Background/Purpose: Rheumatoid arthritis (RA) is associated with an increased frequency of periodontal disease (PD) and antibodies to P. gingivalis (Pg), a major periodontal pathogen. Both Th1 and Th17 immune responses are thought to be important in RA, and a Th17 polarizing milieu has been demonstrated in periodontitis. Here we examined the association of Pg antibodies with specific cytokine and chemokine responses in early RA patients, prior to and during DMARD therapy.

Methods: Sera were obtained from 48 early RA patients, 36 from our cohort and 12 from NYU, who were enrolled prior to initiation of DMARDs, and from 24 healthy control subjects. Sera were tested for Pg IgG antibodies by ELISA using whole Pg sonicate (ATCC 33277). Protein levels of 20 cytokines and chemokines, including those associated with Th1 and Th17 immune responses, were quantified by Luminex in serum and, when available, in synovial fluid (SF).

Results: Prior to DMARD therapy, 23 of the 48 patients (48%) had positive IgG antibody responses to Pg. These patients more often had elevated anti-CCP antibodies than those who were Pg-negative (91% vs. 64%, P=0.06) and tended to have higher serum levels of most cytokines and chemokines tested. The differences between Pg-positive and Pg-negative patients were most striking for the Th17-associated cytokine, IL-23, the levels of which were at least 8-fold higher in serum than the other mediators. In the 7 patients in whom SF was available, IL-23 levels were 4-fold higher in serum than in SF, and serum levels of IL-23 were significantly higher in Pg-positive versus Pg-negative patients (P=0.04). In contrast, the levels of Th1-associated chemokines were more concentrated (>10X) in SF than in serum (CXCL9, P =0.1; CXCL10, P=0.02) of both Pg-positive and Pg-negative patients.

In Pg-positive patients, the levels of anti-CCP antibodies and most inflammatory mediators correlated directly with disease activity (DAS-28-CRP), whereas these correlations were not seen in Pg-negative patients (P≤0.05). Moreover, there was a trend towards a correlation between DAS-28 and the Th17-associated cytokines, IL-23 and IL-17α, in Pg-positive patients (P≤0.1), but not in Pg-negative patients (P≤0.8). During the 12 months of DMARD therapy, disease activity measures and inflammatory mediators declined, whereas the Pg antibody levels did not change significantly. Of the inflammatory mediators and biomarkers studied, Pg antibody levels were the strongest predictor of DAS-non-remission at 12 months (P=0.02) and a similar trend was observed for IL-23.

Conclusion: The levels of IL-23 were higher in serum than in SF of Pg-positive early RA patients, whereas Th1-associated mediators were concentrated in SF of both Pg-positive and Pg-negative patients. This suggests that in Pg-positive patients, IL-23 production may occur in extra-articular sites such as the oral mucosa. Moreover, Pg antibody positivity and high IL-23 levels were associated with a higher frequency of DAS-non-remission at 12 months. Thus, Pg infection is one factor that may contribute to Th17 immune responses and greater inflammation in a subset of early RA patients who may benefit from more aggressive initial therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-high-serum-interleukin-23-levels-with-porphyromonas-gingivalis-antibodies-in-patients-with-early-rheumatoid-arthritis/