Objectives Rheumatoid arthritis (RA) has been associated with a relative expansion of faecal Prevotellaceae. To determine the microbiome composition and prevalence of Prevotella spp. in a group of individuals at increased risk for RA, but prior to the development of the disease. Methods In an ongoing cohort study of first-degree relatives (FDRs) of patients with RA, we identified ‘FDR controls’, asymptomatic and without autoantibodies, and individuals in pre-clinical RA stages, who had either developed anticitrullinated peptide antibodies or rheumatoid factor positivity and/or symptoms and signs associated with possible RA. Stool sampling and culture-independent microbiota analyses were performed followed by descriptive statistics and statistical analyses of community structures. Results A total of 133 participants were included, of which 50 were categorised as ‘FDR controls’ and 83 in ‘pre-clinical RA stages’. The microbiota of individuals in ‘pre-clinical RA stages’ was significantly altered compared with FDR controls. We found a significant enrichment of the bacterial family Prevotellaceae, particularly Prevotella spp., in the ‘pre-clinical RA’ group (p=0.04). Conclusions Prevotella spp. enrichment in individuals in pre-clinical stages of RA, before the onset of RA, suggests a role of intestinal dysbiosis in the development of RA.

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.

Background We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

RA is the most common chronic systemic autoimmune disease, with a higher prevalence in women, suggesting female hormonal factors play a role in the development of the disease. However, many controversies still exist. The aim of this review was to appraise data from recent research concerning female hormonal factors and their association with RA disease development. The study of female hormonal factors is challenging because serum levels may differ throughout a woman's lifetime and interact with various environmental, immunological, genetic and endocrine factors influencing the development of autoimmunity. As some female hormonal factors may be potentially modifiable, understanding their impact on RA development is clinically relevant and may result in specific preventive interventions in high-risk populations.

To analyse the association between female hormonal factors and the development of systemic autoimmunity associated with RA in women at increased risk for RA, namely first-degree relatives of patients with RA (RA-FDRs). In an ongoing cohort study of RA-FDRs, we analysed all women with available ACPA status. The primary outcome was ACPA positivity. The predictors of interest were female hormonal factors, such as oral contraceptives, breastfeeding, post-menopausal status, early post-menopausal period and total number of ovulatory years. A total of 768 female RA-FDRs were analysed, of which 42 (5%) had developed ACPA positivity. ACPA-positive women were older (52 vs 44 years, P = 0.001). Hormonal factors significantly and independently associated with the presence of ACPA were the post-menopausal (P < 0.001) and the early post-menopausal periods (P = 0.040). In women at increased risk of RA, characteristic systemic autoimmunity was associated with menopause, suggesting that the acute decline in ovarian function might contribute to the development of autoimmunity associated with RA and potentially to the increased risk of RA in women.

Rheumatoid arthritis (RA) is known to include a pre-RA stage that can be defined as the presence of familial or genetic risk factors, biomarker abnormalities (eg, anticitrullinated protein antibodies [ACPA]), symptoms, and even abnormal imaging findings prior to the development of the onset of clinical RA with inflammatory arthritis that is apparent on physical examination. Indeed, there are multiple completed or ongoing retrospective case-control as well as prospective observational studies to identify the key biologic drivers of disease. Further, building on the predictive ability of combinations of biomarkers, symptoms, and imaging for future RA, there are multiple clinical trials completed, underway, or in development to identify approaches that may prevent, delay, or ameliorate future clinical RA in at-risk individuals. Importantly, however, although an effective preventive intervention has not yet been identified, at-risk individuals are being increasingly identified in clinical care; this presents a challenge of how to manage these individuals in clinical practice. This review will discuss the current understanding of the biology and natural history of RA development, nomenclature, and current models for prediction of future RA, as well as evaluate the current and ongoing clinical prevention trials with the overall goal to provide insights into the challenges and opportunities in the field of RA prevention. Moreover, this review will provide up-to-date options for clinical management of individuals at risk for RA.