Another Look at the Contribution of Oral Microbiota to the Pathogenesis of Rheumatoid Arthritis: A Narrative Review

Although autoimmunity contributes to rheumatoid arthritis (RA), several lines of evidence challenge the dogma that it is mainly an autoimmune disorder. As RA-associated human leukocyte antigens shape microbiomes and increase the risk of dysbiosis in mucosae, RA might rather be induced by epigenetic changes in long-lived synovial presenting cells, stressed by excessive translocations into joints of bacteria from the poorly cultivable gut, lung, or oral microbiota (in the same way as more pathogenic bacteria can lead to “reactive arthritis”). This narrative review (i) lists evidence supporting this scenario, including the identification of DNA from oral and gut microbiota in the RA synovium (but in also healthy synovia), and the possibility of translocation through blood, from mucosae to joints, of microbiota, either directly from the oral cavity or from the gut, following an increase of gut permeability worsened by migration within the gut of oral bacteria such as Porphyromonas gingivalis; (ii) suggests other methodologies for future works other than cross-sectional studies of periodontal microbiota in cohorts of patients with RA versus controls, namely, longitudinal studies of oral, gut, blood, and synovial microbiota combined with transcriptomic analyses of immune cells in individual patients at risk of RA, and in overt RA, before, during, and following flares of RA.

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Oral Microbiota Identifies Patients in Early Onset Rheumatoid Arthritis

Microorganisms ◽

10.3390/microorganisms9081657 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1657

Author(s):

Anders Esberg ◽

Linda Johansson ◽

Ingegerd Johansson ◽

Solbritt Rantapää Dahlqvist

Keyword(s):

Rheumatoid Arthritis ◽

Early Onset ◽

Amplicon Sequencing ◽

Oral Bacteria ◽

Oral Microbiome ◽

Rrna Gene ◽

Oral Microbiota ◽

Disease Manifestation ◽

Periodontal Status ◽

Quality Register

Rheumatoid arthritis (RA) is the most common autoimmune inflammatory disease, and single periodontitis-associated bacteria have been suggested in disease manifestation. Here, the oral microbiota was characterized in relation to the early onset of RA (eRA) taking periodontal status into consideration. 16S rRNA gene amplicon sequencing of saliva bacterial DNA from 61 eRA patients without disease-modifying anti-rheumatic drugs and 59 matched controls was performed. Taxonomic classification at 98.5% was conducted against the Human Oral Microbiome Database, microbiota functions were predicted using PICRUSt, and periodontal status linked from the Swedish quality register for clinically assessed caries and periodontitis. The participants were classified into three distinct microbiota-based cluster groups with cluster allocation differences by eRA status. Independently of periodontal status, eRA patients had enriched levels of Prevotella pleuritidis, Treponema denticola, Porphyromonas endodontalis and Filifactor alocis species and in the Porphyromonas and Fusobacterium genera and functions linked to ornithine metabolism, glucosylceramidase, beta-lactamase resistance, biphenyl degradation, fatty acid metabolism and 17-beta-estradiol-17-dehydrogenase metabolism. The results support a deviating oral microbiota composition already in eRA patients compared with healthy controls and highlight a panel of oral bacteria that may be useful in eRA risk assessment in both periodontally healthy and diseased persons.

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Roles of Genes in the Susceptibility to and Severity of Rheumatoid Arthritis - A Review

Journal of Medicine ◽

10.3329/jom.v13i1.10048 ◽

1970 ◽

Vol 13 (1) ◽

pp. 51-54

Author(s):

Abul Khair Ahmedullah ◽

Shamim Ahmed ◽

MD Ariful Islam

Keyword(s):

Rheumatoid Arthritis ◽

Genetic Factors ◽

Human Leukocyte ◽

Drug Efficacy ◽

Autoimmune Disorder ◽

Individual Variability ◽

Unknown Etiology ◽

Entire Genome ◽

Gene Effects ◽

Leukocyte Antigen

Rheumatoid arthritis (RA) is a chronic heterogeneous autoimmune disorder of unknown etiology. Genetic factors play an important role in susceptibility to RA as the heritability of RA is between 50% and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. It is conceivable that there is more than one susceptible gene(s) operative in RA, and an interaction of the relevant genes may predispose the offspring to develop the disease under certain conditions .Outside the major histocompatibility complex (MHC) region, some additional risk loci have been identified and validated including PTPN22, STAT4, PADI4, CTLA4 and others Genetic factors are also important in RA pharmacotherapy due to the gene-dependent activity of enzymes involved in the pharmacokinetics and/or pharmacodynamics of RA medications. Indeed, there is great variability in drug efficacy as well as adverse events associated with any anti-rheumatic therapy and genetics is thought to contribute significantly to this inter-individual variability in response. The ability to screen the entire genome for association to complex diseases has great potential for identifying gene effects. DOI: http://dx.doi.org/10.3329/jom.v13i1.10048 JOM 2012; 13(1): 51-54

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Host–microbiota interactions in rheumatoid arthritis

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0283-6 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Yuichi Maeda ◽

Kiyoshi Takeda

Keyword(s):

Rheumatoid Arthritis ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Th17 Cell ◽

Animal Studies ◽

Molecular Mechanisms ◽

Oral Bacteria ◽

Oral Microbiota ◽

Periodontal Bacteria ◽

Growing Body

AbstractThe gut microbiota has been proposed to be an important environmental factor in the development of rheumatoid arthritis (RA). Here, we review a growing body of evidence from human and animal studies that supports the hypothesis that intestinal microbiota play a role in RA. Previous studies from we and others showed an altered composition of the microbiota in early RA patients. A recent study demonstrated that Prevotella species are dominant in the intestine of patients in the preclinical stages of RA. In addition, Prevotella-dominated microbiota isolated from RA patients contributes to the development of Th17 cell-dependent arthritis in SKG mice. Moreover, it was reported that periodontal bacteria correlates with the pathogenesis of RA. In this review, we discuss the link between oral bacteria and the development of arthritis. However, many questions remain to be elucidated in terms of molecular mechanisms for the involvement of intestinal and oral microbiota in RA pathogenesis.

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Dissecting the Genetic Complexity of the Association between Human Leukocyte Antigens and Rheumatoid Arthritis

The American Journal of Human Genetics ◽

10.1086/342407 ◽

2002 ◽

Vol 71 (3) ◽

pp. 585-594 ◽

Cited By ~ 149

Author(s):

Damini Jawaheer ◽

Wentian Li ◽

Robert R. Graham ◽

Wei Chen ◽

Aarti Damle ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Human Leukocyte ◽

Human Leukocyte Antigens ◽

Leukocyte Antigens ◽

Genetic Complexity

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SAT0590 ORAL MICROBIOTA IDENTIFIES PATIENTS WITH EARLY RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2416 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1254.2-1254

Author(s):

A. Esberg ◽

L. Johansson ◽

I. Johansson ◽

S. Rantapää Dahlqvist

Keyword(s):

Rheumatoid Arthritis ◽

Porphyromonas Gingivalis ◽

Aggregatibacter Actinomycetemcomitans ◽

Oral Bacteria ◽

Diagnostic Tools ◽

Oral Microbiota ◽

Healthy Controls ◽

Periodontal Pathogens ◽

Specificity And Sensitivity ◽

Periodontal Infection

Background:Several studies have suggested a link between the two chronic inflammatory diseases, rheumatoid arthritis (RA) and periodontitis (PD) [1]. The diseases share similar environmental and genetic risks factors,e.g.,smoking [2] and the HLA-DRB1 alleles [3]. Several serum markers used in the diagnosis of RA have also been found to be elevated in PD,e.g.,anti-citrullinated proteins antibodies (ACPA) and rheumatoid factor (RF) [4]. The connection between PD and RA has been suggested to be explained by several periodontal pathogens,e.g., Aggregatibacter actinomycetemcomitansandPorphyromonas gingivalis, which have been suggested to induce the production of autoantibodies [5, 6].Objectives:To investigate the composition of the concerted saliva microbiota and its role in the development of RA, with the aim of improving the diagnostic tools.Methods:16S ribosomal RNA gene sequencing of saliva bacterial DNA isolated from a total of 61 early RA (eRA) patients and 59 healthy controls was made. The eRA (symptoms ≤ 12 months) was diagnosed at an Early Arthritis Clinic (fulfilling the 1987 ARA criteria) and matched with the controls for sex and age, except for two of the elderly cases. None of the individuals included in the study had taken antibiotics during the preceding 3 months. No one of the cases were treated with anti-rheumatic drugs except for corticosteroids in 16 cases the latest month.Results:All participants were classified into three hierarchical cluster groups based on their saliva microbiota and the distribution of eRA cases versus controls differed distinctly between the cluster groups. The microbiota from the eRA had higher species richness, differed in beta-diversity, and was enriched for species in the Fusobacterium and Porphyromonas genera, and for the Alloprevotella tannerae, Campylobacter gracilis, Capnocytophaga leadbetteri, Filifactor alocis, Fusobacterium nucleatum subsp. polymorphum, Neisseria elongate, Porphyromionas endodontalis and Prevotella pleuritidis species compared to controls. Combining two topped ranked species,A. tanneraeandCatonella morbisignificantly predicted eRA with an AUC score of 0.86 and a specificity and sensitivity of 0.80 and 0.85, respectively.The predicted functions of the microbiota in eRA patients were dominated by fatty acid metabolism, ornithine metabolism, glucosylceramidase, sphingolipids, beta-lactamase resistance, biphenyl degradation and 17-beta-estradiol 17-dehydrogenase metabolism.Conclusion:In this study a difference in oral microbiota diversity between eRA patients and healthy controls could be shown. Some of the eRA-associated oral bacteria have previously been suggested to play an aetiological role in the development of RA, but others have not been recognized earlier, such as A. tannerae, F. alocis, F. nucleatum subsp. polymorphum, and P. endodontalis, and may therefore be useful in RA risk assessment.References:[1]Fuggle, N.R., et al.,Hand to Mouth: A Systematic Review and Meta-Analysis of the Association between Rheumatoid Arthritis and Periodontitis.Front Immunol, 2016. 7: p. 80.[2]Heliovaara, M., et al.,Smoking and risk of rheumatoid arthritis.J Rheumatol, 1993. 20(11): p. 1830-5.[3]Katz, J., et al.,Human leukocyte antigen (HLA) DR4. Positive association with rapidly progressing periodontitis.J Periodontol, 1987. 58(9): p. 607-10.[4]Mikuls, T.R., et al.,Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis.Arthritis Rheumatol, 2014. 66(5): p. 1090-100.[5]Konig, M.F., et al.,Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis.Sci Transl Med, 2016. 8(369): p. 369ra176.[6]Rosenstein, E.D., et al.,Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis.Inflammation, 2004. 28(6): p. 311-8.Disclosure of Interests:None declared

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Subgingival Microbiota Profile in Association with Cigarette Smoking in Young Adults: A Cross-Sectional Study

Dentistry Journal ◽

10.3390/dj9120150 ◽

2021 ◽

Vol 9 (12) ◽

pp. 150

Author(s):

Krešimir Bašić ◽

Kristina Peroš ◽

Zrinka Bošnjak ◽

Ivana Šutej

Keyword(s):

Pathogenic Bacteria ◽

Periodontal Diseases ◽

Clinical Signs ◽

Cross Sectional Study ◽

Oral Bacteria ◽

Sectional Study ◽

Cross Sectional ◽

Young Smokers ◽

Subgingival Microbiota ◽

Microbiological Analyses

While smoking is recognized as one of the factors for the development and progression of periodontal diseases, a relation between the composition of the subgingival microbiota and smoking is yet to be elucidated. The aim of this study was to investigate the prevalence of subgingival bacteria in young smokers and non-smokers without clinical signs of periodontal disease. In this cross-sectional study, performed at the Department of Pharmacology, School of Dental Medicine, University of Zagreb, we enrolled 32 periodontally healthy smokers and 32 non-smokers, aged 25–35 years old. The number of oral bacteria and the prevalence of particular bacteria were assessed for each subject. Subgingival plaque samples were collected with sterile paper points from two first molars for microbiological analyses with MALDI-TOF mass spectrometry. In smokers, a significantly higher prevalence of Actinomyces odontolyticus was observed compared to non-smokers, and a significantly lower prevalence of Streptococcus sanguinis was observed compared to non-smokers. Smoking affects the composition of subgingival microbiota, either via depletion of beneficial bacteria or the increase in pathogenic bacteria.

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Oral microbial dysbiosis linked to worsened periodontal condition in rheumatoid arthritis patients

10.1101/450056 ◽

2018 ◽

Author(s):

Jôice Dias Corrêa ◽

Gabriel R. Fernandes ◽

Débora Cerqueira Calderaro ◽

Santuza Maria Souza Mendonça ◽

Janine Mayra Silva ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Periodontal Disease ◽

Bacterial Load ◽

Oral Bacteria ◽

The Body ◽

Rrna Gene ◽

Oral Microbiota ◽

Periodontal Inflammation ◽

The Impact ◽

Subgingival Microbiota

AbstractRheumatoid arthritis (RA) is an autoimmune disorder associated with increased periodontal destruction. It is thought that RA increases the risk of periodontal disease; it is not known how it influences the oral microbiota. Our aim was to analyze the impact of RA on subgingival microbiota and its association with periodontal inflammation and RA activity. Forty-two patients with RA were compared to 47 control subjects without RA. Patients were screened for probing depth, clinical attachment level, bleeding on probing and classified as with or without periodontitis. Subgingival plaque was examined by Illumina MiSeq Sequencing of 16S rRNA gene V4 region and inflammatory cytokines were measured in saliva. RA was associated to severe periodontal disease. In addition, the severity of RA, reflected by the number of tender and swollen joints, was significantly correlated with the presence of pathogenic oral bacteria (i.e. Fusobacterium nucleatum and Treponema socransky). Non-periodontitis RA patients compared to healthy controls had increased microbial diversity and bacterial load, higher levels of pathogenic species (Prevotella, Selenomonas, Anaeroglobus geminatus, Parvimonas micra, Aggregatibacter actinomycetemcomitans) and reduction of health-related species (Streptococcus, Rothia aeria, Kingela oralis). Genes involved with bacterial virulence (i.e. lipopolysaccharide biosynthesis, peptidases) were more prevalent in the subgingival metagenome of subjects with RA. In addition, the degree of oral inflammation reflected by IL-2, IL-6, TNF-α, IFN-γ salivary levels was increased in non-periodontitis RA patients in comparison with controls. Our findings support the hypothesis that RA triggers dysbiosis of subgingival microbiota, which may contribute to worsening periodontal status.Author SummaryRheumatoid arthritis (RA) is an autoimmune disease characterized by joints inflammation, swelling, pain and stiffness. Exactly what starts this disease is still unclear. Some recent studies have suggested mucosal surfaces in the body, like those in the gums, could affect the disease process. It has been observed that people with RA have higher risk of periodontitis (a bacterial inflammatory disease of the gums), compared with the general population, and this may be the start of the autoimmune process. Also, periodontitis increases the severity of RA while interventions by treating periodontitis can improve the symptoms of RA. One of the possible mechanisms that link the higher prevalence of periodontitis in RA patients is the dysbiosis of the oral microbiota triggered by the chronic inflammation in RA. Increased levels of molecules of inflammation may affect the oral environment and change the type of bacteria that live there. Here, we examined RA patients and healthy subjects, screening their oral health and inflammatory markers. We collected their saliva and the dental plaque from the space between the teeth and the gum. We found that RA patients exhibited severe periodontitis, increased levels of inflammatory mediators on their saliva and distinct bacterial communities, with higher proportions of bacteria species linked to periodontal disease, even in patients without periodontitis. We also found that the presence of these bacteria species was linked to worse RA conditions. Our study provides new insights to understand the bi-directional mechanisms linking periodontal disease to the development of RA, showing that we need to pay attention to the oral cavity in patients with RA and refer people for dental evaluation. This practice might have a positive impact in the course of RA.

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Significance of Hyaluronic acid as a biomarker with seropositive and seronegative autoantibodies in Rheumatoid arthritis patients

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i2.4683 ◽

2021 ◽

Vol 12 (2) ◽

pp. 1322-1329

Author(s):

Vinod A N ◽

Preeti R Y ◽

Riya K ◽

Ruthvik N ◽

Prahaladh R

Keyword(s):

Rheumatoid Arthritis ◽

Hyaluronic Acid ◽

Statistical Significance ◽

Joint Destruction ◽

Autoimmune Disorder ◽

Cross Sectional Study ◽

Synovial Inflammation ◽

Healthy Controls ◽

Cross Sectional ◽

Female Population

Testing for autoantibodies is a flagship feature of Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder affecting both the male and female population. Synovial inflammation followed by cartilage, bone, and joint destruction in the later stages of RA puts life in peril, especially for those with other comorbidities. In this study, we focused on to measure serum Hyaluronic acid (HA) along with seropositive and seronegative RF, AntiCCP autoantibodies to establish any association with these biomarkers. It was a cross-sectional study involving 152 RA patients based on the 1987 ACR criteria for the diagnosis of RA and 68 age‑ and sex-matched healthy controls. After clinical examination, the traditional markers were assessed to measure the disease activity, such as CRP, ESR, Anti -CCP, and RF in RA patients. The serum HA levels were measured using the ELISA method. All the values were expressed as median (25th–75th percentile). Based on seropositive and seronegative RF and AntiCCP autoantibodies, the patient group was divided into four groups- both seropositive, both seronegative, and the other two mixed groups. The traditional inflammatory markers were significantly increased in RA patients than in controls with (p < 0.001). In our study, there was a significant increase in serum HA levels in RA patients compared to healthy controls (p < 0.03). The serum HA levels were significantly correlated with Anti-CCP, DAS‑28, CRP, and ESR in RA patients. At the same time, serum HA level is increased in the group with seropositive for both antibodies showing statistical significance. Conclusion- serum Hyaluronic acid is involved in synovial inflammation, manifesting a common triggering mechanism more with AntiCCP antibodies than RF, promising for better clinical utility in the early stages of rheumatoid arthritis.

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The Link between HLA-B Alleles and Causative Drugs in Vietnamese Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2020.4906 ◽

2020 ◽

Vol 8 (B) ◽

pp. 395-400

Author(s):

Tran Thi Huyen ◽

Pham Dinh Hoa ◽

Trinh Minh Trang ◽

Nguyen Ba Khanh ◽

Tran Ngoc Que ◽

...

Keyword(s):

Traditional Medicine ◽

Toxic Epidermal Necrolysis ◽

Human Leukocyte ◽

Stevens Johnson Syndrome ◽

Control Group ◽

Laboratory Findings ◽

Cross Sectional ◽

Leukocyte Antigens ◽

Johnson Syndrome ◽

Culprit Drug

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Human leukocyte antigens (HLA) may play an important role in the pathogenesis of SJS/TEN. AIMS: This study aims to identify HLA-B alleles in Vietnamese patients with SJS/TEN and to investigate the possible link between HLA-B alleles and causative drugs. MATERIALS AND METHODS: Sixty patients including SJS (30 patients) and TEN (30 patients) were enrolled in a cross-sectional descriptive study at two hospitals in Hanoi, Vietnam, from July 2018 to July 2019. Clinical features and laboratory findings were noted, HLA-B alleles were analyzed by the polymerase chain reaction (PCR)-sequence-specific oligonucleotide assay and LuminexTM Multiplex Technology. RESULTS: The most common HLA-B allele was HLA-B*15:02 (41.7%) followed by HLA-B*58:01 (25%) and HLA-B*46:01 (15%). Of the 25 patients possessing HLA-B*15:02 allele, culprit medicines were carbamazepine (13 patients; 52%), traditional medicine (two patients; 8%), and unknown drugs (seven patients; 28%). Of the 15 patients carrying HLA-B*58:01 allele, there were 13 patients whose offending medicine was allopurinol. Of the eight patients whose culprit drug was traditional medicine, there were 6 patients (75%) carrying HLA-B*51:02. Patients who carry HLA-B*15:02 were found to have 4 times higher risk of developing carbamazepine-induced SJS/TEN as compared with the tolerant control group (OR=4.17; 95% CI=2.07–8.37; p < 0.001). CONCLUSION: HLA-B*15:02 was the most common HLA-B allele in Vietnamese patients with SJS/TEN. In traditional medicine-induced SJS/TEN patients, HLA-B*51:02 allele might play an important role. The link between the HLA-B genotypes and causative drugs may suggest physicians to avoid risk medications for certain patients.

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