The positive correlation between Porphyromonas gingivalis and Prevotella spp. Response to: ‘Comment on ‘Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population’ by Kishikawa et al.’ by Kitamura et al

ObjectiveThe causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome’s role in RA pathology by a comprehensive metagenome-wide association study (MWAS).MethodsWe conducted MWAS of the RA gut microbiome in the Japanese population (ncase=82, ncontrol=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis).ResultsPhylogenetic case–control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case–control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case–control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls.ConclusionOur shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome’s role in RA aetiology.

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Comment on: ‘Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population’ by Kishikawa et al

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-217808 ◽

2020 ◽

pp. annrheumdis-2020-217808 ◽

Cited By ~ 1

Author(s):

Kaori Kitamura ◽

Hiroshi Shionoya ◽

Kuniaki Terato ◽

Suguru Suzuki ◽

Richio Fukai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Association Study ◽

Gut Microbiome ◽

Japanese Population

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THU0066 DOES PORPHYROMONAS GINGIVALLIS MODULATE GUT MICROBIOME RESULTING IN AGGRAVATION OF DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1368 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 245.1-246

Author(s):

K. Kitamura ◽

K. Terato ◽

R. Fukai ◽

K. Katayama ◽

T. Waritani ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Porphyromonas Gingivalis ◽

Rank Correlation ◽

Inverse Correlation ◽

Inadequate Response ◽

Positive Correlation ◽

E Coli ◽

Antibody Levels ◽

Total Bacteria

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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The Use of Radioiodinated Congo Red in the Study of Amyloidosis

Nuklearmedizin ◽

10.1055/s-0037-1621202 ◽

1963 ◽

Vol 03 (01) ◽

pp. 25-38

Author(s):

Manuel Tubis ◽

William Blahd ◽

John Endow

Keyword(s):

Rheumatoid Arthritis ◽

Multiple Myeloma ◽

Comparative Studies ◽

Congo Red ◽

Half Time ◽

Positive Correlation ◽

Autopsy Findings ◽

Percentage Removal

SummaryA study of the removal of I131-labeled Congo red from the blood of amyloid, non-amyloid, multiple myeloma, rheumatoid arthritis and other patients is presented. The percentage removal of the labeled dye shows the same variation reported by many other workers using Bennhold’s test and its modifications.However, there seems to be a positive correlation between the percentage removal of the labeled dye and the presence of amyloid as revealed by biopsy and autopsy. The half-time of disappearance is also correlated with the amyloidosis.The availability of the I131-labeled dye permits the use of very small weights of the dye thereby drastically reducing the possibility of toxic and sometimes fatal reactions encountered with the unlabeled dye. The I131 present permits easy quantitation of the dye in the blood without separation of plasma and obviates the need of fasting. It also permits external counting and scanning of deposits in the organs containing the dye.The availability and use of the labeled dye may stimulate more comparative studies of the removal of the dye from the blood correlated with biopsy and autopsy findings.

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Can Cytokines be used as an Activation Marker in Rheumatoid Arthritis?

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666201019115030 ◽

2020 ◽

Vol 20 ◽

Author(s):

Fatih Öner Kaya ◽

Yeşim Ceylaner ◽

Belkız Öngen İpek ◽

Zeynep Güneş Özünal ◽

Gülbüz Sezgin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Healthy Volunteers ◽

Venous Blood ◽

Cross Sectional Study ◽

Joint Disease ◽

Control Group ◽

Cross Sectional ◽

Positive Correlation ◽

Das 28 ◽

Tnf Α

Aims: The etiopathogenesis of Rheumatoid Arthritis (RA) is not clearly understood. However, the role of the cytokines takes an important part in this mechanism. We aimed to bring a new approach to the concept of 'remission' in patients with RA. Background: RA is a chronic, autoimmune, inflammatory disease that involves small joints in the form of symmetrical polyarthritis and progresses with exacerbations and remissions. Pain, swelling, tenderness and morning stiffness are typical of the joints involved. Although it is approached as a primary joint disease, a wide variety of extra-articular involvements may also occur. It is an interesting pathophysiological process, the exact cause of which is still unknown, with many environmental, genetic and potentially undiscovered possible factors in a chaotic manner. Objective: In this cross-sectional study, sedimentation rate (ESR), C- Reactive protein (CRP), Tumor necrosis factor (TNF)-α, soluble-TNF-α receptor (TNF-R), Interleukin (IL)-1B and IL-10 were measured in three groups which were healthy volunteers, patients with RA in the active period, and patients with RA in remission. Disease activity score-28 (DAS-28) was calculated in active RA and RA in remission. Methods: This study included 20 healthy volunteers, 20 remission patients with RA and 20 active RA patients. Venous blood samples were collected from patients in both healthy and RA groups. Results: RA group consisted 43 (71.6%) female and 17 (28.4%) male. Control group consisted 11 (55%) female and 9 (45%) male. TNF-R was significantly high only in the active group according to the healthy group (p=0.002). IL-10 was significantly high in active RA according to RA in remission (p=0.03). DAS-28 was significantly high in active RA according to RA in remission (p=0.001). In the active RA group, ESR and TNF-R had a positive correlation (r:0.442; p=0.048). In the active RA group, there was also a positive correlation between TNF-R and CRP (r:0.621; p=0,003). Both healthy and active RA group had significant positive correlation between ESR and CRP (r: 0.481; p=0.032 and r: 0,697; p=0,001 respectively). Conclusion: TNF-R can be the main pathophysiological factor and a marker showing activation. TNF-R can be very important in revealing the effect of TNF on the disease and the value of this effect in the treatment and ensuring the follow-up of the disease with CRP instead of ESR in activation.

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Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

Current Chemical Biology ◽

10.2174/2212796813666181219124924 ◽

2019 ◽

Vol 13 (2) ◽

pp. 140-148

Author(s):

Mai Nasser ◽

Noha M. Hazem ◽

Amany Atwa ◽

Amina Baiomy

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Autoimmune Diseases ◽

Disease Activity ◽

Mrna Expression ◽

Disease Activity Score ◽

Activity Score ◽

Tlr2 Expression ◽

Positive Correlation ◽

Tlr2 Mrna

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

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POS0068 HIGH LEVELS OF PORPHYROMONAS GINGIVALIS AND PREVOTELLA INTERMEDIA ANTIBODIES IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2222 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 240.2-241

Author(s):

F. Zekre ◽

R. Cimaz ◽

M. Paul ◽

J. L. Stephan ◽

S. Paul ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Juvenile Idiopathic Arthritis ◽

Periodontal Disease ◽

Porphyromonas Gingivalis ◽

Joint Disease ◽

Control Group ◽

Prevotella Intermedia ◽

Igg Antibodies ◽

Idiopathic Juvenile Arthritis ◽

High Level

Background:Idiopathic juvenile arthritis (JIA) is a heterogeneous group of pathologies whose origin remains unknown at present (1). They are characterised by a systemic inflammatory and joint disease affecting children under 16 years of age. The current classification groups the different forms of JIA into 7 distinct entities (systemic forms, polyarticular forms with or without rheumatoid factors, oligoarticular forms, inflammatory arthritis associated with enthesopathies (ERA), arthritis associated with psoriasis and unclassifiable arthritis). Exact etiology of JIA is still unknown. To date, the various hypotheses put forward on the occurrence of JIAs integrate the genetic and environmental framework.The link between periodontal disease and rheumatoid arthritis (RA) is largely reported. Recently, Porphyromonas gingivalis (P. gingivalis) infection explained the occurrence of arthritis in rodent and in RA (2). Several studies mention the beneficial effect of P. gingivalis treatment on disease activity.Currently, there are very few studies on the prevalence of P. gingivalis in patients with JIA and the possible involvement of the germ in the development of inflammatory joint diseases in the pediatric population(3)(4).Objectives:The objective of our study is to determine presence of high IgG antibodies against P. gingivalis and Prevotella Intermedia in a cohort of patients with JIA compared to a control population and to determine variation of level according to sub-classes of JIA.Methods:Sera were obtained from 101 patients satisfying the ILAR classification criteria for JIA and in 25 patients with two other dysimmune disorders (type 1 diabetes and juvenile inflammatory bowel disease). Level of IgG antibodies against P. gingivalis and Prevotella Intermedia were obtained by homemade ELISA already used previously (5).Results:In the JIA group, major children were oligarthritis (47.5%), polyarthritis represents 31.7% of JIAs, ERA and systemic forms of JIA are respectively 9 and 11%. For the control group, 10 (40%) children had diabetes and 15 (60%) had IBD.Levels of anti-P. gingivalis anti-Prevotella Intermedia antibodies were higher in AJI group compared at control groups (P<0.01, P<0.05). Theses difference are mainly related to oligoarthritis and ERA subsets for both P. gingivalis and Prevotella Intermedia.Figure 1.Relative titer of antibodies to P. gingivalis and anti Prevotella intermedia. *: P<0.05; **: P<0.01; ***: P<0.001. P. gingivalis (control vs oligoarthritis p= 0.0032. control vs ERA p= 0.0092). Prevotella intermedia (control vs oligoarthritis p= 0.0194. control vs ERA p= 0.0039).Conclusion:We confirmed high level of anti-P. gingivalis and anti-Prevotella intermedia antibodies in JIA compared to other inflammatory disorders. For the first time, we observed that this high level was mainly in oligoarthritis and ERA. Further investigations are required to investigate involvement of oral dysbiosis in AJI pathogenesis. As observed in RA, it could be a new way to integrate in JIA therapy management.References:[1]Thatayatikom A, De Leucio A. Juvenile Idiopathic Arthritis (JIA). StatPearls Publishing; 2020[2]Cheng Z, Meade J, Mankia K, Emery P, Devine DA. Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):19–30.[3]Romero-Sánchez C, Malagón C, Vargas C, Fernanda Torres M, Moreno LC, Rodríguez C, et al. Porphyromonas Gingivalis and IgG1 and IgG2 Subclass Antibodies in Patients with Juvenile Idiopathic Arthritis. J Dent Child Chic Ill. 2017 May 15;84(2):72–9.[4]Lange L, Thiele GM, McCracken C, Wang G, Ponder LA, Angeles-Han ST, et al. Symptoms of periodontitis and antibody responses to Porphyromonas gingivalis in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2016 Feb 9[5]Rinaudo-Gaujous M, Blasco-Baque V, Miossec P, Gaudin P, Farge P, Roblin X, et al. Infliximab Induced a Dissociated Response of Severe Periodontal Biomarkers in Rheumatoid Arthritis Patients. J Clin Med. 2019 May 26;8(5).Disclosure of Interests:None declared.

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