The “Bermuda triangle” of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11–37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci — Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively — have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.

Angiogenesis is the formation of new capillaries from pre-existing vessels. A number of soluble and cell-bound factors may stimulate neovascularization. The perpetuation of angiogenesis involving numerous soluble and cell surface-bound mediators has been associated with rheumatoid arthritis (RA). These angiogenic mediators, among others, include growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as pro-inflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases and others. Among the several potential angiogenesis inhibitors, targeting of VEGF, HIF-1, angiogenic chemokines, tumor necrosis factor-α and the α V β 3 integrin may attenuate the action of angiogenic mediators and thus synovial angiogenesis. In addition, some naturally produced or synthetic compounds including angiostatin, endostatin, paclitaxel, fumagillin analogues, 2-methoxyestradiol and thalidomide may be included in the management of RA.

Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. Both traditional, Framingham risk factors and inflammation-associated factors are involved in RA-associated atherosclerosis. Among imaging techniques, the early determination of common carotid intima-media thickness (ccIMT), flow-mediated vasodilation (FMD), and nitroglycerine-mediated vasodilation (NMD) may be useful to determine atherosclerosis and endothelial dysfunction. We and others found increased ccIMT and impaired FMD in RA patients. Among immunological and metabolic laboratory markers, anticyclic citrullinated peptide (anti-CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), Th0/Th1 T cells, homocysteine, dyslipidemia, decreased folate and vitamin B12 production, and impaired paraoxonase activity may all be involved in the development of vascular disease in RA. The early diagnosis of endothelial dysfunction and atherosclerosis, active immunosuppressive treatment, the use of drugs that control atherosclerosis, changes in sedentary lifestyle, and the close follow-up of RA patients may help to minimize cardiovascular risk in these individuals.

Targeting angiogenesis and restoration of vasculogenesis may be beneficial for the therapy and outcome of RA.

Objective To determine whether myeloid cells (such as granulocytes) present in the synovial fluid (SF) of arthritic joints have an impact on adaptive immunity. Specifically, we investigated the effects of SF cells harvested from the joints of mice with proteoglycan‐induced arthritis (PGIA), on dendritic cell (DC) maturation and antigen‐specific T cell proliferation. Methods We monitored DC maturation (MHCII and CD86 expression) by flow cytometry upon coculture of DCs with SF cells or spleen myeloid cells from mice with PGIA. The effects of these myeloid cells on T cell proliferation were studied using T cells purified from PG‐specific T cell receptor (TCR)–transgenic (Tg) mice. Phenotype analysis of myeloid cells was performed by immunostaining, reverse transcription–polymerase chain reaction, Western blotting, and biochemical assays. Results Inflammatory SF cells significantly suppressed the maturation of DCs upon coculture. PG‐TCR–Tg mouse T cells cultured with antigen‐loaded DCs showed dramatic decreases in proliferation in the presence of SF cells. Spleen myeloid cells from arthritic mice did not have suppressive effects. SF cells were unable to suppress CD3/CD28‐stimulated proliferation of the same T cells, suggesting a DC‐dependent mechanism. SF cells exhibited all of the characteristics of myeloid‐derived suppressor cells (MDSCs) and exerted suppression primarily through the production of nitric oxide and reactive oxygen species by granulocyte‐like cells. Conclusion SF in the joints of mice with PGIA contains a population of granulocytic MDSCs that potently suppress DC maturation and T cell proliferation. These MDSCs have the potential to limit the expansion of autoreactive T cells, thus breaking the vicious cycle of autoimmunity and inflammation.