Pathogens in rheumatoid arthritis: epidemiological, mechanistic, and clinical insights

Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovial inflammation, joint destruction, and systemic comorbidities. Emerging evidence highlights the critical involvement of the microbiome in disease pathogenesis, encompassing bacteria, viruses, fungi, and mycoplasmas. This review synthesizes recent findings on microbiome alterations, summarizing epidemiological, molecular, and mechanistic data. Among the evaluated pathogens, Porphyromonas gingivalis and Prevotella copri currently demonstrate the strongest causal evidence for initiating autoimmunity. Porphyromonas gingivalis directly catalyzes host protein citrullination via its unique peptidylarginine deiminase, driving anti-citrullinated protein antibody production, while Prevotella copri expands during the preclinical phase to drive T helper 17 cell polarization. Furthermore, chronic Hepatitis C virus infection presents compelling causal links, as continuous viral stimulation triggers robust autoantibody production in atypical memory B cells. Other infectious agents, including Epstein-Barr virus and Proteus mirabilis, act as environmental triggers through molecular mimicry, whereas opportunistic pathogens like Pneumocystis jirovecii emerge as severe secondary complications resulting from profound pharmacological immunosuppression. In terms of immediate clinical translation, several microbiome-targeted strategies are poised for routine practice. These include non-surgical periodontal therapy and oral hygiene optimization to reduce systemic disease activity, the utilization of direct-acting antivirals for Hepatitis C virus to concurrently resolve joint inflammation, and targeted prophylaxis using sulfasalazine to prevent Pneumocystis jirovecii pneumonia in highly immunosuppressed populations. Additionally, the immunomodulatory application of Ganoderma lucidum polysaccharides for symptomatic pain relief and the preclinical development of bacterial virulence factor inhibitors represent promising therapeutic avenues. Together, these findings confirm that the microbiome acts as a critical modifier of the inflammatory milieu. Future studies integrating longitudinal cohorts and precision interventional trials will further solidify causality and refine these microbiome-targeted therapies.