA disease activity and severity were evaluated by the Disease Activity Score 28, the Simplified Disease Activity Index, the Clinical Disease Activity Index, rheumatoid factor, anti-citrullinated protein antibody titers, the erythrocyte sedimentation rate, C-reactive protein, presence of extra-articular manifestations and type of RA therapy. Exposure severity was assessed by the following periodontal parameters: plaque index, bleeding on probing, probing pocket depth and clinical attachment levels. Sociodemographic variables and comorbidities were evaluated as confounding variables. Outcome and exposure variables were compared by both parametric and nonparametric tests, and possible associations were assessed through regression analysis with a calculation for the adjusted odds ratio (OR). A significant association was demonstrated between periodontitis and RA with an adjusted OR of 20.57 (95% CI 6.02–70.27, p < 0.001). Compared with controls, all parameters related to periodontal status (plaque index, bleeding on probing, probing pocket depth and clinical attachment levels) were significantly worse in RA patients (p < 0.001). Periodontitis severity was significantly associated with RA disease activity (p < 0.001), showing in an ordinal logistic regression model an association between periodontal severity and disease activity with an adjusted OR of 2.66 (95% CI 1.24–5.74, p = 0.012). A significant association was demonstrated between periodontitis and RA, independent of other confounders. This association was more evident in patients with pronounced periodontal disease and higher RA disease activity.

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Association between severity of periodontitis and clinical activity in rheumatoid arthritis patients: a case–control study

Background: This study evaluates periodontal conditions and microbiologic findings and their influence on rheumatologic disease parameters in patients with rheumatoid arthritis (RA).Methods: One hundred and sixty-eight patients with RA were included. A healthy control group (HC, n = 168) was composed according to age, sex, and smoking habits. Rheumatologic data (duration of illness, Disease Activity Score 28, rheumatic factor [RF], anti-cyclic citrullinated peptide [aCCP], medications) were extracted from patients’ records. Dental examination included: 1) dental findings (decayed, missing, and/or filled adult teeth [DMF-T] index); 2) gingival inflammation (papillary bleeding index [PBI]); and 3) periodontal status (probing depth [PD], attachment loss [AL]). Periodontal condition was classified as healthy/mild, moderate, or severe periodontitis. Subgingival biofilm was analyzed regarding 11 periodontopathogenic bacteria. Statistical analyses included: 1) Kolmogorov–Smirnov test; 2) Mann–Whitney U test; 3) ...

Cross-Sectional Evaluation of Periodontal Status and Microbiologic and Rheumatoid Parameters in a Large Cohort of Patients With Rheumatoid Arthritis.

BACKGROUND The aim of this cross-sectional study was to investigate clinical periodontal findings as well as prevalence of selected potentially periodontal pathogenic bacteria in patients with rheumatoid arthritis (RA) treated with different immunosuppressive rheumatic medications. METHODS One hundred sixty-eight patients with RA undergoing different immunosuppressive medications were included and divided into subgroups according to their medication, which was taken in the past 6 months, in detail, 1) non-steroidal anti-inflammatory drugs (NSAID) and glucocorticoids combined, and the following different disease modifying anti-rheumatic drugs (DMARDs): 2) methotrexate (MTX), 3) leflunomide, 4) MTX and TNF-α antagonists combined, 5) interleukin-6 (IL-6) antagonist, 6) MTX and rituximab combined, and 7) combination therapies of > 2 of these DMARDs. Periodontal examination consisted of papilla bleeding index (PBI), periodontal status with periodontal probing depth (PD), bleeding on probing (BOP), and clinical attachment loss (AL). Periodontitis was classified as none/mild, moderate, or severe. Samples obtained from gingival crevicular fluid were analyzed for presence of 11 periodontal pathogenic bacteria. RESULTS Patients with MTX + TNF-α antagonists therapy showed higher PBI and BOP values compared with leflunomide (P < 0.01) and higher BOP than MTX + rituximab (P = 0.02). Porphyromonas gingivalis (P < 0.01), Treponema denticola (P < 0.01), Fusobacterium nodatum (P = 0.02) and Capnocytophaga species (P = 0.05) was associated with medication subgroup, whereby post hoc testing confirmed singular differences for several medication subgroups. CONCLUSIONS RA medication is associated with periodontal inflammation, without differences in periodontal disease severity. Thereby, combination of MTX + TNF-α shows an increased potential to periodontal inflammation. Additionally, several differences in prevalence of selected bacteria were detected.

Association of different immunosuppressive medications with periodontal condition in patients with rheumatoid arthritis: Results from a cross-sectional study

The aim of this cross-sectional study was to assess oral health-related quality of life (OHRQoL) in patients with rheumatoid arthritis (RA) and its relation to specific RA characteristics. Within the oral examination, the need for dental (carious teeth showing cavitation) and periodontal treatment (presence of a probing depth ≥ 3.5 mm) and the number of missing teeth (M-T) were recorded. OHRQoL was assessed with the German short version of the Oral Health Impact Profile (OHIP G14). The disease activity score (DAS28-ESR), disease duration, number of swollen/painful joints and duration of morning stiffness were retrieved from the patient records. A total of 176 patients with a mean age of 62.5 ± 10.2 years were included. The overall OHIP G14 sum score was 5.4 ± 7.1. The M-T showed a significant correlation with the dimensions of oral function (r = 0.25, p = 0.001) and psychosocial impact (r = 0.20, p = 0.009) and the sum score (r = 0.26, p = 0.001). The DAS28-ESR showed a significant correlation with psychosocial impact (r = 0.19, p = 0.012) and the sum score (r = 0.16, p = 0.041). The duration of morning stiffness was correlated with oral function (r = 0.19, p = 0.019), psychosocial impact (r = 0.18, p = 0.024) and the sum score (r = 0.22, p = 0.006). The effect size of these correlations was interpreted as small. Disease activity, morning stiffness and missing teeth are associated to OHRQoL of patients with RA. Accordingly, multidisciplinary dental care appears necessary for these patients. The prevention of tooth loss as well as the consideration of psychosocial and disease-specific parameters in the multidisciplinary dental care of RA patients is necessary.

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Disease activity, morning stiffness and missing teeth are associated with oral health-related quality of life in individuals with rheumatoid arthritis.

Annegret Rupprecht

Papers

Cross-Sectional Evaluation of Periodontal Status and Microbiologic and Rheumatoid Parameters in a Large Cohort of Patients With Rheumatoid Arthritis.

Association of different immunosuppressive medications with periodontal condition in patients with rheumatoid arthritis: Results from a cross-sectional study

Disease activity, morning stiffness and missing teeth are associated with oral health-related quality of life in individuals with rheumatoid arthritis.