Disease ⇒ Rheumatoid Arthritis {40000107} Record Keys Type:Disease Parent:[ ] Definition:Rheumatoid Arthritis Details Initialisation date:2019-06-16 Other Terms:RA LinksWickipediaMerck Manual Meta Information MedDra ID:10039073 MedDra Level:pt ICD:[ ] Category:Musculoskeletal, Rheumatology, Immunology Zone:[ ] Mechanism:[ ] Notes: - ACPA generation may be associated with larger populations of Prevotellaceae in both oral and intestinal microbiomes. In response to such altered microbial flora, certain predisposed individuals may develop auto-inflammatory disease, through mechanisms that may include the generation of cyclic citrullinated peptides or Th17 cell activation in the intestinal mucosa. (4)Shared Reference Notes [1.1] - Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of the tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidyl-arginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function; hence, PPAD may be involved in deregulation of the host signalling network and immune evasion. [1.2] - Prevotella is a crucial genus in the onset of other chronic inflammatory disorders such as rheumatoid arthritis - Ther is a strong association between Prevotella copri and new-onset untreated rheumatoid arthritis and the higher abundance of Prevotella was associated with a reduction in several beneficial microbes, including Bacteroides. [1.3] - In a region in Eastern India endemic for lymphatic filariasis caused by filarial worms, not a single person with rheumatoid arthritis (RA) tested positive for circulating filarial antigens - Much higher proportion (40%) of people without RA tested positive for the nematode. [1.4] [#Crohn’s disease, #Multiple Sclerosis] - Significantly lower abundances of Coprococcus in CD, Dialister in MS, and Roseburia in RA. - Significantly lower abundances of Coprococcus in CD, Dialister in MS, and Roseburia in RA. [1.5] - reduced abundance of Desulfovibrionaceae Bilophila, Akkermansia, and Veillonellaceae Dialister and increased levels of Lachnospiraceae Clostridium as most predictive of disease state. - increased Clostridiaceae Clostridium and Lachnospiraceae and reduced Erysipelotrichaceae were three of the eight identified in all RA models. [1.6] - Abundance of specific gut bacterial taxa and their genes enhances the clinical response to orthologs related to purine and methotrexate metabolism. [1.7] [#Porphyromonas gingivalis] - The presence of P. gingivalis in the GI microbiota has been linked with a milieu of inflammatory/autoimmune diseases associated with GI dysbiosis including RA and NAFLD [1.8] - Patients with RA showed an altered metabolic capacity for transporting zinc and copper. The study authors suggest that these alterations may significantly influence the perpetuations of the autoimmunity of RA. - Porphyromonas gingivalis (discussed within “Periodontal Microbiome and ACPA” section), Proteus mirabilis, Mycobacterium tuberculosis, and Mycoplasma spp are associated with an increased risk of RA development. [1.9] - Increased serum levels of the antibodies IgM rheumatoid factor (IgM-RF) and antibodies against #Citrullinated Proteins (ACPA) in healthy individuals imply an elevated risk of developing RA - The possible role of #Porphyromonas gingivalis in the immunopathogenesis of RA has been of particular interest due to its capacity to generate #Citrullinated Proteins. - #Prevotella in saliva is at higher relative abundance compared to healthy controls. - RA > #Veillonella in saliva and tongue coating is at higher relative abundance compared to healthy controls. [1.11] [1.12] [#Lipopolysaccharide] - RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters (LPB, LPS, and I-FABP) positively correlating with disease severity. - Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+ and decreases in IL-10+ intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. - Both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. - Exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. - Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. [1.13] [1.14] [#Chronic periodontitis, #Periodontal disease] - #Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative coccobacillus recognized as a pathogen in periodontitis and infective endocarditis. By producing a toxin (#Leukotoxin A, LtxA) that triggers global hypercitrullination in neutrophils, Aa has been recently linked to rheumatoid arthritis. - Aa has been proposed as a link between periodontitis and autoimmunity in rheumatoid arthritis (RA) due to its ability to induce citrullinated autoantigens targeted by anti-citrullinated protein antibodies (ACPAs). [1.15] - #Collinsella is increased in patients with rheumatoid arthritis and is associated with increased gut permeability. [1.16] -IgG and IgA autoantibodies from individuals who are at risk for RA cross-react against gut bacteria in the #Lachnospiraceae and #Ruminococcaceae families. - Analysis identified a bacterial strain from the #Subdoligranulum genus that was associated with autoantibody development. - Mice colonized with this #Subdoligranulum isolate developed arthritis with pathology similar to human RA. [1.17] [#Colorectal cancer, #Crohn’s disease] [#Bacteriophage, #Western-style diet] - the abundance of a class of crAss-like phages, a group of related viruses that includes some of the most abundant viruses of the human gut, were higher in populations with non-westernized dietary habits - several types of crAss-like phages were present at decreased levels in people with rheumatoid arthritis, #Systemic lupus erythematosus, #Ulcerative Colitis and Crohn disease, and at increased levels in people with colon cancer. [1.18] [#Bifidobacterium pseudocatenulatum] [#Secondary bile acids] [#Probiotic Bifidobacterium pseudocatenulatum] - In a collagen-induced arthritis (CIA) mouse model, B. pseudocatenulatum prevented joint damage by protecting the intestinal barrier and reshaped gut microbial composition, thereby elevating bile salt hydrolase (BSH) enzyme activity and increasing the levels of unconjugated secondary BAs to suppress aberrant T-helper 1/17-type immune responses [1.19] - IgG and IgA autoantibodies from individuals who are at risk for RA cross-react against gut bacteria in the #Lachnospiraceae and #Ruminococcaceae families. - RA > a bacterial strain from the Subdoligranulum genus (#Subdoligranulum didolesgii) that was associated with autoantibody development. [#Calprotectin] - High cCLP serum levels are associated with worse structural outcomes in rheumatoid arthritis and to a lesser extent, in #Spondyloarthritis. [1.21] [#Gingipains] - #Porphyromonas gingivalis is a major pathogenic bacterium involved in the pathogenesis of periodontitis. Citrullination has been reported as the underlying mechanism of the pathogenesis, which relies on the interplay between two virulence factors of the bacterium, namely gingipain R and the bacterial peptidyl arginine deiminase. - Gingipain R cleaves host proteins to expose the C-terminal arginines for peptidyl arginine deiminase to citrullinate and generate #Citrullinated Proteins. - Citrullinating proteins present in the host synovial tissues, atherosclerotic plaques and neurons. - both virulence factors are the key factors that trigger distal effects mediated by citrullination, leading to the development of some non-communicable diseases, such as rheumatoid arthritis, #Atherosclerosis, and #Alzheimer’s disease. [1.22] - overabundance of #Prevotella copri in early RA patients - proliferation of the genus Collinsela and some #Lactobacillus species. - Three mechanisms by which microbiota may contribute to RA pathogenesis were proposed: inflammatory responses (#Prevotella copri and #Lactobacillus), molecular mimicry (#Prevotella copri) and loss of intestinal barrier integrity (#Collinsella). [1.23] - Patients with rheumatoid arthritis, #Cancer, autoimmune diseases or other chronic inflammatory conditions are predisposed to #Depression. [1.24] - #Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs). - Citrullination is the conversion of the amino acid arginine into the non-proteinogenic amino acid citrulline. - Patients with RA and #Periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of specific monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. - The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPA B Cells encoded by RA blood plasmablasts. [1.25] [#Prevotella amnii, #Prevotella corporis, #Prevotella denticola, #Prevotella disiens, #Prevotella marshii] - #Prevotella predominates in the intestinal microbiome in the preclinical phase of rheumatoid arthritis, promoting pathological progression in a TH17 cell-dependent manner. - gut microbiome from rheumatoid arthritis patients > five species that belong to the #Prevotella (i.e., P. denticola, P. marshii, P. disiens, P. corporis, and P. amnii) [1.26] [#Parabacteroides distasonis] - The relative abundance of P. distasonis in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28) [#Parabacteroides distasonis] - Oral treatment of arthritic mice with live P. distasonis (LPD) considerably ameliorated RA pathogenesis. - LPD-derived #Lithocholic acid (LCA), #Deoxycholic acid (DCA), #Isolithocholic acid (isoLCA) and #3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. - A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. [1.27] [#Diabetes Type 2] - genus Actinobacterium #Collinsella was confirmed to be associated with #Alzheimer’s disease, as well as rheumatoid arthritis, #Atherosclerosis, and type 2 diabetes. [1.28] - rheumatoid arthritis > #Collinsella may lead to intestinal hyperpermeability by down-regulating the expression of epithelial tight junction [1.29] - RA Patients with more severe symptoms had increased levels of #Ruminococcus gnavus and other pro-inflammatory bacteria compared with those with milder symptom [#Diabetes Type 1] - #Covid-19 patients have a significantly higher risk to develop subsequent autoimmune diseases such as rheumatoid arthritis, #Ankylosing spondylitis, #Systemic sclerosis, type I diabetes mellitus. - In metabolic diseases such as #Obesity, chronically elevated levels of #Leptin are observed, which can induce the production of proinflammatory molecules and impair immune self-tolerance, predisposing to develop conditions such as rheumatoid arthritis, inflammatory bowel disease, #Multiple Sclerosis, and others [1.31] [#Prevotella copri] - P. copri was relatively more abundant in patients with new-onset untreated rheumatoid arthritis (NORA). - During an RA flare of a chronic patient on DMARDs, a peripheral blood mononuclear cell sample contained a P. copri HLA-DR-presented peptide. - This peptide was predicted to be derived from a P. copri 27-kDa protein and is believed to stimulate an immunogenic response via T-helper 1 cells. - P. copri 16S rRNA genes were detected in the synovial fluid of patients with NORA and chronic RA, albeit at low abundance. - correlation between anti-P. copri P27 antibodies with autoantibodies found in RA patients and proposed a potential causal role for P. copri in RA evolution and synovitis. [1.32] - overabundance of #Prevotella copri in early RA and loss of intestinal barrier integrity (possibly caused by increased bacteria like #Collinsella) may be responsible for the inflammatory response. - #Prevotella copri has been strongly implicated in new-onset untreated RA, with evidence immune reactivity to the bacterium in a subgroup of these patients. [#Prevotella copri] - #Prevotella 7 and #Prevotella 9, the latter of which matched in identity to P. copri, have been associated with polygenic risk scores and genetic risk for RA. - A particular strain of #Subdoligranulum from an individual at risk for rheumatoid arthritis (RA) was recently demonstrated to colonize germ-free mice and generate joint swelling similar to early RA by stimulating complement activation and IgG autoantibodies [1.33] [#Cognitive impairment] - decrease in #Prevotella histicola and #Prevotella oulorum > in the oral cavity of patients with rheumatoid arthritis, and cognitive decline [1.34] [#Diabetes Type 1, #Hashimoto’s thyroiditis, #Psoriasis, #Sjögren syndrome ] Patients with psoriatic disease had a significantly higher risk of #Crohn’s disease , #Ulcerative Colitis, #Systemic lupus erythematosus, rheumatoid arthritis, #Ankylosing spondylitis , #Alopecia areata, and type 1 diabetes. - the risk of #Graves’ disease, Hashimoto’s disease, Sjögren’s syndrome, and #Systemic sclerosis was not significantly different between the groups. [1.35] - #Actinobacteria, as a pathogen closely related to RA, may be an important factor that directly induces RA in damp environments - #Deltaproteobacteria, #Bacteroidaceae, and #Actinobacteria were the most common bacteria in #High humidity intervention healthy rats. [#Ruminococcaceae] - #High humidity aggravated joint injury in CIA rats, which may be related to the high abundance of bacterial species such as #Prevotella, #Clostridia, and Ruminococcaceae_UCG_010 induced by #High humidity, which could promote the immune response of Th17 cells. - #Prevotella, #Ruminococcaceae and #Clostridia were associated with RA because they induce the inflammatory response mediated by #IL-6, #IL-17 and IFN-γ cytokines - #High humidity can aggravate the extent of arthritis symptoms, including pathological changes, arthritis score and inflammatory factor expression. - #High humidity intervention reduced the abundance of #Prevotellaceae in healthy rats. - the abundance of #Prevotellaceae decreased during the immune activation stage of CIA [#Reactive Oxygen Species] - The content of mitochondrial ROS in monocytes of RA patients increases fivefold. - #Oxidative stress caused by ROS may be associated with the pathogenesis of RA. [1.36] - Both #Citrulline and #Arginine have anti-inflammatory properties and #Arginine is in phase 2 trial in treatment of RA - #Butyrate also encourages gut homeostasis by stimulating growth of beneficial commensals and suppressing TNF-α production through nuclear factor κB (NF-κB) inhibition in patients with RA [#Eggerthella lenta] - increased abundance of E. lenta in patients with seropositive RA high RF levels [#Eggerthella lenta] - dysbiosis can be responsible for autoantibodies to self-proteins that share sequence similarities with bacterial products. E. lenta shares homology with certain CII peptides, and naïve mice gavaged with E. lenta generate response to those peptides. - E. lenta could result in an autoreactive response to CII-derived proteins during normal physiological processes. [#Eggerthella lenta] [#Tryptophan] - Increased proportion of E. lenta led to a decrease in metabolites, N-acetylglutamine, deoxycarnitine, gamma glutamylmethionine, Trp, N-acetyltryptophan, and #Methionine, which supports our recent data in patients with RA where an increase in these metabolites was associated with a decrease in disease severity - Diet with high #Methionine has been shown to attenuate arthritic severity in rats. [1.37] [#Reactive arthritis] [#Prevotella nigrescens] - In a mouse study, P. nigrescens induced #Periodontal disease, resulting in early-onset severe experimental arthritis [1.38] [#Niacin] - Microbiota derived #Ribosyl nicotinamide (nicotinamide riboside or NR) is one of the main precursors of nicotinamide adenine dinucleotide (NAD+), which has been reported to be significantly reduced in individuals with rheumatoid arthritis. - Administration of NR and other NAD+ precursors leads to improved clinical outcomes for rheumatoid arthritis patients and for a range of other inflammatory, neurodegenerative and cardiovascular diseases [1.39] [#Collagen-induced arthritis , #Spondyloarthritis] [#Lachnospiraceae bacterium] - in CIA (such as Lachnospiraciae and Lactobacillaeae), RA (#Lachnospiraceae bacterium, #Lactobacillus spp., #Faecalibacterium), and SpA (#Ruminococcaceae, #Rikenellaceae, #Porphyromonadaceae, #Bacteroidaceae, #Lachnospiraceae) are either predicted or known to produce #Indole [#Collagen-induced arthritis ] - #kynurenine supplementation, or inhibition of #kynurenine production with the IDO1 inhibitor 1-methyl-#Tryptophan (1-MT) have shown conflicting effects on arthritis severity: - Intra-articular injection of #Indole, but not #kynurenine, into rabbit knees induced RA-like synovitis [#Sjögren syndrome ] - preceding sinusitis was associated with increased risk of several rheumatic diseases, including #antiphospholipid syndrome , Sjögren’s disease , #Vasculitis and #Polymyalgia rheumatica. - Acute sinusitis was also associated with increased risk of seronegative rheumatoid arthritis. - Sinusitis was most associated with any rheumatic disease in the 5-10 years before disease onset [#Systemic lupus erythematosus] - #Ruminococcus gnavus was associated with lupus nephritis, RA and #Spondyloarthritis. [1.41] [#Butyrate] - In mice with #Collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of #Multiple Sclerosis) > SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. [1.42] - In RA > each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. - In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab #Glycans. [1.43] - When compared with controls, participants with RA had increased levels of the #Collinsella aerofaciens species and #Enterococcus genera. Likewise, an increase of arginine deaminase activity was observed, which belonged, in approximately 90%, to the RA genes of the genus Collinsela.References Notes[ ]
