JBI Library of Systematic Reviews

Periodontal Disease as a Risk Factor for Rheumatoid Arthritis: A Systematic Review Reviewers
Sushil Kaur BDS, MDSc (Perio), DClinDent (Perio), FRACDS (Perio) Sarahlouise White BSc (Hons) MSc, PhD
1 2 1,

Mark Bartold BDS, BScDent(Hons), PhD, DDSc, FRACDS (Perio),

1. Colgate Australian Clinical Dental Research Centre (CACDRC), Adelaide Dental Hospital, University of Adelaide, SA 5005, Australia. Associated with the Joanna Briggs Institute, Faculty of Health Sciences, the University of Adelaide, SA 5005 2. The Joanna Briggs Institute, Faculty of Health Sciences, the University of Adelaide, SA 5005.

Corresponding Author : Sushil Kuar email sushil.kuar@adelaide.edu.au

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 1 complex multifactorial pathogenesis affecting joints and other tissues. The natural history of rheumatoid arthritis is poorly defined; its clinical course fluctuates and the prognosis 1 unpredictable. Rheumatoid arthritis affects up to 13% 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. Extraarticular 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. 2 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,

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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 2 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 2 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. 2 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 3 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 4 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 5 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 6 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 10 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 11 with rheumatoid arthritis. Patients with rheumatoid arthritis also have a significantly higher level of immunoglobulin G antibody against P. gingivalis, Prevotella intermedia, and 12 13 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.
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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 14 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 "twohit" model that attempts to link experimental evidence from animal models and is supported 15 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- ). These cytokines are thought to stimulate resident cells in the synovium and the periodontium to produce MMPs mediating connective 16 tissue destruction, and induce the differentiation and activity of osteoclasts to destroy bone In particular, TNF-, 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 17 17 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 18 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.
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Keywords Dental, periodontal, rheumatoid arthritis, association, teeth

Inclusion criteria
Types of participants This review will consider for inclusion, studies that include patients with diagnosed rheumatoid arthritis with or without a clinical diagnosis of chronic periodontitis. Participants will be at least 45 years of age and both genders will be considered. The lower age limit was selected in order to be as inclusive as possible, however, studies specifically focussing aggressive forms

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of periodontitis will not be included as the aetiology is likely to be different. Studies were the focus is patients with co-morbidities that may impact on periodontal disease and/or rheumatoid arthritis will not be considered as they are outside the scope of this review. Diagnosis of periodontal disease should be based on the clinical and radiographic criteria . 19 described by the 1999 Consensus Classification of Periodontal Diseases

Focus of the review The focus of this systematic review is the epidemiological association between periodontal disease and rheumatoid arthritis. Types of outcomes This review will consider studies that aim to establish periodontal disease as a risk factor for rheumatoid arthritis. Outcomes measures considered will include, but are not limited to: Primary Outcomes Studies that include either or both clinical and laboratory measurements that describe 3 rheumatoid arthritis using criteria by the American College of Rheumatology will be considered for inclusion. Outcomes measures such as DAS-28, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), citrullinated proteins (CCP) and rheumatoid factor (RF) will be considered. Secondary Outcomes A secondary outcome of interest in the tooth loss in rheumatoid arthritis sufferers as a result of periodontal disease

Types of studies This systematic review will consider any quantitative studies that examine the association between periodontal disease and rheumatoid arthritis. It is anticipated that the majority of studies will include case-control studies and prospective cohort studies.

Search strategy
The search strategy aims to find both published and unpublished studies in the English language from inception of the database until June 2012. A three-step search strategy will be utilised in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies (Appendix I). The databases to be searched include: Medline/PubMed CINAHL DOSS

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Embase Scopus The search for unpublished studies will include: Web of Knowledge MedNar ProQuest Theses and Dissertations Initial keywords/search terms to be used will be: Rheumatoid arthritis, Periodontal disease, Alveolar bone loss, Tooth loss, Association, Risk factor

Assessment of methodological quality

Quantitative papers selected for retrieval will be assessed by two independent reviewers (SK and MB) for methodological validity prior to inclusion in the review using standardised critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer (SW).

Data collection
Quantitative data will be extracted from papers included in the review using the standardised data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

Data synthesis
Quantitative papers will, where possible be pooled in statistical meta-analysis using JBIMAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. Conflicts of interest None

Acknowledgements
The authors would like to acknowledge the support of: CORAL Joanna Briggs Institute Michael Draper, Research Librarian, the University of Adelaide. There was no external funding for this systematic review.

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References
1. Grassi W, De Angelis R, et al. The clinical features of rheumatoid arthritis. European Journal of Radiology. 1998;27(Suppl 1):S18-24. 2. Anderson D. Harrison's Principles of Internal Medicine 2005.

3. Arnett F, Edworthy S, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis & Rheum 1988;31:315-24. 4. American Academy of Periodontology. Epidemiology of Periodontal Diseases: Position Paper. . Journal of Periodontology 2005;76:1406-19. 5. Bartold P, Marino V, et al. Effect of Porphyromonas gingivalis-induced inflammation on the development of rheumatoid arthritis. Journal of Clinical Periodontology. 2010;37:40511. 6. Cochran D. Inflammation and bone loss in periodontal disease. Journal of Periodontology. 2008;79:1569-76. 7. Kasser UR, Gleissner C, et al. Risk for periodontal disease in patients with longstanding rheumatoid arthritis. Arthritis Rheum. 1997 Dec;40(12):2248-51. 8. Mercado F, Marshall R, et al. Inter-relationships between rheumatoid arthritis and periodontal disease. A review. . Journal of Clinical Periodontology. 2003;30:761-72. 9. Pischon N, Pischon T, et al. Association among rheumatoid arthritis, oral hygiene, and periodontitis. Journal of Periodontology. 2008 Jun;79(6):979-86. 10. Ramamurthy N, Greenwald R, et al. Experimental arthritis in rats induces biomarkers of periodontitis which are ameliorated by gene therapy with tissue inhibitor of matrix metalloproteinases. Journal of Periodontology. 2005;76:229-33. 11. Moen K, Brun J, et al. Synovial inflammation in active rheumatoid arthritis and psoriatic arthritis facilitates trapping of a variety of oral bacterial DNAs. . Clin Exp Rheumatology. 2006(24):656-63. 12. Al-Katma M, Bissada N, et al. Control of periodontal infection reduces the severity of active rheumatoid arthritis. Journal of Clinical Rheumatology. 2007(13):134-7. 13. Ribeiro J, Leo A, et al. Periodontal infection as a possible severity factor for rheumatoid arthritis. Journal of Clinical Periodontology. 2005;32(4):412-6. 14. Ogrendik M. Rheumatoid arthritis is linked to oral bacteria: etiological association. . Mod Rheumatol. 2009;19:453-6. 15. Golub L, Payne J, et al. Can systemic diseases co-induce (not just exacerbate) periodontitis? A hypothetical "two-hit" model. Journal of Dental Research. 2006;85:102-5. 16. McGee J, Tucci M, et al. The relationship between concentrations of proinflammatory cytokines within gingiva and the adjacent sulcular depth. Journal of Periodontology. 1998;69:865-71. 17. Haynes D. Bone lysis and inflammation. Inflamm Res 2004;53:596-600. problems of periodontal disease classification.

18. Velden. Vd. Purpose and Periodontology. 2000;2005(39):13-21.

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19. Armitage G. Development of a classification system for periodontal diseases and conditions. Annals of Periodontology 1999;4:1-6.

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Appendix I: Joanna Briggs Institute critical appraisal instruments

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Appendix III: Joanna Briggs data extraction instruments

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er

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