Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis

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Abstract

Summary

Antibody titers to P. gingivalis are increased in patients with rheumatoid arthritis and are associated with disease-specific autoimmunity.

Background

Periodontitis (PD) has been implicated as a risk factor for rheumatoid arthritis (RA). We sought to characterize antibody titers to P. gingivalis (a pathogen in PD) in subjects with RA, PD, and in healthy controls and to examine their relationship with disease autoantibodies.

Methods

P. gingivalis antibody was measured in subjects with RA (n = 78), PD (n = 39), and in controls (n = 40). Group frequencies of bacterial titer elevations were compared using the Chi-square test and antibody titers were compared using non-parametric tests. Correlations of P. gingivalis titer with C-reactive protein (CRP), antibody to cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were examined in those with RA while CRP and autoantibody concentrations were compared based on seropositivity to P. gingivalis.

Results

Antibody titers to P. gingivalis were highest in PD, lowest in controls, and intermediate in RA (p = 0.0003). Elevations in P. gingivalis (titer  800) were more common in RA and PD (67% and 77%, respectively) than in controls (40%) (p = 0.002). In RA, there were significant correlations with P. gingivalis titer with CRP, anti-CCP-IgM, and -IgG-2. CRP (p = 0.006), anti-CCP-IgM (p = 0.01) and -IgG2 (p = 0.04) concentrations were higher in RA cases with P. gingivalis titers ≥ 800 compared to cases with titers < 800.

Conclusion

Antibodies to P. gingivalis are more common in RA subjects than controls, although lower than that in PD. Associations of P. gingivalis titers with RA-related autoantibody and CRP concentrations suggests that infection with this organism plays a role in disease risk and progression in RA.

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

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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).

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