Objective To profile the subgingival oral microbiota abundance and diversity in never-treated, new-onset rheumatoid arthritis (NORA) patients. Methods Periodontal disease (PD) status, clinical activity and sociodemographic factors were determined in patients with NORA, chronic RA (CRA) and healthy subjects. Massively parallel pyrosequencing was used to compare the composition of subgingival microbiota and establish correlations between presence/abundance of bacteria and disease phenotypes. Anti-P. gingivalis antibodies were tested to assess prior exposure. Results The more advanced forms of periodontitis are already present at disease onset in NORA patients. The subgingival microbiota of NORA is distinct from controls. In most cases, however, these differences can be attributed to PD severity and are not inherent to RA. The presence and abundance of P. gingivalis is directly associated with PD severity as well, is not unique to RA, and does not correlate with anti-citrullinated peptide antibody (ACPA) titers. Overall exposure to P. gingivalis is similar in RA and controls, observed in 78.4% and 83.3%, respectively. Anaeroglobus geminatus correlated with ACPA/RF presence. Prevotella and Leptotrichia species are the only characteristic taxa in the NORA group irrespective of PD status. Conclusions NORA patients exhibit a high prevalence of PD at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota of NORA patients is similar to CRA and healthy subjects of comparable PD severity. Although colonization with P. gingivalis correlates with PD severity, overall exposure is similar among groups. The role of A. geminatus and Prevotella/Leptotrichia species in this process merits further study.

Corticosteroids are the preeminent antinflammatory agents altoh the molular menims that impart their efficacy have not been defined. shown by Northern blot analysis, and expressin of membraneassociated ELAM-1 and ICAM-1, as shown by quantitative immunofluorescence (both P < 0.001, n = 9). De s_ markedly inhibited LPS-stimulated accumul of mRNA for ELAM-1 and expression of ELAM-1 and ICAM-1 (IC_% < 10 nM, both P < 0.001, n = 4-9); inhibition of exp by dexamethasone was reversed by RU-486 (both P < 0.005, n = 4-6). As in the adhesion studies, cortsol but not tetahydro cortisol inhibited expression of ELAM-1 and ICAM-1 (bothP < 0.005, n = 3 or 4). In contrast, sodium sallcylate (1 mM) inhibited neither adhesion nor expressin of these adesn molecules. These studies suggest that antan by de hasone ofendotoxin-induced inflammation is a specifc s of the general biological principle that the glucocortcod receptor is a hormone-dependent regulator of transcription.

The responses of neutrophils to soluble and insoluble stimuli include aggregation, chemotaxis, lysosomal enzyme release, and the generation of active oxygen species such as superoxide anion. These processes, which have been described as stimulus-response coupling, can be influenced by ions, cyclic nucleotides, and metabolites of arachidonate (1) . In recent years, a role for adenosine has been described in the stimulus-response coupling of a variety of cells and tissues. Adenosine receptors and/or hormone like responses to adenosine have been reported in adipocytes, neurons, hepatocytes, smooth muscle cells, coronary arteries, and heart muscle (2-7). These responses have also been described in circulating cells of the blood, i.e., lymphocytes (8-10), macrophages (11), basophils (12), and mast cells (13).Adenosine in the presence of homocysteine thiolactone inhibits transmethylation reactions. These reactions are required for maintenance of high avidity receptors for the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP)t on murine macrophages. Pike and Snyderman (11) found that generation of superoxide anion by macrophages in response to FMLP was inhibited by adenosine. These studies suggested that adenosine might regulate stimulusresponse coupling in neutrophils as well. However, Marone et al. (14) were unable to demonstrate a significant effect of adenosine on the release of lysosomal enzyme (beta-glucuronidase) from human neutrophils stimulated by particle ingestion.We have therefore examined the role of adenosine as a modulator of superoxide anion generation, degranulation, and aggregation in human neutrophils exposed to soluble stimulants. We report that adenosine, at physiological concentrations, is a potent and specific regulator of neutrophil superoxide anion generation but exerts little or no effect on either degranulation or aggregation. Further, we demonstrate that this effect is independent of the cellular uptake of

Rheumatoid arthritis (RA) and adult periodontitis share common pathogenetic mechanisms and immunologic and pathological findings. One oral pathogen strongly implicated in the pathogenesis of periodontal disease, Porphyromonas gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor for RA. We suggest that individuals predisposed to periodontal infection are exposed to antigens generated by PAD, with de-iminated fibrin as a likely candidate, which become systemic immunogens and lead to intraarticular inflammation. PAD engendered antigens lead to production of rheumatoid factor-containing immune complexes and provoke local inflammation, both in gingiva and synovium via Fc and C5a receptors.