Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis☆
Introduction
Rheumatoid arthritis (RA) is a systemic inflammatory disease with its primary manifestation in the joints, a condition characterized by substantial morbidity and accelerated mortality [[1], [2], [3], [4]]. Over the last two decades, the interrelationship between RA and periodontitis (PD) has become increasingly appreciated [5]. Several studies have shown an increased frequency of periodontitis (PD) in patients with RA compared to individuals without RA [[6], [7], [8], [9]]. It also has been found that measures of RA disease severity (e.g. a higher number of swollen joints, increased C-reactive protein concentration and erythrocyte sedimentation rate) are associated with increased periodontal bone loss [10]. Subjects referred for PD treatment are substantially more likely than healthy controls to self-report a diagnosis of RA [11]. Even younger patients with recent-onset RA and those with juvenile idiopathic arthritis (JIA) have been reported to have a higher percentage of sites with deep periodontal pockets and periodontal bone loss than controls [12]. The association of PD with RA appears to be independent of other risk factors including cigarette smoking, socioeconomic status, body mass index, alcohol consumption, and poor oral hygiene [8].
While most studies investigating the possible etiologic relationship of RA and PD have focused on shared inflammatory mechanisms, there has been limited attention given to bacterial infections that act not only as a primary initiator of PD, but may also play a role in peptide citrullination (the post-translational modification of arginine residues to citrulline residues by peptidylarginine deiminase [PAD]). This is extremely important given the specificity of autoantibody binding to cyclic citrullinated peptides (anti-CCP antibody) in RA [13]. Indeed, anti-CCP antibody is associated with disease severity [14], [15] in RA and has been postulated to play a pathogenic role in the disease process [16]. Porphyromonas gingivalis (P. gingivalis) is a gram-negative anaerobic bacterium that is recognized to be a major pathogenic organism in PD and is the only bacteria known to express a PAD enzyme [17]. Although not completely homologous to human PAD, similar to its human counterpart this enzyme is responsible for the post-translational conversion of arginine to citrulline. The ability of P. gingivalis to express PAD suggests that infection with this organism could impact RA onset and progression by facilitating autoantigen presentation and the expression of disease-specific autoantibody targeting citrullinated peptides, antibody responses that have been shown to be nearly exclusive to RA patients [18].
In this study, we sought to confirm prior observations showing a higher prevalence and concentration of antibody to P. gingivalis in RA compared to healthy controls, while also comparing these antibody titers to those with PD. Additionally, we sought to examine the association of antibody directed against P. gingivalis with RA-specific autoantibody expression, specifically the presence of anti-CCP antibody and rheumatoid factor (RF) isotypes.
Section snippets
Study subjects
We examined banked serum samples collected at baseline from 78 RA patients enrolled in previous randomized clinical trials [[19], [20], [21], [22]]. PD status, based on either self-report or clinical probing results, was not known for RA cases. All RA patients satisfied American College of Rheumatology (ACR) classification criteria [23]. PD subjects (n = 39) were identified from a pool of patients undergoing periodontal maintenance therapy (regular cleanings) for moderate to severe chronic PD.
Results
Characteristics of study subjects are summarized in Table 1. Subjects were predominantly Caucasian and were similar across groups with regards to gender and age, although individuals with RA and PD were more likely than healthy controls to be current smokers. Among RA subjects, 91% were seropositive for anti-CCP antibody (as measured using total IgG) and 92% were seropositive for RF-IgM. In contrast, only two of 39 subjects with PD (5%) were seropositive for anti-CCP antibody.
Median P.
Discussion
In this study, we found that both the prevalence and magnitude of antibody responses to P. gingivalis was greater in RA cases compared to healthy controls, although less than that observed in subjects with established and moderate to severe PD. With reports suggesting an overall prevalence of PD approaching 10–20% [30], the relatively high frequency of seropositivity to P. gingivalis in controls suggests that exposure and subsequent antibody responses to this bacterium may be more common then
Acknowledgments
The authors wish to thank Dr. William McArthur (University of Florida, College of Dentistry, Gainesville, FL, USA) for his assistance in the measurement of P. gingivalis antibody and investigators and patients from the Rheumatoid Arthritis Investigational Network (RAIN) and UNMC College of Dentistry clinics for contributing to this effort. This work was supported by a grant from the UNMC Clinical Research Center. Dr. Mikuls receives research support from NIH/NIAMS (K23 AR050004-01A1 and R03
References (49)
- et al.
Enzyme-linked immunosorbent assay (ELISA)
Quantitative assay of immunoglobulin G. Immunochemistry.
(1971) - et al.
Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: results from the Iowa Women's Health Study
Am J Med.
(2002) - et al.
Comorbidity in arthritis
J Rheumatol.
(1999) - et al.
Mortality in rheumatoid arthritis: have we made an impact in 4 decades
J Rheumatol.
(1999) - Mikuls T, Saag K, Criswell L, Merlino L, Cerhan J. Health-related quality of life in women with elderly-onset...
- et al.
Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women: results from the Iowa Women's Health Study
Ann Rheum Dis.
(2002) - et al.
Inter-relationships between rheumatoid arthritis and periodontal disease
A review. J Clin Periodontol.
(2003) - et al.
Risk for periodontal disease in patients with longstanding rheumatoid arthritis
Arthritis Rheum.
(1997) - et al.
Teeth loss and the inflammation of teeth-supporting tissues in rheumatoid disease
Scand J Rheumatol.
(1975) - et al.
Association among rheumatoid arthritis, oral hygiene, and periodontitis
J Periodontol.
(2008)
Serum antibodies and loss of periodontal bone in patients with rheumatoid arthritis
J Clin Periodontol.
Relationship between rheumatoid arthritis and periodontitis
J Periodontol.
Is there a relationship between rheumatoid arthritis and periodontal disease
J Clin Periodontal.
Periodontal and hematological characteristics associated with aggressive periodontitis, juvenile ideopathic arthritis, and rheumatoid arthritis
J Periodontol.
The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide
Arthritis Rheum.
Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesions in rheumatoid arthritis anti-CCP and bone damage in RA
Autoimmunity.
Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis
Arthritis Res Ther.
A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination
Arthritis Rheum.
Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis peptidylarginine deiminase
Infect Immun.
Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies
J Clin Invest.
Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate, and sulfasalazine, or a combination of the three medications
Arthritis Rheum.
Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine
Arthritis Rheum.
Treatment of early rheumatoid arthritis with minocycline or placebo
Arthritis Rheum.
Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications
N Engl J Med.
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Sources of support: Dr. Mikuls receives research support from NIH/NIAMS (K23 AR050004-01A1 and R03 AR054539-01) and the Arthritis Foundation. Dr. Holers' efforts were supported by NIH (RO1 AR051394).