Background/Purpose: Chronic periodontitis has been considered as an important determinant in both occurrence and severity of rheumatoid arthritis (RA). It has been hypothesized that citrullination by the periodontal pathogen Porphyromonas gingivalis may play an important role in the development of RA-specific autoimmunity, by breaking immune tolerance to citrullinated proteins and trigger the production of anti-citrullinated protein antibodies (ACPA). In support of this hypothesis, we have recently demonstrated elevated anti-P. gingivalis antibody levels in RA compared to controls, specifically in ACPA+ RA. The aim of the present study was to further investigate the role of P. gingivalis in RA aetiology, by analysing the anti-P. gingivalis antibody response in plasma samples collected before the onset of RA.

Methods: A case-control study was preformed within the Medical Biobank of Northern Sweden. The study included 251 individuals who donated in total 422 plasma samples predating the onset of clinical symptoms of RA, and 198 population-based controls from the same cohort. The median (IQR) predating time until onset of RA was 5.2 (6.2) years. For 192 individuals diagnosed with RA, plasma was available from the time point of RA diagnosis, and 152 of these patients had also donated plasma before the onset of symptoms. All samples were analysed by in-house ELISAs for the presence of antibodies to virulence factor arginine gingipainB (RgpB) purified from P. gingivalis, and a citrullinated peptide (denoted CPP3) derived from the P. gingivalis PAD enzyme. Based on ROC curve analysis on RA patients and controls, a cut-off for anti-CPP3 IgG positivity was set at the 96^th percentile. The anti-P. gingivalis antibody data was evaluated in relation to the development of the classical ACPA response.

Results: The concentration of anti-RgpB IgG levels was significantly increased in RA patients (mean±SEM; 114.4±16.9 AU/ml), and importantly also in the pre-symptomatic individuals (152.7±14.8 AU/ml), when compared to controls (82.2±12.1 AU/ml, p < 0.001 for both). Antibodies against CPP3 were detected in 8% of the RA population, and in 5% of pre-symptomatic individuals, with elevated levels in both RA patients (9.29±1.81 AU/ml) and in pre-symptomatic individuals (4.33±0.59 AU/ml), compared to controls (2.36±0.58 AU/ml, p < 0.001 for both). The anti-CPP3 antibody response followed the classical ACPA response, with increasing antibody levels over time, whilst the anti-RgpB IgG response was stable in pre-symptomatic individuals during the pre-dating time and (if anything) showed a trend towards lower levels after RA diagnosis, potentially as a result of anti-inflammatory treatment.

Conclusion: Antibody levels against P. gingivalis were significantly increased in RA patients compared to controls, and more importantly, these antibodies were detected years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of autoimmunity and autoimmune disease in a subset of RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasma-concentrations-of-antibodies-to-porphyromonas-gingivalis-are-increased-before-onset-of-symptom-of-rheumatoid-arthritis/