Purpose To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) with rheumatoid arthritis (RA) and to examine associations of PD and Porphyomonas gingivalis (Pg) with disease features. Methods RA cases (N=287) and controls (N=330) underwent a standardized periodontal examination. HLA-DRB1 status was imputed using SNPs from the extended MHC. Circulating anti-Pg antibody was measured using ELISA and subgingival plaque was assessed for the presence of Pg using PCR. Associations of PD with RA were examined using multivariable regression. Results PD was more common in RA (35%, p = 0.022) and aCCP positive RA (n=240; 37%; p = 0.006) vs. controls (26%). There were no RA-control differences in anti-Pg or the frequency of Pg positivity by PCR. Anti-Pg antibody showed weak but statistically significant associations with both anti-CCP (r=0.14, p=0.022) and RF (r=0.19, p=0.001). PD was associated with increased swollen joint counts (p=0.004), DAS-28-CRP (p=0.045), total Sharp scores (p=0.015), aCCP (p=0.011), and RF (p<0.001). Select anti-citrullinated peptide antibody (ACPA; including antibody to citrullinated filaggrin) were higher in patients with subgingival Pg and higher anti-Pg antibody levels irrespective of smoking. Associations of PD with established seropositive RA were independent of all covariates examined including evidence of Pg infection. Conclusions Both PD and Pg appear to shape RA-related autoreactivity in RA. In addition, PD demonstrates an independent relationship with established seropositive RA.

Rheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish whether preferential rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease. Ultimately, understanding the unique mechanisms for cardiovascular disease in rheumatoid arthritis will aid in risk stratification and the identification of novel targets for meaningful reduction of cardiovascular risk in this patient population.

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.

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.

BackgroundRheumatoid arthritis (RA) is characterised by autoimmunity to citrullinated proteins, and there is increasing epidemiologic evidence linking Porphyromonas gingivalis to RA. P gingivalis is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response.ObjectivesTo examine the immune response to PPAD in patients with RA, individuals with periodontitis (PD) and controls (without arthritis), confirm PPAD autocitrullination and identify the modified arginine residues.MethodsPPAD and an inactivated mutant (C351A) were cloned and expressed and autocitrullination of both examined by immunoblotting and mass spectrometry. ELISAs using PPAD, C351A and another P gingivalis protein arginine gingipain (RgpB) were developed and antibody reactivities examined in patients with RA (n=80), individuals with PD (n=44) and controls (n=82).ResultsRecombinant PPAD was a potent citrullinating enzyme. Antibodies to PPAD, but not to Rgp, were elevated in the RA sera (median 122 U/ml) compared with controls (median 70 U/ml; p<0.05) and PD (median 60 U/ml; p<0.01). Specificity of the anti-peptidyl citrullinated PPAD response was confirmed by the reaction of RA sera with multiple epitopes tested with synthetic citrullinated peptides spanning the PPAD molecule. The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA.ConclusionsThe peptidyl citrulline-specific immune response to PPAD supports the hypothesis that, as a bacterial protein, it might break tolerance in RA, and could be a target for therapy.

Objective To examine the relationship of Porphyromonas gingivalis to the presence of autoantibodies in individuals at risk of rheumatoid arthritis (RA). Methods Study participants included the following: 1) a cohort enriched in subjects with HLA–DR4 and 2) subjects at risk of RA by virtue of having a first‐degree relative with RA. None of the study subjects satisfied the American College of Rheumatology 1987 classification criteria for RA. Autoantibodies measured included anti–citrullinated protein antibody (ACPA; by second‐generation anti–cyclic citrullinated peptide antibody enzyme‐linked immunosorbent assay [ELISA]) and rheumatoid factor (RF; by nephelometry or ELISA for IgA, IgM, or IgG isotype). Individuals were considered autoantibody positive (n = 113) if they had ≥1 RA‐related autoantibody; individuals were further categorized as high risk (n = 38) if they had ACPA or positive findings ≥2 assays for RF. Autoantibody‐negative individuals (n = 171) served as a comparator group. Antibody to P gingivalis, P intermedia, and F nucleatum were measured. Associations of bacterial antibodies with group status were examined using logistic regression. Results Anti–P gingivalis concentrations were higher in high‐risk (P = 0.011) and autoantibody positive group (P = 0.010) than in the autoantibody negative group. There were no group differences in anti–P intermedia or anti–F nucleatum concentrations. After multivariable adjustment, anti–P gingivalis concentrations (but not anti–P intermedia or anti–F nucleatum) were significantly associated with autoantibody‐positive and high‐risk status (P < 0.05). Conclusion Immunity to P gingivalis, but not P intermedia or F nucleatum, is significantly associated with the presence of RA‐related autoantibodies in individuals at risk of RA. These results support the hypothesis that infection with P gingivalis may play a central role in the early loss of tolerance to self antigens that occurs in the pathogenesis of RA.

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Objectives The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) is well described in rheumatoid arthritis (RA). However, the mechanisms underlying the potential interaction between these two distinct autoantibodies has not been well defined. We sought to evaluate the epidemiologic and molecular interaction of ACPA and RF with both disease activity as well as measures of RA-associated inflammation. Methods In a cohort of 1,488 Veterans with RA, measures of disease activity and levels of serum cytokines and multiplex ACPA were compared between the double-negative (aCCP-/RF-), ACPA-positive and RF-negative (aCCP+/RF-), ACPA-negative and RF-positive (aCCP-/RF+), or double-positive (aCCP+/RF+) subgroups. Studies were additionally performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA-ICs in the presence or absence of monoclonal IgM RF, and TNFα production measured as readout of macrophage activation. Results Compared with the double negative (as well each single positive) subgroup, the aCCP+/RF+ subgroup exhibited higher disease activity, serum CRP, and inflammatory cytokines (all P<0.001). In vitro stimulation of macrophages by ACPA-ICs induced increased cytokine production with the addition of monoclonal IgM RF as compared to ACPA-ICs alone (P=0.003) Conclusions The combined presence of ACPA and IgM RF mediates increased proinflammatory cytokine production in vitro, and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM RF enhances the capacity of ACPA-ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA-ICs in RA.