Background/Purpose: Chronic periodontitis has been associated with rheumatoid arthritis (RA), and Porphyromonas gingivalis has been proposed as the mechanistic link, due to its unique property among pathogens to express a citrullinating enzyme (denoted P. PAD). We have recently demonstrated elevated anti-P. gingivalis antibody levels in patients with anti-citrullinated protein antibody (ACPA) positive RA compared to controls. To investigate this aetiological hypothesis further, we have analysed the anti-P. gingivalis antibody response in pre-RA individuals in relation to the development of the ACPA response.

Methods: Incident cases of RA were identified among participants (n=30447) in a community based health survey linked to local and national registers, followed by a structured review of the medical records. One control from the health survey, matched for age, sex and year of inclusion, was selected for each validated case. Anti-CCP2 antibody status was determined by the standard commercial ELISA method (Euro-Diagnostica AB). Anti-P. gingivalis IgG were detected by in-house ELISAs, using a citrullinated peptide derived from P. PAD (CPP3) and the arginine-containing equivalent (RPP3), or purified arginine gingipainB (RgpB) protein, as coating antigens. Cut off values for these antibodies were set at the 98^th percentile among the controls. Analyses were stratified by time from inclusion in the health survey to RA diagnosis (1-5 and 6-13 years, respectively).

Results:

Serum was available from 166 cases (78% women), diagnosed with RA at a median of 5 years (IQR 3-8; range 1-13) after inclusion in the health survey. Anti-CPP3 and anti-RPP3 antibodies were detected in 6.0% and 5.4% of the pre-RA cases, respectively, whereas anti-CCP2 was positive in 22.3% of pre-RA cases. Positive anti-CPP3 antibodies were more frequent among anti-CCP2 antibody positive pre-RA cases (13.5 % vs. 3.9 %; p=0.04), whereas there was no such difference for anti-RPP3 IgG. Anti-CCP3 and anti-RPP3 antibodies occurred 1-5 years before RA diagnosis (7.2 % for both antibodies) as well as among those investigated 6-13 years before RA diagnosis (4.8% and 3.6%, respectively). Among anti-CPP3 positive pre-RA cases, levels of anti-CPP3 IgG were higher in those sampled ≤5 years before diagnosis (median 22.6 AU/ml (interquartile range (IQR) 17.0-29.2) vs. median 13.7 AU/ml (IQR 12.7-14.7; p=0.001), whereas there was no such difference for anti-RPP3 IgG (median 5.7 AU/ml; IQR 3.5-8.7 vs. median 4.2 AU/ml; IQR 3.9-14.6; p=0.71). Anti-RgpB IgG levels were not significantly different in pre-RA cases compared to controls (median 110.4 AU/ml;IQR 53.0-233.5 vs. median 94.4 AU/ml IQR 45.5-194.1; p=0.15).

Conclusion: Antibodies to P.gingivalis antigens occur years before RA diagnosis in a subset of pre-RA individuals. Presence of anti-CPP3 antibodies is associated with anti-CCP2 antibody positivity in the pre-clinical phase of RA, suggesting that the antibody response to citrullinated P.PAD in the context of chronic periodontitis could be one mechanism through which the early RA-specific immune phenotype can develop.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-antibody-response-to-porphyromonas-gingivalis-detected-in-sera-years-before-the-clinical-onset-of-rheumatoid-arthritis/