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Research during the last decade has produced mounting support for a link between patients’ oral health status and overall systemic health. In particular, a number of prevalent and progressive chronic diseases, including diabetes mellitus, inflammatory bowel disease, cardiovascular disease, and rheumatoid arthritis, appear to be epidemiologically associated with the presence of periodontal disease (PD).1-5 However, despite this wealth of epidemiologic evidence, the biologic basis for these associations remains uncertain.
In this article, the authors address the question of how PD and rheumatoid arthritis (RA) might be related. Because informative reviews have recently been published on this topic,1,6 this article focuses specifically on immunologic mechanisms that potentially underlie this association. Ultimately, an understanding of these mechanisms may lead to effective new therapies for both disorders.
How Are Periodontal Disease and Rheumatoid Arthritis Associated?
PD is one of the most common chronic inflammatory disorders in humans1,7 and caused by gram-negative anaerobic bacteria that occupy the tooth-associated biofilm or microbial plaque in subgingival sites. The clinical spectrum is wide and ranges from mild gingivitis to progressive destructive periodontitis.8 Its reported prevalence in adult populations also is extensive, ranging from 8% to 60%. The World Health Organization reports 15% of adults worldwide have advanced PD (defined as a pocket depth of 6 mm or more).7,9
While bacteria are the primary etiologic agents for periodontitis, the tissue damage and progression associated with this chronic inflammatory process are dependent on complex cellular and molecular networks within the host, many of which are now known to be genetically regulated. Networks regulating innate and acquired immunity, inflammation, wound healing, and calcified tissue turnover all play a role in the pathogenesis and ultimate outcome of this disease. Recent insights suggest the up-regulation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which are primarily products of innate immune cells such as macrophages and neutrophils, play a key role in the chronic inflammatory lesion. These cytokines stimulate and activate resident fibroblasts in the periodontal tissues to produce matrix metalloproteinase (MMP) and other proteases, which degrade the surrounding connective tissue. These cytokines also are potent stimulators of local osteoclastogenesis, which leads to efficient degradation of adjacent calcified tissue in the teeth.10
RA is a chronic inflammatory arthritis affecting 1% of the North American population. RA involves the synovial membrane of multiple joints in the body. Although the early events in RA are not well understood, it is now known that the onset of clinically detectable disease in the joints is preceded by a variable period of “benign autoimmunity,” a period in which RA autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), are detectable in the serum.11,12 At some point, triggered by heretofore undefined environmental factors, the synovial membrane of one or more joints becomes inflamed. Whether the RA autoantibodies preceding joint disease actually play a role in triggering the synovial inflammation is a question that continues to be investigated. The reasons the immune/inflammatory response specifically targets the synovial membranes are also unclear. Over time, particularly if initiation of effective therapy is delayed, the inflammatory process becomes chronic and leads to the activation and proliferation of the synovial tissue in a process called pannus formation (Figure 1). As with the chronic inflammation of periodontitis, TNF-α, IL-1β, and other key proinflammatory cytokines play a key role in the activation, proliferation, and destructiveness of the synovial pannus.13 The proliferative pannus tissue attaches to the adjacent cartilage and bone, invading the connective tissue with mechanisms that are similar to those a tumor uses to invade tissue. The invasion and degradation of cartilage is mediated by matrix-degrading proteases, such as MMP.
Osteoclastogenesis is also a key destructive process in which osteoclast precursors found in the synovial membrane and the adjacent bone marrow are stimulated to form mature osteoclasts that “erode” adjacent periarticular bone. Ultimately, if the synovitis is not effectively controlled, this process completely destroys the articular cartilage and periarticular bone, causing severe deformity and functional loss (Figure 2). Untreated RA also is associated with a higher prevalence of cardiovascular disease. Although the joints are the primary site of the inflammatory process, the inflammation in RA can involve other organs, such as the skin, lungs, eyes, and salivary glands.
Unlike periodontitis, in which a bacterial etiology is well defined, a single specific etiology for RA has not been determined, despite extensive investigation during the past half century. The accepted model involves one or more environmental factors acting on a predisposing genetic background. For the past two decades, considerable progress has been made in understanding the genetic risk and environmental factors that might interact with it. This understanding is beginning to provide important insights that ultimately may lead to preventive strategies.
The major genetic risk for RA is now well known to reside in the human leukocyte antigen (HLA) locus, which is a cluster of genes that serves to shape adaptive immune responses mediated by T cells. In RA, the strongest association is with the major histocompatibility complex, class II, DRβ1 (HLA-DRβ1) gene. This highly polymorphic gene encodes for a cell surface molecule expressed prominently on antigen presenting cells, such as dendritic cells, macrophages, and B cells. This molecule mediates peptide antigen presentation to T cells, thus activating them to respond to these antigens. Several variants of HLA-DRβ1 have been shown to be associated with RA.14-16 Intriguingly, the same variants also are associated with periodontitis.17,18 The association resides in a key segment of five key amino acids situated in the side wall of the HLA-DRβ1 molecule (Figure 3). This sequence has been named the shared epitope (SE), and disease susceptibility requires the presence of the positively charged amino acids arginine or lysine in position 71 of the HLA-DRβ1 molecule. This positively charged motif appears to facilitate the presentation of peptides containing the amino acid citrulline to T cells.18-23 The amino acid citrulline is generated by an enzymatic modification of the amino acid arginine by a family of enzymes called peptidylarginine deiminase (PADs). Citrullination plays a physiologic role in the regulation of protein folding and degradation and is prominently involved in processes such as cornification of the skin. Thus the generation of citrullinated peptides is certainly not unique to RA, but the development of antibody responses to citrullinated peptides is quite specific to RA. These are the ACPA autoantibodies; their specificity for RA has been demonstrated in multiple studies in populations worldwide.24,25 The demonstration that the disease predisposing SE encoding alleles serve to facilitate the presentation of citrullinated peptides to T cells and, in turn, promote the generation of ACPA has been a major step forward in the understanding of RA pathogenesis and the genetic basis for this disease.17,18 Indeed, several studies have shown a close association between carriage of SE alleles and the presence of ACPA in patients with RA.26 In even more exciting recent developments, studies of banked serum from individuals who subsequently developed RA have shown the presence of ACPA in combination with carriage of SE alleles imparted a 66-fold increased risk for future disease development.27 These studies have provided an important impetus for achieving a better understanding of the preclinical “benign autoimmunity” stage of the disease, in which environmental factors may stimulate the development of ACPA or the amplification of these autoantibodies, which ultimately leads to the development of RA.
It has recently been hypothesized that one such environmental factor that could potentially play a role in breaking tolerance to citrullinated autoantigens, in a genetically susceptible host, is porphymonas gingivalis, a gram-negative anaerobic rod, one of the major pathogens associated with periodontal disease.5,17 P gingivalis is the only pathogen known to express the PAD enzyme and is capable of citrullinating terminal arginine residues on peptides.18 Thus, it is possible that the presence of this bacterium in chronically inflamed periodontal tissue may lead to the local generation of citrullinated peptides. In such a chronic inflammatory oral lesion, presentation of citrullinated antigens to T cells by local antigen presenting cells would be facilitated by a microenvironment rich in proinflammatory cytokines, such as TNF-α and IL-1β, which serve to stimulate and accelerate this process. In turn, through a process of molecular mimicry, the immune response would be directed toward other homologous citrullinated human autoantigens and become progressively amplified and evolved. A study showed one such candidate antigen is the ubiquitous enzyme enolase, the citrullinated form of which has been identified as an autoantigen in RA.28 Moreover, the same group of researchers has shown the human enzyme and the bacterial enzyme have striking homology in the immunodominant epitopes recognized by the immune system. These studies provide a conceptual framework around which chronic periodontitis, caused by P gingivalis, could be involved in the initiation of the autoimmune processes that precede the onset of RA.
Clinical Evidence for an Association between RA and PD
Several clinical studies have shown an association between RA and periodontal disease.5 The largest of these studies examined data from the Third National Health and Nutrition Examination Survey (NHANES III). This is a nationally representative cross-sectional survey of the noninstitutionalized civilian US population, which includes home interviews and medical and dental examinations performed by physicians and dentists, respectively, in a mobile examination center. In total, 4461 individuals had both detailed musculoskeletal and comprehensive dental examinations.
Investigators found 103 individuals with RA, as defined by American College of Rheumatology classification criteria, and 658 people with PD. Those with RA had a higher rate of periodontitis (odds ratio [OR] 4.13) than people without RA, independent of age, race/ethnicity, sex, and smoking. Interestingly, RA was associated with an almost 2-fold increase in the odds of PD, particularly strong for those with seropositive RA.
Why is PD higher in patients with RA? Both diseases share common risk factors, such as age and smoking. Patients with RA might be less likely to obtain dental care. However, in the previously noted study population, there was no difference in the frequency of dental care among people with periodontitis and those without periodontitis (among dentate participants with RA).
Temporomandibular joint involvement, severe hand dysfunction (caused by arthritis), decreased saliva from secondary Sjögren’s syndrome, and the use of chronic corticosteroids all impact oral health of patients with RA. Indeed, the NHANES III study also showed a significantly higher rate of tooth loss in patients with RA, only some of which is explained by periodontitis.
Smoking is strongly associated with PD.6,15,29-32 Smoking also increases the risk of developing RA and acts with genetic factors to strongly increase the likelihood. The risk of developing RA for people who smoke compared with those who do not ranges from OR 1.7 to 2.4 when smoking alone is studied. Epidemiologic studies from Sweden suggest those who smoked and had two copies of the HLA SE had a 16-fold increased risk compared with people who are SE-negative and do not smoke. This association is limited to patients with RA who are seropositive for ACPA.30
Studies of RA in Indigenous North American Native Populations
The North American Native (NAN) population offers a unique perspective from which to study the development of RA and its association with PD. RA has been documented in multiple pre-Columbian North American populations and may have originated in these individuals.33 Prevalence rates for RA in the NAN population vary from 2.2% to 5%, which is significantly higher than what is reported in Caucasians. The NAN population has a high prevalence of SE; in the authors’ Canadian cohort of First Nations People, rates of smoking were twice that of the general Canadian population. Rates of PD were increased in Pima Indians, a population with a high prevalence of RA.24 The rate of periodontitis in many Canadian communities has not been reported; however, early childhood caries and poor overall oral health are major problems in several First Nation communities.34-36
Investigators at the University of Manitoba have collected much data from a large cohort of NAN patients with RA, as well as information about their unaffected first-degree relatives (FDRs). Given a shared genetic and environmental background, which includes high rates of smoking, it is expected that a small but significant proportion of FDR will develop RA. Subsequently, this can provide unique insight into the pathogenesis of RA and its relation to periodontitis.
Using this Cree and Ojibway population, the authors of this article have measured rheumatoid factor (RF), ACPA, and immunoglobulin G (IgG) antibody responses to P gingivalis lipopolysaccharide in FDRs and patients with RA. RF and ACPA were each present in 15% to 20% of unaffected FDRs, suggesting a subpopulation at higher risk for developing RA.37 Interestingly, only 5% of the FDRs were positive for both RF and ACPA, suggesting these potentially predisposing autoantibodies may develop because of separate processes. NAN with established RA tended toward higher levels of anti-P gingivalis antibodies than the unaffected FDRs. More importantly, in unaffected FDRs, the anti-P gingivalis levels were significantly higher in ACPA-positive than in ACPA-negative individuals.38 In contrast, no clear association was noted between the presence of RF and exposure to P gingivalis in FDRs. RF autoantibody was associated with immune responses to Proteus mirabilis and Escherichia coli.39
In a proposed model based on these observations (Figure 4), PD is an important, potentially modifiable risk factor for the development of RA. To further explore this hypothesis, a community-wide screening of unaffected NAN population is underway. That research is assessing the presence of significant PD, non-HLA genetic predispositions, and the association of RA autoantigens. Long-term follow-up of these individuals will allow for detection of RA at disease-onset and may help clarify the potential role of PD in the development of RA.
RA and PD share many similarities in their pathogenesis. The chronic inflammatory lesion that characterizes both of these disorders leads to strikingly similar consequences to the surrounding calcified and soft tissues. The clinical association between these two disorders, now demonstrated in several populations, is complex and may relate to a number of biologic factors, particularly shared genetic risk. An emerging understanding of the preclinical immune mechanisms that are involved in the development of the autoimmunity that leads to RA may be pointing toward the oral cavity as a major battleground. If PD proves to be a key element in breaking immune tolerance to citrullinated antigens, this offers important opportunities for intervention, both in terms of dental procedures and tolerance-inducing immunologic manipulations. These interventions ultimately may lead to the prevention of RA in susceptible individuals.
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About the Authors
Irene Smolik, PhD, Research Associate, Division of Rheumatology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
David Robinson, MDAssociate Professor of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Hani S. El-Gabalawy, MD, Professor of Medicine and Immunology, University of Manitoba, Winnipeg, Manitoba, Canada