CD28 and rheumatoid arthritis: Intriguingly, the frequency rate of this clonal expansion, which rarely exceeds 1% in the elderly, quite often reaches values between 5% and 10% in RA patients, where it is associated with extra-articular manifestations, such as early atherosclerotic vessel damage [94], probably due to the ability of CD4+CD28− T-cells to exert a cytotoxic activity and directly attack the vascular tissue [182].