The role of inflammation in periodontal disease and rheumatoid arthritis: similar pathologies.

Abstract

Arthritis is a nonspecific term that means inflammation of the joints. Arthritic disease encompasses a group of rheumatic disease disorders that affect bone, joint and muscles. More than 100 arthritic diseases affect different parts of the body. Some of the more common types include rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, scleroderma, Sjogren's syndrome, gout, ankylosing spondylitis, Lyme disease, fibromyalgia and psoriatic arthritis.

The relationship between rheumatoid arthritis (RA) and the progression of inflammatory conditions elsewhere in the body, such as chronic periodontitis (CP), is controversial. The inflammatory response in a healthy individual is our protective response to infection and trauma injuries such as wounds and insect bites. However, the inflammatory response can also result in deleterious effects when inflammation persists and fails to resolve. Thus, the inflammatory response is commonly described as a double-edged sword. The intent of this review is to compare the inflammatory process occurring in RA with that of the periodontal diseases and review the literature on the emerging evidence in this area.

Introduction

Robert J. Genco, DDS, PhD, editor emeritus of the Journal of Periodontology (1) has stated, "Periodontal disease and rheumatoid arthritis have very similar pathologies. Damage caused by the immune system and chronic inflammation are central to both diseases. A better understanding of the biological processes common to these diseases may help us find new ways to treat them with medications that modify the body's response to inflammation."

Clinical Features of RA and Periodontitis

Pain, swelling and deformity of joints are the prominent features of RA. The clinical characteristics of RA vary from one patient to another and also within the same patient over the course of the disease.

The periodontal tissues in health exist in steady-state equilibrium of tissue degradation and repair. However, if the balance between host response and bacterial virulence is disturbed, disease and consequent tissue destruction will occur. During the inflammatory process of periodontitis, there is a marked accumulation of lymphocytes and monocytes within the connective tissue, resulting in tissue swelling and matrix degradation. In contrast to RA, the development of periodontitis is not associated with pain.

Some scientists suggest that the immune system and chronic inflammation play a role in both RA and periodontal disease. Mercado et al. (2) demonstrated that individuals who have moderate to severe RA are also likely to suffer from moderate to severe periodontitis. There were no differences in the plaque and bleeding indices between the control and RA groups. The RA group did however, have more missing teeth than the control group, and a higher percentage of these subjects had deeper pocketing. It is their hypothesis that there is an underlying disregulation of the molecular pathways in the inflammatory response in these individuals, even though not clearly established as a causal relationship.

Pischon et al. (3) suggests that patients with RA have significantly increased periodontal attachment loss compared to controls and that oral hygiene may only partially account for this association. Some scientists have speculated a bacterial infection may trigger the disease process in some of the estimated 2.1 million people with RA. Despite close investigation and intense efforts, no infectious agents have been identified as the cause of RA.

Recent studies have focused on the clarification of the relationship between RA and CP due to the similarity of their pathogenesis. Active tissue destruction, the cell infiltrations and inflammatory mediators ([PGE.sub.2], TNF-[alpha] and IL-1[beta]) are similar in both diseases. (4-6) It was suggested that the lack of anti-inflammatory cytokines such as IL-4 and IL-10 may contribute to the initiation and progression of inflammation during chronic synovitis in RA joints. (7-9) It has been further suggested that the initiation and progression of inflammation in both RA and CP may be due to an inappropriate response of the anti-inflammatory cytokines. In addition, Th-1, Th-2 and monocyte cytokines are found in RA, gingival tissues and gingival crevicular fluid (GCF). Even a minimal imbalance between pro- and anti-inflammatory cytokine production may contribute to bone and collagen destruction in periodontal disease (Tables I and II).

The Role of Cytokines and Inflammation in Periodontitis and Rheumatoid Arthritis

Cytokines, produced by host cells, play an important role in the pathogenesis of both RA and CP. Cytokines are a group of proteins and peptides released by many types of cells that are used in organisms as signaling compounds. They regulate all of the important biological processes, such as cell proliferation, cell growth, cell activation, inflammation, immunity and repair. The immune response underlying the pathogenesis of the chronic inflammatory diseases such as CP and RA has been studied for the past three decades. (4,10,11) One of the important effects of memory or native T cells and monocytes is the synthesis of cytokines, which modulate the inflammatory response (Table I). (12-14) Van Dyke and Serhan, et al. reported that although some individuals are able to stop the inflammatory response, others are not. The answer may lie in our genes.

In recent years, the cytokine receptors have been the subject of interest of many researchers.

Cytokines increase the permeability of blood vessel walls, facilitating the migration of white blood cells into joint spaces that then become sites of inflammation. Cytokine release also leads to the proliferation of fibroblasts, synovial cells, increased prostaglandin and matrix-degrading protease activity and ultimately, the resorption of bone. IL-1, a cytokine secreted primarily by macrophages, is one of the key mediators of local inflammation, tissue damage, immunologic reactions and bone resorption.

During the inflammatory reaction the pro-inflammatory cytokines battle with the inhibitory "immune-regulating" molecules (Table III). The cytokine producing cells and their target cells exchange signals continuously. This supports primarily tissue homeostasis.

Periodontal disease has also been correlated to various systemic conditions and diseases. (15-19) Most of these associations are explained in part by the excessive production of pro-inflammatory cytokines and other inflammatory mediators, of which prostaglandin [E.sub.2] ([PGE.sub.2]), tumor necrosis factor (TNF) [alpha], and interleukin (IL-6) appear to dominate.

Rheumatoid Arthritis, Periodontal Disease and Coronary Artery Disease: Inflammatory Connection?

Abou-Raya et al. (20) evaluated the association between RA, PD and coronary artery disease (CAD) and the influence of systemic inflammatory factors by comparing inflammatory markers. A total of 100 active RA patients, of which 50 had established CAD and 50 were without CAD, were assessed for PD. All subjects underwent a clinical, cardiac, dental, laboratory and radiological evaluation. Blood samples were obtained, and the level of high sensitivity C-reactive protein (hs-CRP), total white blood counts (WBC), erythrocyte sedimentation rate (ESR), fibrinogen and tumor necrosis factor (TNF) [alpha], total cholesterol (TC), and high density lipoprotein (HDL) were assayed. The findings of this study demonstrated an association between RA, PD, and CAD. The RA patients with CAD had significantly more PD than RA patients without CAD. The inflammatory markers, hsCRP, ESR, WBC, fibrinogen, and TNF-[alpha], were raised in all patients but were significantly higher in RA patients with CAD who also had PD. HDL levels were lower in RA patients with CAD when compared to RA patients without CAD. Evidence from this study shows an association between RA, PD, CAD, and systemic levels of the inflammatory mediators. The implication is that inflammation may be the central link between the chronic inflammatory, autoimmune disorders, and atherosclerosis.

Role of T Cells in Pro-and Anti-Inflammatory Responses

It is generally agreed that control and balance of the T helper cells, Th-1/Th-2, are central to the immunoregulation of periodontal disease. There is increasing evidence in humans that the stable periodontal lesion is mediated by Th-1 cells, while the progressive lesion sees a shift toward Th-2 cells. In the presence of IL-12, IL-18 induces Th-1 responses while, in the absence of IL-12, promotes Th2 responses. Since IL-18 has the ability to induce either Th-1 or Th-2 differentiation it becomes important to consider its role in periodontal disease. (21)

Can Inflammation Be "Turned Off"?

The body's failure to turn off the inflammatory response to infection results in chronic inflammation, which causes much of the tissue damage that we observe in periodontal disease. Pro-inflammatory mediators, such as prostaglandins and leukotrienes, are balanced by counter-regulatory signals provided by a class of molecules called lipoxins. Van Dyke, Serhan et al. (24,25) noted that inflammation's failure to enter its last or resolution phase can have serious consequences. This final phase has traditionally been considered a passive event--a petering out of immune activity that paled in comparison to the acute phase's neutrophil attack. Serhan has reported that neutrophils, which lead the white cell onslaught during inflammation's acute phase, secrete two compounds well known for provoking inflammation and attracting additional white cells to the area: leukotriene B4 followed by prostaglandin [E.sub.2]. But at the end of the acute phase, neutrophils stopped secreting classic inflammatory chemicals and instead began collaborating with other cells to synthesize compounds they termed lipoxins that halted inflammation. Serhan recently discovered yet another family of inflammation resolving compounds called resolvins, derived from arachidonic acid, that are available from the omega 3 fatty acids derived from the diet. Serhan, et al. postulate that the resolvins may in part account for the anti-inflammatory properties of these fatty acids, specifically from the omega-3 fatty acids that are especially plentiful in certain types of fish.

The Role of the Dental Hygienist

Medical complications due to RA and its treatment can affect oral health care. Oral health care providers need to recognize and identify modifications of dental care based on the medical status of patients with RA. The dental hygienist needs to be knowledgeable about the relationship between periodontal diseases and systemic diseases. Dental hygienists play an important role in the overall education and care of these patients (Table IV).

Summary

The similarities between periodontal disease and RA and the emerging evidence in this area have been outlined in this review. Although the etiology of these two diseases may differ, the underlying pathogenic mechanisms are remarkably similar and it is possible that individuals manifesting both periodontitis and RA may suffer from a unifying underlying systemic dysfunction of the inflammatory response. Replication of existing studies, in addition to ongoing research in randomized, controlled trials are necessary to clearly establish a causal relationship. Treatment implications for future research may include the use of disease-modifying medications.

Daniel M. Meyer, the associate executive director of the Division of Science at the American Dental Association, is quoted in Scientific American Presents: Oral and Whole Body Health 2006 (26) (A custom publication production in collaboration with the Procter & Gamble Company) as cautioning:

   Whether or not treating oral health conditions will affect systemic
   health depends on the disease- and we'll know more about that
   as future research unfolds. Until we have (intervention) studies,
   where we can measure results in consideration of other variables
   that may influence health, I think we have to be guarded in
   treatment recommendations, but treating oral conditions such as
   periodontal disease has its own undisputed benefits and may
   have broader systemic health outcomes.

References

(1.) Dr. Robert Genco quoted in the Journal of the California Dental Association, Impressions/National Campaign Will Promote Oral Cancer Awareness, Debra Belt, August,2001.

(2.) Mercado FB, Marshall RI, Klestov AC, Bartoid PM. Relationship between rheumatoid arthritis and periodontitis. J Periodontol 2001; 72: 6, 779-87.

(3.) Pischon N, Pischon T. Association between rheumatoid arthritis, oral hygiene, and periodontitis. J Periodontol Posted online on May 15, 2008.

(4.) Holmstrup P, Glick M. Treatment of periodontal disease in the immunodeficient patient. Periodontol 2000 2002; 28: 190-205.

(5.) Seymour RA, Steele JG. Is there a link between periodontal disease and coronary heart disease? Br Dent J 1998; 184: 33-8.

(6.) Research, Science and Therapy Committee of the American Academy of Periodontology. Periodontal disease as a potential risk factor for systemic diseases. J Periodontol 1998; 69:841-50.

(7.) Walmsley M, Katsikis PD, Abney E, et al. Interleukin-10 inhibition of the progression established collagen induced arthritis. Arthritis Rheum 39, 1996: 495-503.

(8.) Katsikis PD, Chu CQ, Brennan FM et al. Immunoregulatory role of Interleukin-10 in rheumatoid arthritis, J Exp Med 1994; 179: 1517-27.

(9.) Van Roon JAG, Van Roy JL Gmelig-Meyling AM, et al. Prevention and reversal of cartilage degradation in rheumatoid arthritis by inteleukin-10 and in terleukin-4. Arthritis Rheum 1996; 39: 829-35.

(10.) Kinane DF, Davies RM. Periodontal manifestations of systemic disease. In: Jones H, Mason DK (eds.). Oral manifestations of systemic disease. London: WB Saunders; 1990: 512-36.

(11.) Holmstrup P, Westergaard J. HIV infection and periodontal disease. Periodontol 2000 1998;18:37-46.

(12.) Keil U. Coronary artery disease: the role of lipids, hypertension and smoking. Basic Res Cardiol 2000; 95: 152-8.

(13.) Wood D. Established and emerging cardiovascular risk factors. Am Heart J 2001; 141: 49-57.

(14.) Nieto FJ. Infections and atherosclerosis: new clues from an old hypothesis? Am J Epidemiol 1998; 148: 937-48.

(15.) Offenbacher S, Katz VL, Fertik GS, et al. Periodontal infection as a risk factor for pre-term low birth weight. J Periodontol 1996; 67: 1103-13.

(16.) DeStefano F, Anda RF, Kahn S, et al. Dental disease and risk of coronary heart disease and mortality. Br Med J 1993; 306: 688-69.

(17.) Mattila KJ, Valle MS, Nieninen MS, et al. Dental infections and coronary atherosclerosis. Atherosclerosis 1993; 103: 205-11.

(18.) Beck JD, Garcia R, Heiss G, et al. Periodontal disease and cardiovascular disease. J Periodontol 1996; 67: 1123- 7.

(19.) Salvi GE, Lawrence HP, Offenbacher S, Beck J. Influence of risk factors on the pathogenesis of periodontitis. Periodontol 2000 1997; 14: 173-201.

(20.) Abou-Raya S, Abou-Raya A, Naim A, Abuelkheir H. Rheumatoid arthritis, periodontal disease and coronary artery disease. Clin Rheumatol 2007.

(21.) Orozco A, Gemmell E, Bickel M, Seymour GJ. Interleukin 18 and periodontal disease. J Dent Res 2007; 86(7): 586-93.

(22.) Page RC, Offenbacher S, Schroeder H, et al. Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontol 1997; 14: 216-47.

(23.) Mercado FB, Marshall RI, Bartold PM: Inter-relationships between rheumatoid arthritis and periodontal disease. J Clin Periodontol 2003; 30: 761-72.

(24.) Van Dyke TE, Serhan CN. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J Dent Res 2003; 82(2): 82-90.

(25.) Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunology 2008 (5) 349-61.

(26.) Daniel M. Meyer quote, Scientific American: American Presents: Oral and Whole Body Health 2006 (A custom publication production in collaboration with the Procter & Gamble Company) 2006.

By Joanne C. Fletcher, RDH, MS

Joanne C. Fletcher RDH, MS, is the director of dental hygiene at Collin College in McKinney, Texas. She had been a member of the Journal of Dental Hygiene Editorial Review Board for 25 years, member of the Dental Hygiene II National Board Test Construction Committee for 5 years and an accreditation consultant for the Commission on Dental Accreditation the past 12 years. Didactically, she teaches periodontology, nutrition, radiology lecture and oral medicine.

Table I. Examples of Cytokines

Interleukins
Cytotoxic factors (tumor necrosis factor=TNF[alpha] and [beta])
Interferons (anti-viral IFN [alpha] and [beta])
Colony stimulating factors (CSF)
Growth Factors (GF)

Table II. Comparison of Periodontitis Rheumatoid Arthritis

Chronic Periodontitis (CP)          Rheumatoid Arthritis (RA)

Classic example of chronic          Perhaps several different
inflammatory diseases               mechanisms may lead to the initial
                                    tissue injury and precipitate
                                    synovial inflammation.

Both are clinically characterized   Same as Chronic Periodontitis
by local destruction of hard
and soft tissue as a consequence
of an inflammatory response

Bacterial etiology, however,        Research does not support the
bacteria alone insufficient to      concept that a single antigen
cause disease progression unless    is driving the synovial
there is an associated              inflammation.
inflammatory response. (22)

Continuing presence of high         Same as Chronic Periodontitis
levels of pro-inflammatory
cytokines (23)

Cytokine Imbalance: Low Th-1,       Cytokine Balance: Th-1 = Th-2
High Th-2                             * Same explanation as noted
  * Th-1 (T helper cells                under Periodontitis column
    group 1) produce the
    proinflammatory responses
  * Th-2- (T helper cells           A well balanced Th1 and Th2
    type 2) cytokines include       response, suited to the immune
    interleukin-10, which has       challenge is optimal.
    more of an anti-
    inflammatory response.

Role of macrophage and              Same as Chronic Periodontitis
  dendritic (antigen
  presenting) cells
Chronic inflammatory                Same as Chronic Periodontitis
  disease

Genetic and environmental           Same as Chronic Periodontitis
  influences

Table III. Examples of Cytokines

Pro-Inflammatory    Anti-Inflammatory    Other Inflammatory
Cytokines           Cytokines            Mediators

IL-1 [beta]         IL-1ra               [PGE.sub.2]
IL-6                IL-10                TNF-[alpha]
IL-8                TGF [beta]           IL-6
TNF-[alpha]         IL-4
IFN y

Table IV. Dental Considerations: RA Patients

Patient comfort                          Short appointments
                                           Physical supports (pillows,
                                           towels, etc.)
                                         Allow patient to change
                                           positions
Drug actions and
  interactions

Salicylates, pheny-       [right arrow]  Bleeding increased however
  lbutazones and NSAIDs                    not clinically significant

Systemic Corticosteroids  [right arrow]  Adrenal suppression possible,
  for prolonged periods                    masking of oral infection,
  including local                          impaired healing, check
  corticosteroids for                      with physician
  TMJ

Systemic medications      [right arrow]  Include anti-malarials, gold
                                           salts, and immuno-
                                           suppressive agents that
                                           result in increased
                                           infections, delayed
                                           healing, prolonged
                                           bleeding

Complications                            Salivary gland swelling and
                                           its related complications
                                           including secondary
                                           Sjogren's syndrome,
                                           xerostomia, etc.
                                         Increased susceptibility to
                                           infections
                                         Impaired hemostasis
                                         Untoward drug actions and
                                           interactions.
Joint prosthesis                         Possible prophylactic
                                           antibiotic when immuno-
                                           suppression is indicated,
                                           check with physician
Temporo-mandibular                       May be result of occlusal
  pathology                                changes due to arthritis
                                         * Soft diet
                                         * Movements of mandible
                                           limited
                                         * Occlusal appliance to
                                           decrease joint loading
                                         * Medications: Anti-
                                           inflammatory drug therapy,
                                           such as salicylates,
                                           phenylbutazone and NSAIDs
                                           and rest
                                         * Local corticosteroid
                                           injections sometimes
                                           utilized
                                         * May require supplemental
                                           glucocorticosteroid
                                           replacement therapy
                                         * Moist heat or ice to
                                           face/jaw
                                         * Surgery
Clinical implication for                 * Patient education emphasize
  the dental hygienist                     importance of good oral
                                           hygiene (RA friendly
                                           toothbrushes and
                                           periodontal aids)
                                         * Xerostomia and related
                                           complications
                                         * Early recognition, control
                                           of periodontitis
                                         * Correlation of disease
                                           associated periodontitis
                                           and patient's
                                           susceptibility to infection
                                         * Smoking cessation program
                                           if indicated
                                         * Impaired homeostasis