Interleukin (IL)-6 is produced locally in response to an inflammatory stimulus, and is able to induce systemic manifestations at distance from the site of inflammation. Its unique signaling mechanism, including classical and trans-signaling pathways, leads to a major expansion in the number of cell types responding to IL-6. This pleiotropic cytokine is a key factor in the pathogenesis of rheumatoid arthritis (RA) and is involved in many extra-articular manifestations that accompany the disease. Thus, IL-6 blockade is associated with various biological effects beyond the joints. In this review, the systemic effects of IL-6 in RA comorbidities and the consequences of its blockade will be discussed, including anemia of chronic disease, cardiovascular risks, bone and muscle functions, and neuro-psychological manifestations.