A statistically significant association between periodontal disease (PD) and systemic diseases has been identified. Rheumatoid arthritis (RA), which is a chronic inflammatory joint disease, exhibits similar characteristics and pathogenesis to PD. The association between RA and PD has been investigated, and numerous publications on this subject exist. Approximately 20 bacterial species have been identified as periodontal pathogens, and these organisms are linked to various types of PD. The most analyzed species of periodontopathic bacteria are Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans. Antibodies and DNA from these oral pathogens have been isolated from the sera and synovial fluids of RA patients. This rapid communication describes the role of periodontal pathogens in the etiopathogenesis of RA.
etiopathogenesis; chronic arthritis; periodontitis; Porphyromonas gingivalis; systemic disease; animal models; antibiotics
Growth of scientific evidence suggests an exquisite association between oral infection and systemic diseases. Though etiologies of periodontitis and rheumatoid arthritis (RA) are separate, their underlying pathological processes are sufficient to warrant consideration of hypothesis that individuals at risk of developing RA may also be at the risk of developing periodontitis and vice versa.
Materials and Methods:
To test their relationship, a study was carried out on 80 individuals. Part A: Forty subjects having rheumatoid arthritis (RA group) were compared to 40 controls without arthritis (NRA group). Their periodontal indices rheumatoid arthritis clinical laboratory parameters were also correlated with periodontitis in group. Part B: Omplete periodontal treatment was done for 10 patients of group suffering from periodontitis. All parameters of periodontal indices were measured pre-operatively and weeks after completion of periodontal treatment.
(1) There was high prevalence of mild (12.5%) to moderate (75%) periodontitis in group. (2) Extent severity of periodontal disease rheumatoid arthritis were positively correlated. (3) Statistically significant differences were present in periodontal parameters of RA group compared to NRA group. (4) There was statistically, significant reduction in parameters postoperatively with concomitant decrease in periodontal parameters in RA group.
Thus, an association exists between periodontal disease with an underlying dysregulation of the molecular pathways in the inflammatory response. Also, there are significant management implications in the future as new host modifying medications are developed.
Inflammation; periodontitis; relationship; rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that leads to joint damage, deformity, and pain. It affects approximately 1% of adults in developed countries. Periodontitis is a chronic oral infection, caused by inflammatory reactions to gram-negative anaerobic bacteria, and affecting about 35 to 50% of adults. If left untreated, periodontitis can lead to tooth loss. A significant association has been shown to exist between periodontitis and RA in observational studies. Some intervention studies have suggested that periodontal treatment can reduce serum inflammatory biomarkers such as C-reactive protein, or erythrocyte sedimentation rate. We hypothesize that periodontitis could be an aggravating factor in patients with RA, and that its treatment would improve RA outcomes. The aim of this clinical trial is to assess the effect of periodontal treatment on the biological and clinical parameters of patients with RA.
The ESPERA (Experimental Study of Periodontitis and Rheumatoid Arthritis) study is an open-label, randomized, controlled trial. Subjects with both RA and periodontitis will be recruited at two university hospitals in southwestern France. In total, 40 subjects will be randomized into two arms (intervention and control groups), and will be followed up for 3 months. Intervention will consist of full-mouth supra-gingival and sub-gingival non-surgical scaling and root planing, followed by systemic antibiotic therapy, local antiseptics, and oral hygiene instructions. After the 3-month follow-up period, the same intervention will be applied to the subjects randomized to the control group.
The primary outcome will be change of in Disease Activity Score in 28 Joints (DAS28) at the end of the follow-up period. Secondary outcomes will be the percentages of subjects with 20%, 50%, and 70% improvement in disease according to the American College of Rheumatology criteria. Health-related quality of life assessments (the Health Assessment Questionnaire and the Geriatric Oral Health Assessment Index) will also be compared between the two groups.
Evidence-based management of potential aggravating factors in subjects with active RA could be of clinical importance, yet there are few randomized controlled trials on the effect of periodontal treatment on the clinical parameters of RA. The ESPERA trial is designed to determine if non-surgical periodontal treatment could improve clinical outcomes in patients with active RA, and the quality of life of these patients.
The ESPERA Trial was registered in Current Controlled Trials [ISRCTN79186420] on 2012/03/20. The trial started recruiting on 2012/03/06.
Rheumatoid arthritis; Periodontal diseases; Periodontitis; Randomized controlled trial; Protocol
Current concept in periodontal diseases (PDs) states that it is the host's response toward the periodontal pathogens which leads to tissue destruction and attachment loss. Hence the role of immune response in the progression and resolution of PD must be considered vital. Any alteration in the immune system disturbs the homeostasis of the periodontium. Decline in immune system is the hallmark of aging, leading to increased susceptibility of elderly individuals to bacterial infections. The periodontal apparatus which is being constantly exposed to plaque biofilm is more vulnerable to destruction in aged individuals. Ageing related alterations in immune system has been discussed elsewhere as a contributor to various chronic inflammatory diseases like atherosclerosis, preterm, and low birth weight, etc. This paper reviews on the possible role of aging in periodontal destruction through altered immunity. Aging has long been associated with altered systemic inflammation. It has been discussed whether (1) this systemic inflammation is a consequence of increased occurrence of chronic inflammatory diseases upon aging or (2) aging associated systemic inflammation leads to such diseases. The immune responses which are protective at the first stages of life might result detrimental in the elderly. Hence it might be very difficult to individuate genetic profiles that might allow to identify individuals with a major risk for one or more age related diseases. Taking this into consideration, the cause of PDs in elderly is addressed with a systemic approach in order to understand the complex interplay between the aging immunity and PDs.
Aging; immunesenescence; immunity; inflammaging; periodontal diseases
Periodontal disease is characterized by both inflammation and bone loss. Advances in research in both these areas have led to a new appreciation of not only each field but also the intimate relationship between inflammation and bone loss. This relationship has resulted in a new field of science called osteoimmunology and provides a context for better understanding the pathogenesis of periodontal disease. In this review, we discuss several aspects of the immuno-inflammatory host response that ultimately results in loss of alveolar bone. A proposal is made that periodontal inflammation not only stimulates osteoclastogenesis but also interferes with the uncoupling of bone formation and bone resorption, consistent with a pathologic process. Furthermore, arguments based on experimental animal models suggest a critical role of the spatial and temporal aspects of inflammation in the periodontium. A review of these findings leads to a new paradigm to help explain more fully the impact of inflammation on alveolar bone in periodontal disease so that it includes the effects of inflammation on uncoupling of bone formation from resorption.
adaptive immunity; bone matrix; cytokine; innate immunity; IL-1; osteoblast; osteoclast; RANK ligand; TNF
Background and aim
Many risk factors that might contribute to the pathogenesis of atherosclerosis have been proposed, including chronic inflammation and infection. Furthermore, systemic inflammatory responses to periodontal bacteria have been suggested as a pathogenetic link between periodontal disease and atherosclerosis. The purpose of this study was to estimate the white blood cell (WBC) and platelet counts in chronic periodontitis patients.
Materials and methods
Fifty patients with chronic periodontitis and 50 patients with healthy periodontium were included in this study. Oral hygiene status, pocket probing depth (PPD) and clinical attachment level (CAL) were measured. During clinical evaluation, venous blood samples were taken to analyze the WBC and platelet counts. Statistical analysis was utilized to compare differences across groups.
Periodontitis patients demonstrated a significantly higher WBC count (7.22 ± 1.42 × 109 cells/L) than that of control patients (5.64 ± 1.56 × 109 cells/L; P < 0.001). The platelet count of patients with chronic periodontitis (290.73 ± 56.56 × 109 cells/L) was also significantly higher compared to the healthy group (223.37 ± 50.27 × 109 cells/L; P < 0.001).
Levels of WBCs and platelets are elevated in periodontitis patients compared to healthy controls.
WBC; RBC; Systematic disease; Thrombocyte; Periodontitis; Coronary heart disease; Oral conditions
Rheumatoid arthritis (RA) and periodontitis (PD) are common chronic inflammatory conditions. Recent studies have shown a beneficial effect of periodontal treatment on reducing the severity of active RA. This study was undertaken to further examine the effect of non-surgical periodontal treatment on signs and symptoms of RA in patients treated with or without anti-Tumor Necrosis Factor (TNF)-α medications. The effect of anti-TNF-α therapy on periodontitis also was assessed.
Forty participants diagnosed with moderate/severe RA (under treatment for RA) and severe periodontitis were randomly assigned to receive initial non-surgical periodontal therapy with scaling/root planing and oral hygiene instructions (n=20) or no periodontal therapy (n=20). To control RA, all participants had been using disease-modifying anti-rheumatic drugs (DMARDs), and 20 had been using anti-TNF-α in addition to DMARDs before randomization. Periodontal probing depth (PD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival (GI) and plaque (PI) indices, RA disease activity score (DAS-28) and erythrocyte sedimentation rate (ESR) were measured at baseline and six weeks afterwards. Linear mixed models were used to identify significant differences between subjects receiving periodontal treatment and those who did not.
Patients receiving periodontal treatment showed a significant decrease in the mean DAS28, ESR (p < 0.001) and serum TNF-α (p < 0.05). There was no statistically significant decrease in these parameters in those patients not receiving periodontal treatment. Anti- TNF-α therapy resulted in a significant improvement in CAL, PD, BOP and GI.
Non-surgical periodontal therapy had a beneficial effect on signs and symptoms of RA regardless of the medications used to treat this condition. Anti-TNF-α therapy without periodontal treatment has no significant effect on the periodontal condition.
Rheumatoid arthritis; Periodontitis; TNF-α therapy
An association between oral disease/periodontitis and rheumatoid arthritis (RA) has been considered since the early 1820s. The early treatment was tooth eradication. Epidemiological studies suggest that the prevalence of RA and periodontitis may be similar and about 5% of the population are aged 50 years or older. RA is considered as an autoimmune disease whereas periodontitis has an infectious etiology with a complex inflammatory response. Both diseases are chronic and may present with bursts of disease activity. Association studies have suggested odds ratios of having RA and periodontitis varying from 1.8:1 (95% CI: 1.0–3.2, NS) to 8:1 (95% CI: 2.9–22.1, p<0.001). Genetic factors are driving the host responses in both RA and periodontitis. Tumor necrosis factor-α, a proinflammatory cytokine, regulates a cascade of inflammatory events in both RA and periodontitis. Porphyromonas gingivalis is a common pathogen in periodontal infection. P. gingivalis has also been identified in synovial fluid. The specific abilities of P. gingivalis to citrullinate host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains can induce autoimmune responses in RA through development of anticyclic citrullinated peptide antibodies. In addition, P. gingivalis carries heat shock proteins (HSPs) that may also trigger autoimmune responses in subjects with RA. Data suggest that periodontal therapies combined with routine RA treatments further improve RA status.
Periodontal infection (P. gingivalis) carries a unique risk for development of autoimmune antibodies associated with RA. Patients with RA have either lost many teeth or usually have severe periodontitis. Additional research, both in regards to basic mechanisms as well as clinical studies, are necessary before it can be said that there are causative links between RA and periodontitis. Cross-disciplinary research in well-defined populations should be performed to further enhance knowledge and develop clinical strategies how to coordinate therapy and risk assessments of RA and periodontitis.
rheumatoid arthritis; periodontitis; bacteria; inflammation; Porphyromonas gingivalis; citrullination; genetics; review
Periodontitis, a prime cause of tooth loss in humans, is implicated in the increased risk of systemic diseases such as heart failure, stroke, and bacterial pneumonia. The mechanisms by which periodontitis and antibacterial immunity lead to alveolar bone and tooth loss are poorly understood. To study the human immune response to specific periodontal infections, we transplanted human peripheral blood lymphocytes (HuPBLs) from periodontitis patients into NOD/SCID mice. Oral challenge of HuPBL-NOD/SCID mice with Actinobacillus actinomycetemcomitans, a well-known Gram-negative anaerobic microorganism that causes human periodontitis, activates human CD4+ T cells in the periodontium and triggers local alveolar bone destruction. Human CD4+ T cells, but not CD8+ T cells or B cells, are identified as essential mediators of alveolar bone destruction. Stimulation of CD4+ T cells by A. actinomycetemcomitans induces production of osteoprotegerin ligand (OPG-L), a key modulator of osteoclastogenesis and osteoclast activation. In vivo inhibition of OPG-L function with the decoy receptor OPG diminishes alveolar bone destruction and reduces the number of periodontal osteoclasts after microbial challenge. These data imply that the molecular explanation for alveolar bone destruction observed in periodontal infections is mediated by microorganism-triggered induction of OPG-L expression on CD4+ T cells and the consequent activation of osteoclasts. Inhibition of OPG-L may thus have therapeutic value to prevent alveolar bone and/or tooth loss in human periodontitis.
This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 106:R59–R67 (2000).
Recently, it has been recognized that oral infection, especially periodontitis, may affect the course and pathogenesis of a number of systemic diseases, such as cardiovascular disease, bacterial pneumonia, diabetes mellitus, and low birth weight. The purpose of this review is to evaluate the current status of oral infections, especially periodontitis, as a causal factor for systemic diseases. Three mechanisms or pathways linking oral infections to secondary systemic effects have been proposed: (i) metastatic spread of infection from the oral cavity as a result of transient bacteremia, (ii) metastatic injury from the effects of circulating oral microbial toxins, and (iii) metastatic inflammation caused by immunological injury induced by oral microorganisms. Periodontitis as a major oral infection may affect the host's susceptibility to systemic disease in three ways: by shared risk factors; subgingival biofilms acting as reservoirs of gram-negative bacteria; and the periodontium acting as a reservoir of inflammatory mediators. Proposed evidence and mechanisms of the above odontogenic systemic diseases are given.
Cancer is marked by the uncontrolled growth of cells, tissue invasion and metastasis to various organs via the circulatory and lymphatic systems. Recent data have expanded the concept that inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. The tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival, and migration. Periodontal disease, a chronic inflammatory condition is characterized by an oral bacterial infection leading to inflammation within the supporting tissues of the teeth, which often leads to the destruction of the periodontal tissues and alveolar bone that support the teeth. This oral inflammation often has systemic effects leading to an increased concentration of circulating inflammatory markers with the severity of disease being correlated directly with levels of serum inflammatory markers. Periodontal infection has been linked to organ and systemic diseases. There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers, and periodontal disease. This articles reviews and summarizes the possible biological mechanisms involved between periodontal infection and cancer.
Cancer; periodontitis; plausible mechanisms
Diabetes mellitus is a systemic disease characterized by increased blood glucose levels and abnormalities of lipid metabolism due to absence or decreased level of insulin. It affects all the body organs and their functions either directly or indirectly. Every dentist should have a basic understanding of the etiopathogenesis, oral and systemic manifestations of this disease. The periodontal diseases are a consequence of extension of the gingival inflammation into the underlying supporting structures of the periodontium, initiated by the presence of plaque and its products on the surfaces of the teeth and the adjoining structures. The progression of periodontal disease is influenced by variety of factors like microorganisms, host response, systemic background, and genetic makeup of the host. Amongst them, diabetes mellitus tops the list. Diabetes and periodontitis influence the clinical outcome of each other and control of both influences the clinical improvement of each.
Diabetes mellitus; periodontitis; vascular changes
Rheumatoid arthritis (RA) and periodontal disease (PD) have shown similar physiopathologic mechanisms such as chronic inflammation with adjacent bone resorption in an immunogenetically susceptible host; however, PD has a well-recognized bacterial etiology while the cause of RA is unclear. Some reports have indicated that an infectious agent in a susceptible host could be one possible trigger factor for RA, and it has been suggested that oral microorganisms, specialty periodontal bacteria could be the infectious agent (mainly Porphyromonas gingivalis). It has been reported that PD is more frequent and more severe in patients with RA, suggesting a positive association between both diseases. There have been reports regarding the detection of antibodies against periodontal bacteria while other studies have identified periodontal bacterial DNA in serum and synovial fluid of RA patients and have explored the possible pathways of transport of periodontal bacterial DNA. In conclusion, there is no question that RA and PD have pathologic features in common and there is strong evidence of an association between both diseases, but further studies, including experimental models, are needed to demonstrate the arthritogenicity of oral microorganisms.
rheumatoid arthritis; periodontal disease; oral bacteria; bacterial DNA
The recent focus on the potential link between periodontal and cardiovascular disease (PD and CVD) is part of the larger renewed interest on the role of infection and inflammation in the etiology of atherosclerosis and its clinical manifestations. Periodontal Disease is an inflammatory process affecting the periodontium, the tissue that surrounds and supports the teeth. The process usually starts with an inflammatory process of the gum (gingivitis) but it may progress with an extensive involvement of the gum, as well as the periodontal ligament and the bone surrounding the teeth resulting in substantial bone loss. Periodontal disease is a common oral pathological condition in the adult age and represents the leading cause of tooth loss. PD prevalence increases with age and there are estimates that up to 49,000,000 Americans may suffer from some form of gum disease. The gingival plaque associated with PD is colonized by a number of gram-positive and gram-negative bacteria that have been shown to affect the initiation and development of PD and have been associated with the potential etiological role of PD in CVD and other chronic conditions. A potential etiological link between PD and CVD may have important public health implications as both the exposure (PD) and the outcomes (CVD) are highly prevalent in industrialized societies. In situations in which both the exposure and the outcome are highly prevalent even modest associations, like those observed in the studies reporting on the link between PD and CVD outcomes, may have relevance. There are not definite data on the effect of periodontal treatment on CVD clinical outcomes (either in primary or secondary prevention) however it should be pointed out that the limited (both in terms of numbers and study design) experimental evidence in humans suggests a possible beneficial effect of periodontal treatment of indices of functional and structural vascular health.
It is now well accepted that besides the cholesterol associated mechanisms of atherogenesis, inflammation plays a crucial role in all stages of the development of the atherosclerotic lesion. This “inflammation hypothesis” raises the possibility that, through systemic elevations of pro-inflammatory cytokines, periodontal diseases might also contribute to systemic inflammation and, therefore, to atherogenesis. In fact, there is evidence that periodontal diseases are associated with higher systemic levels of high-sensitivity C-reactive protein and a low grade systemic inflammation. This phenomenon has been explained based on mechanisms associated with either the infectious or the inflammatory nature of periodontal diseases. The purposes of this article are to review (1) the evidence suggesting a role for oral bacterial species, particularly periodontal pathogens, in atherogenesis; (2) the potential mechanisms explaining an etiological role for oral bacteria in atherosclerosis; (3) the evidence suggesting that periodontal infections are accompanied by a heightened state of systemic inflammation; (4) the potential sources of systemic inflammatory biomarkers associated with periodontal diseases; and (5) the effects of periodontal therapy on systemic inflammatory biomarkers and cardiovascular risk.
Cardiovascular disease; atherosclerosis; periodontal diseases; infection; periodontal pathogens; bacteremia; inflammatory response; systemic biomarkers; C-reactive protein
Understanding of the personal risks for rheumatoid arthritis (RA) and other rheumatic diseases remains poor, despite advances in knowledge of their pathogenesis, therapeutics, and clinical impact, in part because the personal lifetime risk of developing these diseases is unknown.
To estimate the lifetime risk of RA, as well as other inflammatory autoimmune rheumatic diseases, including systemic lupus erythematosus, psoriatic arthritis, polymyalgia rheumatica (PMR), giant cell arteritis, ankylosing spondylitis, and Sjögren’s syndrome, and to provide an overall estimate of the risk for developing inflammatory autoimmune rheumatic disease over a lifetime.
Using the incidence rates obtained from our population-based studies of rheumatic diseases among residents of Olmsted County, Minnesota, and mortality rates from life tables for the general population, we estimated sex-specific lifetime risk of rheumatic disease.
The lifetime risk of RA developing in US adults is 3.6% for women and 1.7% for men, and the lifetime risk of rheumatoid factor positive RA is 2.4% for women and 1.1% for men. The second most common inflammatory autoimmune rheumatic disease is PMR with a lifetime risk of 2.4% for women and 1.7% among men. The overall lifetime risk of inflammatory autoimmune rheumatic disease was 8.4% for women and 5.1% for men.
One in 12 women and 1 in 20 men will develop inflammatory autoimmune rheumatic disease during their lifetime. These results can serve as useful guides in counseling patients regarding their lifetime risk of these conditions and have important implications for disease awareness campaigns.
Angiogenesis is important in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes rheumatoid arthritis and systemic sclerosis. Rheumatoid arthritis is the rheumatic disease in which the role of angiogenesis has been studied most extensively. However, whereas rheumatoid arthritis is characterized by excessive angiogenesis, the situation is not as clear cut in other rheumatic diseases. For example, systemic sclerosis is characterized by reduced capillary density with insufficient angiogenic responses. Results with angiogenesis inhibitors are controversial, and there is – in parallel – a wide range of upregulated angiogenic factors such as vascular endothelial growth factor. Dysregulation of angiogenesis in systemic sclerosis is accompanied by other pathogenic processes, including fibrosis, autoimmunity and vasculopathy. Animal models with at least partial features of the vasculopathy observed in systemic sclerosis include wound healing models, graft versus host disease models and, in particular, the University of California at Davis line 200 chicken model of systemic sclerosis.
Although the complement system is centrally involved in host defense, its overactivation or deregulation (e.g., due to inherent host genetic defects or due to pathogen subversion) may excessively amplify inflammation and contribute to immunopathology. Periodontitis is an oral infection-driven chronic inflammatory disease which exerts a systemic impact on health. This paper reviews evidence linking complement to periodontal inflammation and pathogenesis. Clinical and histological observations show a correlation between periodontal inflammatory activity and local complement activation. Certain genetic polymorphisms or deficiencies in specific complement components appear to predispose to increased susceptibility to periodontitis. Animal model studies and in vitro experiments indicate that periodontal bacteria can either inhibit or activate distinct components of the complement cascade. Porphyromonas gingivalis, a keystone species in periodontitis, subverts complement receptor 3 and C5a anaphylatoxin receptor signaling in ways that promote its adaptive fitness in the presence of non-productive inflammation. Overall, available evidence suggests that complement activation or subversion contributes to periodontal pathogenesis, although not all complement pathways or functions are necessarily destructive. Effective complement-targeted therapeutic intervention in periodontitis would require determining the precise roles of the various inductive or effector complement pathways. This information is essential as it may reveal which specific pathways need to be blocked to counteract microbial evasion and inflammatory pathology or, conversely, be enhanced to promote host immunity.
Background and objective
Young mice do not develop measurable periodontal bone loss, unless heavily infected with human periodontal pathogens. However, mice with genetically altered immune system are unable to control their own oral flora and develop periodontitis early in life. Based on the potential of the indigenous oral microbiota to cause periodontitis, we hypothesized that normal mice may ultimately develop inflammatory periodontal bone loss, i.e., as a function of age. If confirmed, this could serve as an aging model of chronic periodontitis.
Materials and methods
Periodontal bone levels were measured as the distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC), in young (8-10 weeks of age), old (≥ 18 months of age), and mice of intermediate ages. Differential expression of inflammatory mediators in the gingivae of young and old mice was determined by quantitative real-time PCR.
In comparison to young mice, old mice displayed significantly (p < 0.05) increased periodontal bone loss, accompanied by elevated expression of proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-17A) and innate immune receptors involved in the induction or amplification of inflammation (Toll-like receptor 2, CD14, CD11b, CD18, complement C5a receptor, and triggering receptor expressed on myeloid cells-3).
Mice develop naturally-induced periodontal bone loss as a function of age. This aging model of periodontitis represents a genuinely chronic model to study mechanisms of periodontal tissue destruction.
Animal model; Alveolar bone; Chronic periodontitis; Inflammation; Innate immunology
It has become clear in recent years that periodontitis is an inflammatory disease initiated by oral microbial biofilm. This distinction implies that it is the host response to the biofilm that destroys the periodontium in the pathogenesis of the disease. As our understanding of pathways of inflammation has matured, a better understanding of the molecular basis of resolution of inflammation has emerged. Resolution of inflammation is an active, agonist-mediated, well-orchestrated return of tissue homeostasis. There is an important distinction between anti-inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution is biologic pathways restoring homeostasis. A growing body of research suggests that chronic inflammatory periodontal disease involves a failure of resolution pathways to restore homeostasis. This article reviews the resolution of inflammation in the context of periodontal disease and the potential for the modification of resolution pathways for the prevention and treatment of periodontal diseases. Proof-of-concept studies in the 1980s demonstrated that pharmacologic anti-inflammation prevented and slowed the progression of periodontal diseases in animals and man. However, the side-effect profile of such therapies precluded the use of non-steroidal anti-inflammatory drugs or other enzyme inhibitors or receptor antagonists in periodontal therapy. The isolation and characterization of resolving agonist molecules has opened a new area of research using endogenous lipid mediators of resolution as potential therapeutic agents for the management of inflammatory periodontitis. Work in animal models of periodontitis has revealed the potential of this therapeutic approach for its prevention and treatment and forced the reconsideration of our understanding of the pathogenesis of human periodontal diseases.
Anti-inflammatory; lipoxins; Porphyromonas gingivalis; periodontal disease; resolvin E1
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which the progressive destruction of joint causes morbidity. It is also associated with an increased risk of atherosclerosis, which can result in cardiovascular disease and mortality. The therapeutic goal is to control the systemic inflammation to obtain not only the remission of symptoms, but also improve general state of health. Although recent biologic immunosuppressive therapies targeting pro-inflammatory cytokines have spawned a paradigm shift regarding the prognosis of RA, these therapies possess inherent side effects. Also, early diagnosis of the disease remains confounded by uncertainty. While the mechanisms responsible for the onset of RA remain unclear, reactive oxygen species (ROS) play a significant role in the pathogenesis of RA. ROS play a central role both upstream and downstream of NF-κB and TNFα pathways, which are located at the center of the inflammatory response. Among the ROS, the hydroxyl radical is the most harmful, and molecular hydrogen (H2) is a selective scavenger for this species. Recently, it has been shown that H2 is useful when administered along with the conventional therapy in RA as it acts to reduce oxidative stress in the patients. Especially in the early stage, H2 showed significant therapeutic potential, which also seemed to assist diagnosis and treatment decisions of RA. The possible expectations regarding the potential benefits of H2 by reducing the oxidative stress, resulting from inflammatory factors, are raised and discussed here. They include prevention of RA and related atherosclerosis, as well as therapeutic validity for RA
Rheumatoid; atherosclerosis; prevention; Oxidative Stress; 5 ppm; Molecular Hydrogen; 8-hydroxylguanine; Hydroxyl Radical.
Periodontitis is a common human chronic inflammatory disease that results in the destruction of the tooth attachment apparatus and tooth loss. Although infections with periopathogenic bacteria such as Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) are essential for inducing periodontitis, the nature and magnitude of the disease is determined by the host's immune response. Here, we investigate the role played by the NK killer receptor NKp46 (NCR1 in mice), in the pathogenesis of periodontitis. Using an oral infection periodontitis model we demonstrate that following F. nucleatum infection no alveolar bone loss is observed in mice deficient for NCR1 expression, whereas around 20% bone loss is observed in wild type mice and in mice infected with P. gingivalis. By using subcutaneous chambers inoculated with F. nucleatum we demonstrate that immune cells, including NK cells, rapidly accumulate in the chambers and that this leads to a fast and transient, NCR1-dependant TNF-α secretion. We further show that both the mouse NCR1 and the human NKp46 bind directly to F. nucleatum and we demonstrate that this binding is sensitive to heat, to proteinase K and to pronase treatments. Finally, we show in vitro that the interaction of NK cells with F. nucleatum leads to an NCR1-dependent secretion of TNF-α. Thus, the present study provides the first evidence that NCR1 and NKp46 directly recognize a periodontal pathogen and that this interaction influences the outcome of F. nucleatum-mediated periodontitis.
Periodontal disease is a common bacterial-induced inflammatory process in which F. nucleatum and P. gingivalis infections lead to the destruction of the teeth supporting attachment apparatus. Previous reports demonstrated that immune cells aggravate the severity of the disease. However, whether NK cells in general and NKp46 (a major killer receptor expressed by NK cells) in particular, play a protective or destructive role in this disease is unknown. Using mice deficient in NCR1 (the mouse orthlogue of NKp46), we demonstrate that oral infection of mice with F. nucleatum, but not with P. gingivalis results in an NCR1-dependent alveolar bone loss. In addition, we show that F. nucleatum is recognized by NCR1 and NKp46 directly and that this recognition leads to the secretion of TNF-α, a central cytokine critically involved in the pathogenesis of periodontal destruction. Collectively, we show that NCR1 and NKp46 play a critical role in the pathogenesis of F. nucleatum-mediated periodontitis.
In periodontal disease, host recognition of bacterial constituents, including lipopolysaccharide (LPS), induces p38 MAPK activation and subsequent inflammatory cytokine expression, favoring osteoclastogenesis and increased net bone resorption in the local periodontal environment. In this paper, we discuss evidence that the p38/MAPK-activated protein kinase-2 (MK2) signaling axis is needed for periodontal disease progression: an orally administered p38α inhibitor reduced the progression of experimental periodontal bone loss by reducing inflammation and cytokine expression. Subsequently, the significance of p38 signaling was confirmed with RNA interference to attenuate MK2-reduced cytokine expression and LPS-induced alveolar bone loss. MAPK phosphatase-1 (MKP-1), a negative regulator of MAPK activation, was also critical for periodontal disease progression. In MPK-1-deficient mice, p38-sustained activation increased osteoclast formation and bone loss, whereas MKP-1 overexpression dampened p38 signaling and subsequent cytokine expression. Finally, overexpression of the p38/MK2 target RNA-binding tristetraprolin (TTP) decreased mRNA stability of key inflammatory cytokines at the posttranscriptional level, thereby protecting against periodontal inflammation. Collectively, these studies highlight the importance of p38 MAPK signaling in immune cytokine production and periodontal disease progression.
The association between rheumatoid arthritis (RA) and periodontitis is suggested to be linked to the periodontal pathogen Porphyromonas gingivalis. Colonization of P. gingivalis in the oral cavity of RA patients has been scarcely considered. To further explore whether the association between periodontitis and RA is dependent on P. gingivalis, we compared host immune responses in RA patients with and without periodontitis in relation to presence of cultivable P. gingivalis in subgingival plaque.
In 95 RA patients, the periodontal condition was examined using the Dutch Periodontal Screening Index for treatment needs. Subgingival plaque samples were tested for presence of P. gingivalis by anaerobic culture technique. IgA, IgG and IgM antibody titers to P. gingivalis were measured by ELISA. Serum and subgingival plaque measures were compared to a matched control group of non-RA subjects.
A higher prevalence of severe periodontitis was observed in RA patients in comparison to matched non-RA controls (27% versus 12%, p < 0.001). RA patients with severe periodontitis had higher DAS28 scores than RA patients with no or moderate periodontitis (p < 0.001), while no differences were seen in IgM-RF or ACPA reactivity. Furthermore, RA patients with severe periodontitis had higher IgG- and IgM-anti P. gingivalis titers than non-RA controls with severe periodontitis (p < 0.01 resp. p < 0.05), although subgingival occurrence of P. gingivalis was not different.
Severity of periodontitis is related to severity of RA. RA patients with severe periodontitis have a more robust antibody response against P. gingivalis than non-RA controls, but not all RA patients have cultivable P. gingivalis.
Rheumatoid arthritis (RA) is a chronic multi-systemic disease that causes damage to the bone and connective tissues. This study was conducted in order to accurately measure the correlation between RA and periodontitis, and to obtain an unbiased estimate of the effect of RA on periodontal indices.
In this historical cohort study, which was conducted from February to May 2011 in Hamadan city, Iran, 53 exposed people (with RA) were compared with 53 unexposed people (without RA) in terms of clinical periodontal indices (the outcomes of interest) including 1) plaque index (PI), 2) bleeding on probing (BOP), and 3) clinical attachment loss (CAL).
A sample of 106 volunteers were evaluated, 53 rheumatoid versus 53 non-rheumatoid subjects. There was a statistically significant correlation between RA and BOP (P<0.001) and between RA and CAL (P<0.001). However, there was no statistically significant correlation between RA and any of the periodontal indices. No correlation was seen between gender and any of the indices either. There was a strong positive correlation between age and all three periodontal indices (P<0.001).
The present study indicated a potential effect of RA on periodontal indices. However, much more evidence based on a prospective cohort study is needed to support the cause and effect relationship between RA and periodontal indices.
Rheumatoid arthritis; Periodontitis; Periodontal index; Iran