Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes.Trial registration: UMIN CTR UMIN000012200

Intestinal bacterial compositions of rheumatoid arthritis (RA) patients have been reported to be different from those of healthy people. Dysbiosis, imbalance of the microbiota, is widely known to cause gut barrier damage, resulting in an influx of bacteria and their substances into host bloodstreams in animal studies. However, few studies have investigated the effect of bacterial substances on the pathophysiology of RA. In this study, eighty-seven active RA patients who had inadequate responses to conventional synthetic disease-modifying antirheumatic drugs or severe comorbidities were analyzed for correlations between many factors such as disease activities, disease biomarkers, intestinal bacterial counts, fecal and serum lipopolysaccharide (LPS), LPS-binding protein (LBP), endotoxin neutralizing capacity (ENC), and serum antibacterial substance IgG and IgA antibody levels by multiple regression analysis with consideration for demographic factors such as age, sex, smoking, and methotrexate treatment. Serum LBP levels, fecal LPS levels, total bacteria counts, serum anti-LPS from Porphyromonas gingivalis (Pg-LPS) IgG antibody levels, and serum anti-Pg-LPS IgA antibody levels were selected for multiple regression analysis using Spearman’s correlation analysis. Serum LBP levels were correlated with disease biomarker levels, such as erythrocyte sedimentation rate ( p < 0.001 ), C-reactive protein ( p < 0.001 ), matrix metalloproteinase-3 ( p < 0.001 ), and IL-6 ( p = 0.001 ), and were inversely correlated with hemoglobin ( p = 0.005 ). Anti-Pg-LPS IgG antibody levels were inversely correlated with activity indices such as patient global assessments using visual analogue scale (VAS) ( p = 0.002 ) and painVAS ( p < 0.001 ). Total bacteria counts were correlated with ENC ( p < 0.001 ), and inversely correlated with serum LPS ( p < 0.001 ) and anti-Pg-LPS IgA antibody levels ( p < 0.001 ). These results suggest that substances from oral and gut microbiota may influence disease activity in RA patients.

Background:Oral Porphyromonas gingivalis (Pg) infection in rheumatoid arthritis (RA) model revealed aggravation of arthritis, dysbiosis and higher serum LPS (1). We reported that IgA/IgG antibody against Pg-LPS ratio among the patients with RA related to disease marker levels and disease activities (2). However, there are still few reports related to Gut-Oral axis.Objectives:Firstly, how total intestinal bacteria, well-known 5 species of gut bacteria behave in relation to disease activities and markers. Secondly, how infection by Pg aggravate RA in relation to microflora, disease activities and markers.Methods:Eighty-seven RA patients with inadequate response to conventional synthetic DMARDs were evaluated. Age: 68.1±8.7 years, female (%): 79.3, disease duration: 136±91 months, DAS28-ESR: 4.68±0.98. Fecal bacteria numbers of total bacteria, Bifidobacterium, Lactobacillus, E. coli, Bacteroides and Staphylococcus were determined by PCR analysis. Fecal and serum LPS levels were measured by LAL assay. Serum endotoxin neutralizing activity (ENC) was determined along with RA disease activity and markers measurement. Infection of Pg was proofed by IgG and IgA anti-LPS antibody measurement. The statistical relationships between variables were analyzed by Spearman’s non-parametric rank correlation analysis and expressed as Spearman’s rank correlation coefficient “ρ”.Results:At first, we could neglect background effects as duration, methotrexate dose for measuring total or each bacterial number (data not shown). As shown in Figure 1, total bacteria only showed positive correlation with IL-6 levels (ρ= 0.230, p = 0.034), however inversely correlated with disease activities such as pVAS (ρ= -0.223, p = 0.038) and Pain VAS (ρ= -0.260, p = 0.015). While no significant relationship was observed between the numbers of each of 5 species of bacteria and the disease activities and makers except Bifidobacterium. In contrast, LPS-related markers showed positive correlation with disease activities and markers. Among LPS-related biomarker values, serum LBP levels mainly correlated with most of RA biomarker-ESR (ρ= 0.497, p <0.0001), CRP (ρ= 0.697, p <0.0001), MMP3 (ρ= 0.546, p <0.0001) and so on. Fecal LPS level was shown significant positive correlation with disease activities, however almost no correlation was observed in serum LPS level. IgA anti-LPS antibody levels to Pg, resulted in inverse correlation with total bacteria (ρ= -0.441, p<0.0001), Lactobacillus (ρ= -0.224, p=0.037), Bacteroides (ρ = -0.200, p = 0.064) and E. coli (ρ= -0.260, p = 0.015), moreover, positive correlation with serum LPS (ρ= 0.284, p = 0.008) and LBP (ρ= 0.247, p = 0.021) and inverse correlation with ENC (ρ = -0.321, p = 0.002) were found. On the other hand, IgG anti-Pg-LPS antibody levels which reflect systemic infection, inversely correlated SDAI (ρ = -0.308, p = 0.004), PainVAS (ρ = -0.433, p < 0.0001), and so on.Conclusion:Serum LBP highly associated with RA activity and markers, which suggests bacterial LPS as roles in triggering and perpetuating disease activity in RA. In contrast, IgA anti-Pg-LPS, IgG anti-Pg-LPS antibody reflecting infection of Pg, negatively associated with intestinal total bacteria (ρ=-0.4405, p<0.0001), RA disease activities, respectively. These results may show a possible oral -gut relationship resulting in aggravation of disease activity in RA.Disclosure of interest:None declaredReferences:[1]Sato K, Takahashi N, Kato T et al. Aggravation of collagen induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system. Sci Rep 2017; 7:6955.[2]Kuniaki Terato, Takaki Waritani, Richio Fukai et al. Contribution of bacterial pathogens to evoking serological disease markers and aggravating disease activity in rheumatoid arthritis. PloS One. 2018;13(2): e0190588.Disclosure of Interests:None declared

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One-year RAPID3 remission maintenance may predict good radiographic outcomes.