Review objective: The objective of this systematic review is to identify and synthesise the best available evidence to examine whether periodontal disease is a risk factor for rheumatoid arthritis.
Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology and has a complex multifactorial pathogenesis affecting joints and other tissues. The natural history of rheumatoid arthritis is poorly defined; its clinical course fluctuates and the prognosis unpredictable. Rheumatoid arthritis affects up to 1-3% of the population, with a 3:1 female preponderance disappearing in older age. There is also evidence of a genetic predisposition to the disease. Rheumatoid arthritis is characterised by progressive and irreversible damage of the synovial-lined joints causing loss of joint space, bone and function, leading to deformity. Extracellular matrix degradation is a hallmark of rheumatoid arthritis which is responsible for the typical destruction of cartilage, ligaments, tendons, and bone.Rheumatoid arthritis is characteristically a symmetric arthritis (symmetrical swelling of the joints). Articular and periarticular manifestations include joint swelling and tenderness to palpation, with morning stiffness and severe motion impairment in the involved joints. Extra-articular signs can involve pulmonary, cardiovascular, nervous, and reticuloendothelial systems. The clinical presentation of rheumatoid arthritis rheumatoid arthritis varies, but an insidious onset of pain with symmetric swelling of the small joints is the most frequent finding. Rheumatoid arthritis onset is acute or subacute in about 25% of patients. Early rheumatoid arthritis is characterised by symmetric polyarthritis involving the small joints of the hands and feet with no radiologic changes. Rheumatoid arthritis most frequently affects the metacarpophalangeal, proximal interphalangeal and wrist joints. Although any joint, including the cricoarytenoid joint, can be affected, the distal interphalangeal, the sacroiliac and the lumbar spine joints are rarely involved, which is peculiar because these are some of the most typical targets of seronegative spondylarthropathies, such as psoriatic arthritis and ankylosing spondylitis. The clinical manifestations of rheumatoid arthritis vary, depending on the involved joints and the disease stage. The clinical features of synovitis are particularly apparent in the morning. Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement is a typical sign of rheumatoid arthritis. It is a subjective sign and the patient needs to be carefully informed as to the difference between pain and stiffness. Morning stiffness duration is related to disease activity. Progression of rheumatoid arthritis can be measured by laboratory tests and clinical evaluation (questionnaires of disease activity and physical examination). Laboratory tests include blood tests for Rheumatoid factor (RF) and Acute-phase reaction tests while clinical evaluation can be measured by the Disease activity using the Disease Activity Score (DAS). Periodontitis is a destructive inflammatory disease of the dental supporting tissues which leads to erosion of bone around teeth resulting in tooth loss. Severe periodontitis affects about 5-15% of the adult population. In periodontitis, the clinical findings of bone resorption and loss of clinical attachment level around tooth are a result of inflammatory mediated alterations to the bone remodelling balance. The inflammatory infiltrate present between the plaque biofilm, bone and connective tissues regulate the host immune response to the bacteria. The host produces proteases and substances that degrade the extracellular matrix, and lead to resorption of the alveolar bone, resulting in irreversible loss of tissue attachment.Bone is a dynamic tissue and bone homeostasis involves the opposing events of resorption and apposition; dissolution of the existing bone mineral, resorption of the extracellular matrix, and formation of a new matrix. Bone homeostasis mechanisms maintain bone integrity in the alveolar bone (regulates periodontal bone loss) and, elsewhere in the body. It also functions to regulate the calcium balance within the body; this is an important ion as it is involved in the clotting of blood, formation of glandular secretions and regulation of the cardiac pacemaker.Rheumatoid arthritis and periodontitis are arguably the most prevalent chronic inflammatory diseases in humans and associated with significant morbidities. rheumatoid arthritis and periodontitis share similar clinical and pathogenic characteristics. Both rheumatoid arthritis and periodontitis present an imbalance between pro-inflammatory and anti-inflammatory cytokines, which is thought to be responsible for the tissue damage. In this sense, both conditions are associated with destruction of bone, mediated by inflammatory cytokines such as interleukin-1, tumour necrosis factor and prostaglandin E2.Several studies have suggested a relationship between periodontitis and rheumatoid arthritis; rheumatoid arthritis may have a negative impact on periodontal condition and vice versa. Mercado et al. in 2001 reported a significantly high prevalence of moderate to severe periodontitis in individuals with rheumatoid arthritis. In addition, the converse is true: periodontitis patients have a higher prevalence of rheumatoid arthritis compared to the general population. One study found that induction of experimental arthritis in rats resulted in periodontal destruction and increased cytokines and matrix metalloproteinases in the periodontal tissues.Oral bacterial DNA (deoxyribonucleic acids) is detected in serum and synovial fluid of patients with rheumatoid arthritis. Patients with rheumatoid arthritis also have a significantly higher level of immunoglobulin G antibody against P. gingivalis, Prevotella intermedia, and Tannerella forsythia. Furthermore, two recent clinical trials suggested that the treatment of periodontal disease might have a significant impact on rheumatoid arthritis severity. Similarly, subjects with rheumatoid arthritis have significantly increased periodontal attachment loss.In a recent research article, Ogrendik et al. in 2009 concluded that antibodies formed against these oral bacteria could be important to the aetiopathogenesis of rheumatoid arthritis. They recommended that gingival tissue infections should be considered in rheumatoid arthritis pathogenesis and that periodontal infections should be treated and prevented from becoming chronic. If successful results are observed against periodontal infections in clinical, radiologic, and laboratory data of the rheumatoid arthritis patients, the essential role of these bacteria in the aetiology of rheumatoid arthritis can be proven. One hypothesis that links rheumatoid arthritis and periodontitis is the recently published "two-hit" model that attempts to link experimental evidence from animal models and is supported by evidence from human clinical studies. In this theory, the first "hit" involves the periodontopathic subgingival biofilm and its microbial products, such as endotoxin. The second "hit" involves a medical systemic disease, such as rheumatoid arthritis, which increases biomarkers of systemic inflammation in the circulation, including C reactive protein (CRP), cytokines (e.g. IL-6), prostanoids (e.g. PGE2), and matrix metalloproteinases (e.g. MMP-9), and tumour necrosis factor alpha (TNF- α). These cytokines are thought to stimulate resident cells in the synovium and the periodontium to produce MMPs mediating connective tissue destruction, and induce the differentiation and activity of osteoclasts to destroy bone In particular, TNF-α, also promotes bone resorption: (i) by up-regulating inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO); and (ii) by modulating the receptor activator of nuclear factor _B (NF_B) ligand (RANKL) in osteoblasts, and its antagonist osteoprotegerin (OPG), thus altering the RANKL/OPG ratio, which enhances osteoclast activity, and finally, lead to periodontal breakdown. Most recently Bartold et al, reported a series of experiments to examine the plausibility of the "two hit" theory investigated whether the onset and severity of experimental arthritis in a rodent model was influenced by the presence of a pre-existing extra-synovial chronic inflammatory reaction to P. gingivalis. They discovered that severe arthritis developed more rapidly in animals with a pre-existing P. gingivalis induced inflammatory lesion, thus providing further evidence for a relationship between the presence of periodontal pathogen-associated inflammation and the development of rheumatoid arthritis. Aggressive periodontitis is rapid progression of periodontal disease with severe periodontal breakdown. The amount and pattern of periodontal destruction is very aggressive indicating there may be other characteristics in addition that contribute to its rate of destruction, and hence is outside of the scope of this review.Before undertaking this review, the JBI Library of Systematic Reviews, Cochrane Library of Systematic Reviews, Medline and CINAHL were searched. As no systematic review has been identified as been either published or underway on this topic, the aim of this systematic review is to identify and synthesise the best available evidence of periodontal disease as a risk factor for rheumatoid arthritis.