The pathogenesis of rheumatoid arthritis (RA) is incompletely understood. HLA class II alleles and T cells have been implicated for many years. The discovery of anticitrullinated peptide antibodies (ACPAs), along with the effectiveness of biological treatments targeting cytokines, such as TNF-?, IL-6, and also T cells and B cells, reinforced the pathogenetic role of the respective factors. ACPAs, induced by cigarette smoking and periodontitis in individuals with HLA-DRB1 shared epitope, appear to be autoantigens that initiate the inflammatory immune response in RA. MicroRNAs, part of epigenetic mechanisms, which also include DNA methylation, and histone modification, as well as microbiota, the composition of microbes in body cavities, also appear to influence arthritis and are discussed in this book.