INTRODUCTION

Pathogenesis

Clinical Parameters

Arthritis is a common disease in the general population, and women are more often affected. Rheumatoid arthritis is a chronic polyarthritis including synovial inflammation, pain, swelling, tenderness, synovium hypertrophy, and excess joint synovial fluid. Joint destruction is due to the degradation of tissues, ligaments, tendons, and capsules. The serum of rheumatoid arthritis patients generally contains rheumatoid factors, which are autoantibodies. The presence of high rheumatoid factor titers is the sign of an aggressive rheumatic disease and the presence of extra-articular manifestations. Serum anticitrullinated peptide autoantibodies (ACPA) are more specific of rheumatoid arthritis, but less sensitive than rheumatoid factors. Serum acute-phase reactants such as erythrocyte sedimentation rate, C-reactive protein, and fibrinogen are generally elevated because of systemic inflammation. Magnetic resonance imaging and radiographs generally show the articular cartilage degradation, bone erosions, and juxta-articular bone loss. Disease severity is characterized by:

• the number of swollen joints,
• high erythrocyte sedimentation rate,
• high titer rheumatoid factors,
• bone erosions, and
• phenotype HLA DRB1*0401 and HLA DRB1*0404.

Medical therapy generally includes prescription of analge­sics, nonsteroidal anti-inflammatory drugs, corticosteroids, disease-modifying antitheumatic drugs (DMARDS).

Chronic Inflammation

Autoimmune diseases are mediated by the humoral immune response with the action of B lymphocytes, by immune cell–mediated response with T lymphocytes and monocytes, and phagocytosis with macrophages and leukocytes.

Immune response to pathogens is composed of lymphocytes T and B, macrophages, natural killer cells, neutrophils, eosinophils, and basophils. There are many phases in the immune response:

• migration of leukocytes to antigens
• recognition of pathogens by macrophages
• recognition of antigens by lymphocytes T and B
• amplification of response by effector cells
• destruction of antigens by phagocytosis or cytotoxicity.

An infectious microorganism can be the cause of a chronic inflammatory arthritis. Many mechanisms may explain this phenomenon, such as persistent or chronic infection and pathologic immune cross-reactions between microbial antigens and some joint molecules. An altered immune response can be produced against a persistent microbial antigen such as Chlamydia, a modified autoantigen such as filaggrin, and an immunoglobulin or a heat shock protein. Joints are infiltrated by a majority of T lymphocytes CD4⁺ and B lymphocytes with antibody-producing plasma cells. Synovial fibroblasts produce destructive enzymes such as collagenases and cathepsins. CD4⁺ lymphocytes induce the production of interferon gamma, and macrophages produce cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). Cytokines are responsible for regulation and activation of the immune system and inflammatory response. There are many categories of cytokines: IL-2, interferon, IL-10, IL-1α, IL-1β, IL-18, IL-17, chemokines, and IL-8. There is an increased migration of leukocytes in synovial tissues with production of reactive oxygen species and cytokines. IL-1 and TNF-α induce the production of collagenases and the activation of osteoclasts, which are the bone-resorbing cells.

Major Histocompatibility Complex

The major histocompatibility complex is composed of HLA class I and class II genes; they play a certain role in many autoimmune diseases. Class II major histocompatibility allele HLA-DR4 is a genetic risk factor for rheumatoid arthritis, and related alleles HLA-DRB1*0401 and HLA-DRB1*0404 are associated with a greater disease risk. HLA molecules play a role in T lymphocyte activation. They bind antigenic peptides and present them to T lymphocytes to induce an immune response. Class I genes are composed of different alleles: HLA-A, HLA-B, and HLA-C. Class II genes are composed of different regions: HLA-DR, HLA-DQ, and HLA-DP. Resistance to pathogens is based on differences of HLA genotype; certain HLA alleles are associated with autoimmune diseases (Kasper et al. 2008).

Class I alleles HLA-B27 are associated with spondyloarthropathies, HLA-Cw6 with psoriasis, and class II alleles HLA-DRB1 locus and HLA-DPB1 locus are associated with juvenile idiopathic arthritis. HLA-DRB1*0401 and HLA-DRB1*0404 genes are associated with rheumatoid arthritis. These genes encode a distinctive sequence of DRB molecule called the shared epitope, which is a disease severity risk factor.

HLA DR4 antigens are associated with both periodontitis and rheumatoid arthritis (Fauci et al. 2008).

Periodontitis and Arthritis

Rheumatic diseases and periodontitis are common inflammatory diseases. Autoimmune diseases include immunological and inflammatory modifications of connective tissues. Many cytokines are produced in synovium: TNF-α, IL-1, IL-6, IL-8. Prostaglandins and matrix metalloproteinases are responsible for connective tissue destruction.

There are many rheumatic diseases:

• Rheumatoid arthritis
• Ankylosing spondylitis and spondylarthropathies of different origins
• Sjögren syndrome
• Juvenile idiopathic arthritis

Rheumatoid arthritis is a chronic inflammatory disease of synovial tissues with some extra-articular symptoms. Rheumatoid arthritis, juvenile idiopathic arthritis, and sometimes Sjögren syndrome may be associated with periodontitis. Rheumatoid arthritis is a systemic autoimmune disease with joint destruction by chronic inflammation and synovial hyperplasia. Patients with severe rheumatoid arthritis have an increased risk for periodontitis, and patients with periodontitis present a higher prevalence of arthritis.

There are some similar features in the inflammatory response between periodontitis and rheumatoid arthritis, in periodontitis ligaments and bone around teeth are destructed; in arthritis there is joint bone, ligament, and cartilage tissue destruction. Patients may present with a dysregulation of the inflammatory response. The medical complications due to chronic arthritis can also affect oral health; these patients need attention from dentists for regular care and periodontitis prevention. Patients with rheumatic diseases sometimes present alterations in saliva flow rate and saliva composition. Patients with rheumatoid arthritis present higher serum inflammatory markers when arthritis is associated with periodontal disease. Localized oral infection induces periodontal tissue inflammation and bone loss because of the action of osteoclast cells responsible for bone resorption. In arthritis and periodontitis, the bone loss is due to an excess of bone resorption. In periodontitis, bone loss is mediated by leukocytes, with aspects of tissue destruction similar to those seen in arthritis. Excessive neutrophil activation induces periodontal tissue damage and articular destruction, secondary to the excess of neutrophil degranulation and the release of reactive oxygen species such as superoxide radical. Periodontitis may also be responsible for the dissemination of pathogens in general circulation. The presence of bacterial products, cells, and enzymes in circulation is responsible for an immune response, producing increased levels of antibodies and cytokines present either in serum or in gingival fluid.

There are some similarities between the two diseases, and the treatment of one of them may influence the evolution of the other (Mercado, Marshall, and Bartold 2003). The treatment of periodontal disease may have a beneficial effect on the clinical and biological markers of arthritis disease activity. Periodontal treatment can improve the systemic rheumatic disease markers for rheumatoid arthritis patients presenting with severe periodontitis. Inflammatory markers are increased in gingival crevicular fluid, and their levels are lower after anti-inflammatory treatment (Abou Raya et al. 2007; Abou Raya, Naim, and Abuelkheir 2007; Al Katma et al. 2007; Bartold, Marshall, and Haynes 2005; Ebersole et al. 1997; Havemose-Poulsen et al. 2006; Kasser et al. 1997; Mercado et al. 2000; Miia et al. 2005; Miranda et al. 2003; Moen 2005 et al.; Ribeiro, Leao, and Novaes 2005; Welbury et al. 2003; Zhang et al. 2005).

PERIODONTITIS AND ARTHRITIS

Periodontitis and Rheumatoid Arthritis

Clinical Manifestations

There are some similarities between periodontitis and rheumatoid arthritis. Patients with rheumatoid arthritis present oral manifestations such as missing teeth and a high percentage of deeper pockets (Mercado et al. 2001). They are more likely to be edentulous and to have periodontal disease (de Pablo, Dietrich, and McAlindon 2008). These patients have a higher percentage of sites with probing depth greater than 4 mm, a higher percentage of attachment loss greater than 2 mm, and radiographic alveolar bone loss greater than 2 mm. These parameters are correlated with serum IgM and IgA rheumatoid factor levels (Havemose-Poulsen et al. 2006). Rheumatoid arthritis prevalence is significantly increased in periodontitis, and rheumatoid arthritis patients also present advanced forms of periodontal disease (Mercado et al. 2000). C-reactive protein levels, erythrocyte sedimentation rate levels, fibrinogen, and TNF-α are elevated in rheumatoid arthritis patients also presenting with periodontitis (Abou Raya, Naim, and Abuelkheir 2007). In patients with rheumatoid arthritis and periodontitis, erythrocyte sedimentation rate, high-sensitivity C-reactive protein, fibrinogen, and TNF-α are higher (Abou Raya et al. 2007). Periodontal disease is more frequent among rheumatoid arthritis patients. The presence of moderate to severe alveolar bone loss is associated with some arthritis manifestations:

• Longer morning joint stiffness
• Accelerated erythrocyte sedimentation rate
• Elevated C-reactive protein (Zhang et al. 2005)

Patients with rheumatoid arthritis present more severe periodontitis because of the excess production of inflammatory cytokines and matrix metalloproteinases, inducing both periodontal bone and articular joint destruction (Bartold, Marshall, and Haynes 2005). Some clinical manifestations of rheumatic diseases, such as the ability to control oral hygiene, xerostomia (or dry mouth), temporomandibular joint disease, and some medical treatments such as corticosteroids or immunomodulators, may influence oral and dental care (Treister and Glick 1999). Rheumatoid arthritis and advanced age are two significant predictors of periodontitis. Rheumatoid arthritis patients have a significant 8.05 times increased odds ratio of having periodontal disease, and they present significantly increased periodontal attachment loss (Pischon et al. 2008). Rheumatoid arthritis patients have more gingival bleeding, and they present more tooth loss and alveolar bone loss. Severity of periodontitis correlates with arthritis disease duration, the number of tender and swollen joints, serum C-reactive protein level, and erythrocyte sedimentation rate. Alveolar bone loss also correlates with the percentage of radiographic articular erosions (Abou Raya, Abou Raya, and El Kheir 2004). Rheumatoid arthritis is associated with connective tissue destruction and cartilage and bone erosions. Active rheumatoid arthritis is associated with the following:

• Greater prevalence of periodontitis
• Higher rate of gingival bleeding
• Greater probing depth and attachment loss
• Higher number of missing teeth (Kasser et al. 1997).

Pathophysiology

There is an association between rheumatoid arthritis and periodontitis. Rheumatoid arthritis and periodontal disease may have a common pathobiology because they are both chronic inflammatory diseases (Abou Raya et/>