Rheumatoid arthritis is a chronic inflammatory autoimmune disease that is associated with reduced life expectancy. The disease is heritable and an extensive repertoire of genetic variants have been identified. The gut microbiota might represent an environmental risk factor for rheumatoid arthritis. We aimed to assess whether known rheumatoid arthritis risk alleles were associated with the gut microbiota in a large population who do not have rheumatoid arthritis. In this cross-sectional study done in the UK and Switzerland, we used genotyping and microbiota data from previous studies of the TwinsUK cohort, excluding participants who had ever had a diagnosis of rheumatoid arthritis, as well as their unaffected co-twins. We used blood samples for genotyping and stool samples for the assessment of the gut microbiota. We generated a polygenic risk score (PRS) for rheumatoid arthritis in 1650 TwinsUK participants without the disease, based on 233 GWAS-identified single nucleotide polymorphisms associated with rheumatoid arthritis. We validated the PRS using logistic regression against rheumatoid arthritis diagnosis in 2686 UK Biobank individuals with a confirmed diagnosis of rheumatoid arthritis. Amplicon sequence variants (ASVs) were generated from 16S rRNA gene sequencing of stool samples and assessed for association with the PRS for rheumatoid arthritis. We validated the findings in an independent sample comprised of first-degree relatives of patients with rheumatoid arthritis from the SCREEN-RA cohort. Differential abundance of ASVs present in more than 5% of samples, grouped by ASV taxon annotation, against the rheumatoid arthritis PRS as a continuous variable was assessed using fixed-effects covariates. To account for multiple testing, the false discovery rate calculation was applied to all p values to generate q values, with a significance threshold of 0·05 determined a priori. We found that presence of Prevotella spp were positively associated with the rheumatoid arthritis PRS in TwinsUK participants (q<1 × 10−7). This finding was validated in SCREEN-RA participants (n=133) carrying established shared epitope risk alleles (q=0·0011). We also found an association between Prevotella spp and presence of preclinical rheumatoid arthritis phases (q=0·021). Prevotella spp in the gut microbiota are associated with the rheumatoid arthritis genotype in the absence of rheumatoid arthritis, including in individuals at high risk of developing rheumatoid arthritis. Our findings suggest that host genotype is associated with microbiota profile before disease onset. Versus Arthritis.

Evidence about the role of nutritional factors and microbiota in autoimmune diseases, and in rheumatoid arthritis (RA) in particular, has grown in recent years, however many controversies remain. The aim of this review is to summarize the role of nutrition and of the intestinal microbiota in the development of RA. We will focus on selected dietary patterns, individual foods and beverages that have been most consistently associated with RA or with the occurrence of systemic autoimmunity associated with RA. We will also review the evidence for a role of the intestinal microbiota in RA development. We propose that diet and digestive microbiota should be considered together in research, as they interact and may both be the target for future preventive interventions in RA.

Purpose Rheumatoid arthritis (RA) is an insidious autoimmune disease, with an immunological onset years before diagnosis. Early interventions in preclinical stages could prevent or minimise the progression towards irreversible joint damage. The SCREEN-RA cohort (Evaluation of a SCREENing strategy for Rheumatoid Arthritis) aims to characterise the preclinical stages of the disease, to identify environmental risk factors, and to discover or validate novel biomarkers predictive for RA development. Participants SCREEN-RA includes an at-risk population for RA, namely first-degree relatives of patients with established RA. Findings to date The cohort started in 2009 is composed of mostly asymptomatic healthy individuals (total n=1458, 7262 person-years), with a mean age of 44 years at enrolment, 74% female and 91% Caucasian ethnicity. During the study period, 16 participants have developed RA. All participants provide baseline serum, DNA and RNA samples, and in a subset, stool samples and oral examination are performed for microbiota assessment. At enrolment, 10% of participants had asymptomatic autoimmunity associated with RA (n=147), 10% presented ‘clinically suspect arthralgias’ (n=143) and 3% reported arthralgias in conjunction with autoimmunity or high genetic risk (n=51). Studies with this cohort have uncovered risk factors for RA development, such as female hormonal factors, poor oral health or intestinal dysbiosis. Future plans Future directions include immunological and ‘multiomics’ approaches to discover new biological markers of progression towards RA, as well as testing preventive interventions in ‘high-risk’ population.

Rheumatoid arthritis and spondyloarthropathy are the most common inflammatory rheumatic diseases. As the human microbiome is involved in the immune homeostasis, it has the potential to be a key factor in the development of autoimmune diseases and rheumatic diseases. In this article, we review the role of various human microbiota on the pathogenesis of rheumatic diseases, focusing on spondylarthritis and rheumatoid arthritis.

To examine whether serum antibodies against selected periodontal pathogens are associated with early symptoms of RA development in healthy individuals at risk of developing the disease. Within an ongoing study cohort of first-degree relatives of patients with RA (RA-FDRs), we selected four groups corresponding to specific preclinical phases of RA development (n = 201). (i) RA-FDR controls without signs and symptoms of arthritis nor RA-related autoimmunity (n = 51); (ii) RA-FDRs with RA-related autoimmunity (n = 51); (iii) RA-FDRs with inflammatory arthralgias without clinical arthritis (n = 51); and (iv) RA-FDRs who have presented at least one swollen joint (‘unclassified arthritis’) (n = 48). Groups were matched for smoking, age, sex and shared epitope status. The primary outcome was IgG serum levels against five selected periodontal pathogens and one commensal oral species assessed using validated-in-house ELISA assays. Associations between IgG measurements and preclinical phases of RA development were examined using Kruskal–Wallis or Mann–Whitney tests (α = 0.05). None of the IgGs directed against individual periodontal pathogens significantly differed between the four groups of RA-FDRs. Further analyses of cumulated IgG levels into bacterial clusters representative of periodontal infections revealed significantly higher IgG titres against periodontopathogens in anti-citrullinated protein antibodies (ACPA)-positive RA-FDRs (P = 0.015). Current smoking displayed a marked trend towards reduced IgG titres against periodontopathogens. Our results do not suggest an association between serum IgG titres against individual periodontal pathogens and specific preclinical phases of RA development. However, associations between cumulative IgG titres against periodontopathogens and the presence of ACPAs suggest a synergistic contribution of periodontopathogens to ACPA development.