Antibodies to Porphyromonas gingivalis Indicate Interaction Between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology

Abstract

Objective: To investigate the role of the periodontal pathogen Porphyromonas gingivalis in the etiology of rheumatoid arthritis (RA) by analyzing the antibody response to the P gingivalis virulence factor arginine gingipain type B (RgpB) in relation to anti-citrullinated protein antibodies (ACPAs), smoking, and HLA-DRB1 shared epitope (SE) alleles in patients with periodontitis, patients with RA, and controls.

Methods: Anti-RgpB IgG was measured by enzyme-linked immunosorbent assay in 65 periodontitis patients and 59 controls without periodontitis, and in 1,974 RA patients and 377 controls without RA from the Swedish population-based case-control Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study. Autoantibody status, smoking habits, and genetic data were retrieved from the EIRA database. Differences in antibody levels were examined using the Mann-Whitney U test. Unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (95% CIs) for the association of anti-RgpB IgG with different subsets of RA patients.

Results: Anti-RgpB antibody levels were significantly elevated in periodontitis patients compared to controls without periodontitis, in RA patients compared to controls without RA, and in ACPA-positive RA patients compared to ACPA-negative RA patients. There was a significant association between anti-RgpB IgG and RA (OR 2.96 [95% CI 2.00, 4.37]), which was even stronger than the association between smoking and RA (OR 1.37 [95% CI 1.07, 1.74]), and in ACPA-positive RA there were interactions between anti-RgpB antibodies and both smoking and the HLA-DRB1 SE.

Conclusion: Our study suggests that the previously reported link between periodontitis and RA could be accounted for by P gingivalis infection, and we conclude that P gingivalis is a credible candidate for triggering and/or driving autoimmunity and autoimmune disease in a subset of RA patients.

Figure 1

Anti-RgpB IgG levels varied between patient and control populations. Significantly higher anti-RgpB IgG levels were detected in PD patients (n=65) compared to non-PD controls (n=59) (A); in RA (n=1,974) compared to non-RA controls (n=377) (B); and in ACPA-positive RA (n=1,381) compared to ACPA-negative RA (n=593) (C). The dashed line in A indicates the cut-off value (450AU/ml) for elevated anti-RgpB antibody levels, based on the 95^th percentile among the non-PD controls. The red solid lines indicate median values. ACPA = anti-citrullinated peptide/protein antibodies; AU = arbitrary units; IgG = immunoglobulin G; PD = periodontitis; RA = rheumatoid arthritis; RgpB = arginine gingipain B.