Clinical correlations with Porphyromonas gingivalis antibody responses in patients with early rheumatoid arthritis
© Arvikar et al.; licensee BioMed Central Ltd. 2013
Received: 25 February 2013
Accepted: 9 September 2013
Published: 9 September 2013
Prior studies have demonstrated an increased frequency of antibodies to Porphyromonas gingivalis (Pg), a leading agent of periodontal disease, in rheumatoid arthritis (RA) patients. However, these patients generally had long-standing disease, and clinical associations with these antibodies were inconsistent. Our goal was to examine Pg antibody responses and their clinical associations in patients with early RA prior to and after disease-modifying antirheumatic drug (DMARD) therapy.
Serum samples from 50 DMARD-naïve RA patients were tested using an enzyme-linked immunosorbent assay with whole-Pg sonicate. For comparison, serum samples were tested from patients with late RA, patients with other connective tissue diseases (CTDs), age-similar healthy hospital personnel and blood bank donors. Pg antibody responses in early RA patients were correlated with standard RA biomarkers, measures of disease activity and function.
At the time of enrollment, 17 (34%) of the 50 patients with early RA had positive immunoglobulin G (IgG) antibody responses to Pg, as did 13 (30%) of the 43 patients with late RA. RA patients had significantly higher Pg antibody responses than healthy hospital personnel and blood bank donors (P < 0.0001). Additionally, RA patients tended to have higher Pg antibody reactivity than patients with other CTDs (P = 0.1), and CTD patients tended to have higher Pg responses than healthy participants (P = 0.07). Compared with Pg antibody-negative patients, early RA patients with positive Pg responses more often had anti-cyclic citrullinated peptide (anti-CCP) antibody reactivity, their anti-CCP levels were significantly higher (P = 0.03) and the levels of anti-Pg antibodies correlated directly with anti-CCP levels (P < 0.01). Furthermore, at the time of study entry, the Pg-positive antibody group had greater rheumatoid factor values (P = 0.04) and higher inflammatory markers (erythrocyte sedimentation rate, or ESR) (P = 0.05), and they tended to have higher disease activity scores (Disease Activity Score based on 28-joint count (DAS28)-ESR and Clinical Disease Activity Index) and more functional impairment (Health Assessment Questionnaire). In Pg-positive patients, greater disease activity was still apparent after 12 months of DMARD therapy.
A subset of early RA patients had positive Pg antibody responses. The responses correlated with anti-CCP antibody reactivity and to a lesser degree with ESR values. There was a trend toward greater disease activity in Pg-positive patients, and this trend remained after 12 months of DMARD therapy. These findings are consistent with a role for Pg in disease pathogenesis in a subset of RA patients.
The etiology of rheumatoid arthritis (RA) is unknown, but both environmental and genetic factors are likely to play roles in its pathogenesis. Periodontal disease (PD), an inflammatory disease of tooth-supporting structures, may be an environmental trigger for RA. Compared with healthy controls, PD is more frequent in RA patients, both in those with new-onset and in those with long-standing disease, even when potential confounding factors such as smoking are taken into account [1–5].
Furthermore, there is increasing evidence of a role for PD pathogens, particularly Porphyromonas gingivalis (Pg), in RA pathogenesis. Pg is the only prokaryote known to possess a peptidylarginine deiminase (PAD), an enzyme that catalyzes the posttranslational modification of arginine residues to citrulline. Although citrullination may occur more generally in sites of inflammation, antibodies to citrullinated proteins (anti-cyclic citrullinated peptide (anti-CCP) antibodies) are specific for RA and are now valuable diagnostic markers for the disease . CCP antibodies are associated with a more aggressive course  and may be detected prior to the onset of clinical disease , suggesting a role in RA pathogenesis. Pg, through its PAD enzyme, may citrullinate host or bacterial proteins , altering their antigenicity and triggering autoimmunity and RA in predisposed individuals [9, 10]. Further support for this hypothesis comes from animal models. Pg enolase has been found to cause arthritis in DR4-IE-transgenic mice , and Pg infection has been shown to exacerbate collagen antibody-induced arthritis .
Prior studies have demonstrated increased frequencies of antibody responses to Pg in RA patients compared with healthy controls [5, 13–16]. However, in these studies [5, 13, 15, 16], patients generally had long-standing disease and were presumably receiving disease-modifying antirheumatic drugs (DMARDs), factors which may affect infection with PD pathogens and serum antibody responses. Moreover, clinical correlations with Pg responses have been inconsistent. Some investigators have noted an association of Pg antibodies with anti-CCP antibody levels, but not with RF values [14, 15], whereas others found a correlation of Pg immunoglobulin G (IgG) antibodies with RF levels, but not with CCP antibody values [5, 16]. Additionally, some researchers found an association of Pg antibodies and elevated C-reactive protein (CRP) levels [13, 14], but others noted no correlation between these antibodies and Disease Activity Score based on 28-joint count (DAS28)-CRP values .
Patients with early RA are an important group to study because they may benefit the most from treatment interventions for Pg and PD. In the only previous study in which Pg antibodies were examined in early RA patients, Scher et al.  found no significant difference in antibodies to a specific Pg antigen (Pg-specific chaperone protein HtpG) in patients with new-onset or chronic RA compared with control participants. However, antibody responses to whole-Pg antigen preparations have not yet been reported in early RA patients. Furthermore, Pg antibody responses in RA patients have not been compared to those of patients with other connective tissue diseases (CTDs), such as lupus, which are associated with broad immune stimulation.
In this study, we determined Pg antibody responses in patients with early RA and in comparison groups and correlated these results with standard RA biomarkers, disease activity scores and measures of function. We report here that both early and late RA patients had significantly more frequent and higher IgG antibody responses to whole-Pg sonicate antigens than healthy control participants and tended to have higher Pg antibody reactivity than patients with other CTDs. In early RA patients prior to DMARD therapy, Pg antibody responses correlated significantly with anti-CCP antibody reactivity and, to a lesser degree, with erythrocyte sedimentation rate (ESR) values. Moreover, there was a trend toward higher disease activity and more functional impairment in patients with Pg antibodies, and these trends remained during 12 months of DMARD therapy. Our observations are consistent with a role for Pg in disease pathogenesis in a subset of RA patients.
Patients and methods
Early rheumatoid arthritis cohort study and other subject groups
Newly diagnosed adult patients with early RA were recruited from the Rheumatology Clinic at Massachusetts General Hospital (MGH). The study was approved by the MGH Institutional Review Board, and written consent was obtained from each participant. Patients with disease of less than RA of one year's duration who had not yet received methotrexate (MTX) or biologic DMARD treatment were eligible to participate. Study physicians calculated a classification criteria score for each patient referred to the study, based on clinical assessment, electronic medical record (EMR) review or both. Only those patients with a score ≥6/10 were included, as required by the 2010 rheumatoid arthritis classification criteria promulgated by the American College of Rheumatology/European League Against Rheumatism Collaborative Initiative . For comparison, sera were obtained from patients with long-standing RA seen in the MGH Rheumatology Clinic. Sera were also collected from patients with other CTDs who were evaluated in the MGH Rheumatology Clinic or identified from the MGH Clinical Immunology Laboratory. For healthy control groups, sera were collected from blood bank donors and from healthy hospital personnel. Hospital personnel did not report a history of RA or PD and were similar in age to those in the early RA group. However, clinical examinations for PD were not performed at the time of the study for any of the participants.
Clinical and laboratory assessments of the early RA patients were performed at study entry and at 12-month follow-up visits. Demographic data, including smoking history, were recorded at the time of enrollment. At each study visit, patients completed a Health Assessment Questionnaire (HAQ), and they marked a self-assessment of global health on a 10-cm Visual Analogue Scale. Study physicians performed a clinical assessment, including a 28-joint count, and they marked the physician's global disease score on a 10-cm Visual Analogue Scale. This information was recorded in the patient's EMR using the rheumatology-specific, informatics-based application Rheumatology OnCall (ROC), which was previously developed in our department . The DAS28-ESR value was automatically calculated in the ROC application, which integrates institutional laboratory values for ESR and CRP with physician-entered swollen and tender joint counts and patient global DAS for each date of visit. Clinical Disease Activity Index (CDAI) score was calculated by study physicians using information from the ROC application. Study physicians treated patients according to the standard of care.
Serum samples were collected at each visit. RF and anti-CCP antibodies were measured at the time of study entry in the MGH Clinical Immunology Laboratory by nephelometry (IMMAGE 800; Beckman Coulter, Brea, CA, USA) and enzyme-linked immunosorbent assay (ELISA) (QUANTA Lite CCP3 IgG ELISA kit; INOVA Diagnostics, San Diego, CA, USA), respectively. ESR and CRP values were determined at each visit by MGH Clinical Laboratories. Serum samples from each visit were frozen at -70°C for subsequent determinations, including Pg antibody levels.
Pg antibody responses were determined in our laboratory by ELISA using a sonicate preparation of whole, formalin-fixed Pg ATCC 33277 (American Type Culture Collection, Manassas, VA, USA) . On the day prior to testing, 96-well polystyrene ELISA plates (Easy Wash; Corning, Tewksbury, MA, USA) were coated with Pg antigens (diluted 1:50) and incubated overnight at 4°C. On the next day, each well was incubated with 200
l of blocking buffer (5% nonfat dry milk in phosphate-buffered saline and Tween 20) at room temperature for 1 h. Following washing between each step, wells were incubated at room temperature with 100
l of each of the following: the patient's serum sample (diluted 1:400) and goat anti-human IgG conjugated to horseradish peroxidase (1:2,000), in each instance for 1.5 h, and then tetramethylbenzidine for 5 min, followed by sulfuric acid. The absorbance was measured at 450 nm using an ELISA plate reader (Model 550; Bio-Rad Laboratories, Hercules, CA, USA). To control for interassay variation, each assay included eight serial dilutions of a reference positive control sample as well as eight negative control samples, and all samples from the same patient were included on the same plate. A positive antibody response was defined as >2 SD above the mean absorbance of the 19 age-similar healthy hospital personnel. Pg antibody responses were not determined until after completion of the 12-month study period, and therefore treatment decisions were not influenced by these results.
Pg geometric mean antibody levels were compared between groups by performing an unpaired t-test with the Welch correction. Categorical data were analyzed using Fisher's exact test. Median values for clinical parameters in early RA patients were compared using the Mann-Whitney U test. Correlations between Pg antibody values and clinical parameters were performed using Pearson's correlation test. All statistical analyses were performed with GraphPad Prism version 5.01 software (GraphPad Software, La Jolla, CA, USA). A P value < 0.05 was considered statistically significant. All P values are two-tailed.
Clinical characteristics of patient groups
Clinical findings at study entry in patients with early rheumatoid arthritisa
Data (N= 50)
Age, years (range)
52 (30 to 80)
Smoking history, n (%)
Disease duration, months
4 (1 to 12)
Rheumatoid factor (RF), no. positive (%)
RF or anti-CCP
Erythrocyte sedimentation rate (ESR), mm/h (range)
23 (3 to 98)
C-reactive protein (CRP), mg/L (range)
7.6 (0.2 to 118)
4.7 (1.6 to 8.1)
Tender joint count (TJC), n (range)
8 (0 to 26)
Swollen joint count (SJC), n (range)
3 (0 to 23)
Clinical Disease Activity Index (CDAI)
19.2 (2 to 57.7)
Health Assessment Questionnaire (HAQ)
0.35 (0 to 2.55)
Medications prior to study entry, n (%)
Nonsteroidal anti-inflammatory drug (NSAID)
Tumor necrosis factor (TNF) inhibitor
Age and sex of the early rheumatoid arthritis group and comparison groupsa
( N = 19)
Blood bank donors
( N = 53)
( N = 17)
( N = 17)
( N = 50)
( N = 43)
48 (36 to 80)
44 (25 to 59)
50 (27 to 88)
53 (30 to 80)
60 (21 to 85)
By definition, healthy hospital personnel were selected because they were of similar age to those in the early RA group. Patients in the third CTD group also had similar ages as the individuals in these groups. However, compared with the early RA group, the lupus patients were significantly younger (P = 0.003) and those with late RA were significantly older (P = 0.01). As is typical of these rheumatic diseases, the RA patients and other CTD patients were predominantly female and the lupus patients were exclusively female. The majority of age-similar hospital personnel were men. No demographic or clinical information about blood bank donors was available.
Porphyromonas gingivalis immunoglobulin G antibody responses
When similar groups were combined, RA patients (early and late RA patients) had a significantly greater mean Pg antibody response than healthy control participants (blood bank donors and age-similar healthy control individuals) (P < 0.0001) (Figure 1B). Moreover, RA patients had higher mean Pg antibody responses than patients with CTD (lupus and other CTDs) (P = 0.1), and CTD patients had a higher mean Pg response than healthy control participants (P = 0.07), which were differences of possible significance.
Clinical correlation of Porphyromonas gingivalis antibody responses with anti-CCP antibodies and other standard RA biomarkers
In addition, 13 (76%) of the 17 patients with positive Pg antibody responses had elevated ESR levels compared with 18 (55%) of the 33 patients who lacked Pg antibodies (P = 0.2). Furthermore, ESR values were significantly higher in patients with positive Pg antibody responses (P < 0.05), and ESR levels correlated with Pg antibody levels (r = 0.32, P = 0.03) (Figure 3B). Patients with positive Pg antibody responses also had higher CRP values, but the magnitude of these values did not correlate significantly with Pg antibody responses. Overall, although most patients had positive test results for RF and anti-CCP autoantibodies and elevated inflammatory markers, the values were higher in the group with Pg antibodies.
Measurements of disease activity and function prior to and after disease-modifying antirheumatic drug therapy
After their first visit, all 50 patients with early RA were treated with DMARDs, usually MTX, and in some cases TNF inhibitors. During the following 12-month period, Pg antibody levels remained the same or declined slightly (data not shown), and no patient with an initial negative Pg antibody response developed a positive response during the study period. Conversely, the ESR and disease activity measures (DAS28-ESR and CDAI) generally improved, and functional scores (HAQ) usually returned to normal. However, compared with patients who lacked Pg antibody responses, those with positive Pg responses still tended to have higher DAS28-ESR scores and significantly higher ESR values at the 12-month follow-up visit (Figure 4). Moreover, at 12 months, only 6 (38%) of the 16 patients who had positive Pg antibody responses achieved DAS28 remission compared with 14 (64%) of the 22 patients who lacked Pg antibodies (P = 0.2), though this trend was not statistically significant. Thus, in patients with elevated Pg antibodies, the trend toward greater disease activity, as measured by DAS28 scores, remained after 12 months of DMARD therapy.
In this study, 34% of patients with early RA, prior to DMARD therapy, had positive IgG antibody responses to Pg. These antibody responses were of significantly greater frequency and magnitude than those of age-similar healthy hospital personnel or blood bank donors. Most of the RA patients were women, and the majority of hospital personnel were men. Although men may carry a greater risk of PD than women , a highly significant difference was still shown between the RA patients and healthy participants. In addition, Pg antibody levels in early RA patients were similar to or even higher than those in late RA patients, even though the latter group had more risk factors for PD, including older age and more frequent smoking history . Furthermore, the similar or higher Pg antibody levels in DMARD-naïve early RA patients compared with DMARD-treated late RA patients suggest that immunosuppression from DMARD therapy did not alter or enhance Pg antibody reactivity. Although 26% of the early RA patients at the time of enrollment were receiving steroids, which may potentially lower antibody levels, Pg antibody levels tended to be higher in patients receiving steroids, suggesting that steroid treatment did not decrease Pg antibody levels.
We also included a comparison group consisting of patients with other CTDs typically associated with systemic inflammation and autoantibody production, including lupus, mixed CTD, Sjögren syndrome or scleroderma. About 20% of these patients had positive antibody responses to Pg, which was a lesser percentage than RA patients (34%) but greater than age-similar healthy control participants (5%). We hypothesize that Pg reactivity in patients with other CTD may have been caused by PD, nonspecific immune stimulation or both. However, because almost all of the patients with other CTDs lacked anti-CCP antibodies, cross-reactivity with citrullinated proteins does not appear to account for increased Pg reactivity in the non-RA patient groups. Thus, we conclude that a subset of RA patients seen early in the illness prior to DMARD therapy have positive Pg IgG antibody responses, which were more frequent and of higher magnitude than those in individuals in the other groups we tested.
Determining which Pg antigens to use for serologic tests is problematic. Using whole-Pg lysates, a Pg-specific lipopolysaccharide or recombinant citrullinated Pg PAD, other investigators have previously demonstrated increased frequencies of Pg antibody responses in patients with chronic RA compared with healthy control participants [5, 13–16, 22], as we did using whole-sonicate antigens. In the only previous study of new-onset RA patients, antibody responses to Pg specific chaperone protein HtpG were not significantly different from those in healthy control participants . However, antibody responses to this protein may protect against PD and may even be higher in healthy subjects . In our study, we chose to use whole-sonicate antigens because little is known about the frequencies of reactivity with specific Pg antigens, even in patients with PD. Therefore, the use of whole-sonicate antigens, which encompass many Pg proteins, would increase the possibility of detecting responses. Although such preparations would presumably also increase the potential for false-positive results because of cross-reacting antibodies to other organisms or cross-reactivity between bacterial and host citrullinated proteins , we attempted to address this issue by testing serum samples from multiple comparison groups. Future serologic studies using multiple types of assays, such as ELISA and Western blot analysis, as well as different antigen preparations, including noncitrullinated Pg proteins, will be important to define further the sensitivity and specificity of Pg antibody responses in RA patients.
In our study, a limitation in our ability to interpret Pg antibody responses is the lack of dental examinations in case and control participants. In our study, the cutoff value for a positive response was 2 SD above the mean value in the age-similar healthy control participants who reported no history of PD. Yet, it is possible that some of these individuals had PD, which might obscure a difference between RA patients and control participants. However, a highly significant difference was still shown between these groups. Others have previously noted an increased frequency of PD in RA patients [1–5]. Pg antibody responses correlate well with the presence of PD , and higher Pg antibody titers and DAS28 scores have been noted in RA patients with more severe PD . However, Pg antibodies may also be associated with a host protective response or carriage of Pg as a commensal opportunistic pathogen [23, 26]. Therefore, in future studies, it will be important to perform Pg antibody studies along with dental examinations, as we have now initiated in our cohort.
In addition to RA, increased frequencies and severity of PD have been reported in several other rheumatic diseases, including ankylosing spondylitis , scleroderma  and psoriatic arthritis . Although patients with Sjögren syndrome have xerostomia, periodontitis does not seem to be more frequent in these patients . In addition to Pg reactivity, antibody responses to several other PD pathogens have been found in RA patients, including Prevotella intermedia, Prevotella melaninogenica, Actinobacillus actinomycetemcomitans and Bacteroides forsythus [13, 16]. Thus, among rheumatic diseases, increased frequencies of PD may not be unique to RA and increased frequencies of positive antibody responses to PD pathogens may include organisms other than Pg.
What does seem to be unique in RA is the association between Pg and anti-CCP antibody responses. Consistent with previous reports [14, 15], our early RA patients with Pg antibodies more often had anti-CCP antibody reactivity. Their anti-CCP responses were significantly higher, and the levels of anti-Pg antibodies correlated directly with anti-CCP levels. In contrast, anti-CCP antibody responses were rarely found in patients with other CTDs, and, if present, the levels were very low. Moreover, these responses were not present in healthy control participants. Mikuls et al. recently noted that Pg antibodies may be present prior to the development of synovitis , and, in our study, no patient who initially had negative results for Pg antibodies developed these antibodies during 12 months of DMARD therapy. Taken together, these observations suggest that immunity to Pg is one factor that may set the stage for autoimmunity and inflammatory synovitis in a subset of RA patients.
Citrullination of proteins may occur within the joint as well as at other sites of inflammation, such as the lung and periodontium [32, 33]. In our study, Pg-negative RA patients were more likely to be smokers, suggesting that the lung, rather than the gingiva, may have been the site of protein citrullination in these patients. Further studies which examine the lung and periodontium in RA patients are needed to evaluate this hypothesis. Although Pg may be involved in RA pathogenesis through citrullination, there may be other important mechanisms by which Pg contributes to disease activity in RA. For example, the organism may be more likely to skew CD4+ T-cell reactivity to a Th17 phenotype , a response which has been implicated in autoimmunity .
Despite specific mechanisms that may account for the association of Pg immunity with RA, we found, as others have [5, 14, 16], that RF, general markers of inflammation (ESR), scores of disease activity (DAS28 and CDAI) and functional impairment (HAQ) were also greater in patients with Pg antibody responses. Moreover, the trends remained for the DAS28-ESR and ESR values during 12 months of DMARD therapy. Although the CDAI scores were also slightly higher in the Pg antibody-positive group, the differences were not as great as those in the DAS28-ESR, suggesting that ESR is an important contributor to differences in disease activity scores between the groups. Thus, Pg antibodies may simply be a marker for PD, a chronic inflammatory condition that may itself be associated with elevation of inflammatory markers. However, the trend toward more severe disease activity in Pg antibody-positive patients using indices (HAQ and CDAI) that do not incorporate inflammatory markers suggests that Pg itself may contribute to RA disease activity.
There are possible confounding issues in the association of Pg antibody reactivity with greater disease activity in RA. For example, certain health behaviors, such as lack of routine dental care, might extend to noncompliance with RA treatment. Factors not studied here, such as the shared epitope (SE), may contribute to the severity of PD  as well as RA, and the SE has been associated with periodontal bone destruction in RA patients . However, other studies in RA patients have not found a correlation between the SE and PD or Pg antibodies [5, 14]. Because of the heterogeneous environmental and host factors involved in RA, patient cohorts may vary, accounting for inconsistent results in clinical correlations among studies [4, 5, 14–16]. However, consistent with our results, there is general agreement that Pg immunity is associated with greater inflammation in RA patients.
In a preliminary study of patients with established RA, Ortiz et al. reported that disease activity, as measured by DAS28 score and swollen joint counts, improved with nonsurgical treatment of PD . Pg antibodies as a marker for PD may prove to be useful in the identification of patients who would benefit from such treatments. It will be particularly important to conduct studies of therapies for PD and Pg in patients with early RA because PD treatment may make the most difference in early stages of the disease.
A subset of early DMARD-naïve RA patients had positive Pg antibody responses which were more frequent and of higher magnitude than those in patients with other CTDs or healthy control participants. Compared with patients who lacked Pg antibodies, those with positive Pg responses more often had anti-CCP antibody reactivity, their anti-CCP levels were significantly higher and the levels of anti-Pg antibodies correlated directly with anti-CCP levels. Furthermore, there was a trend toward higher disease activity and more functional impairment in patients with Pg antibody responses, and these trends remained during 12 months of DMARD therapy. These findings are consistent with a role for Pg in disease pathogenesis in a subset of RA patients.
American College of Rheumatology
anti-cyclic citrullinated peptide
Clinical Disease Activity Index
connective tissue disease
Disease Activity Score based on 28-joint count
disease-modifying antirheumatic drug
European League Against Rheumatism
enzyme-linked immunosorbant assay
erythrocyte sedimentation rate
Health Assessment Questionnaire
Massachusetts General Hospital
nonsteroidal anti-inflammatory drug
This study was supported in part by the American College of Rheumatology grant program "Within our Reach: Finding a Cure for Rheumatoid Arthritis"; the Dana Foundation; the English Bonter Mitchell Foundation; the Mathers Foundation; the Ounsworth-Fitzgerald Foundation; the Nathan Littauer Foundation; the Lyme/Arthritis Research Fund at MGH; the Eshe Fund; and the National Institutes of Health (NIH) (grant CA069212). SLA was supported by an NIH training grant (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR-007258) and a postdoctoral fellowship award from the Arthritis Foundation. The authors thank Dr Mandakolathur Murali, director of the MGH Clinical Immunology Laboratory, for assistance in obtaining patient serum samples and performing anti-CCP antibody testing and Colin Gorman, the study coordinator, for help with administrative aspects of the study.
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