Tocilizumab: The First Interleukin-6-Receptor Inhibitor

Anthony Sebba, M.D.


Am J Health Syst Pharm. 2008;65(15):1413-1418. 

In This Article

IL-6 in RA Pathogenesis

Cytokines have intricate signaling capabilities, with regulatory, chemotactic, and stimulatory effects on surrounding cells.[17,18] Of the many cytokines present in rheumatoid synovium, proinflammatory cytokines—among them the interleukins—appear to be most directly linked to the disease process and play a critical role in joint destruction. An example of this is tumor necrosis factor (TNF), which acts as a major cytokine in the cytokine cascade and regulates the production of several other proinflammatory molecules, including interleukin-1, IL-6, interleukin-9, interleukin-15, and granulocyte-macrophage colony-stimulating factor. Modulation of TNF with anti-TNF agents has been shown to have a significant clinical effect in patients with RA. Interestingly, as with hormones, some effects of cytokines occur at local sites and some at distant sites. IL-6 is a cytokine associated with arthritis that appears also to have systemic effects, such as the hepatic production of CRP.

IL-6 is produced by a variety of cell types in response to infection, trauma, and immunologic challenge.[19] IL-6 plays a prominent role in disease processes and has both proinflammatory and antiinflammatory characteristics (Figure 1).[20,21] It promotes inflammatory events through the expansion and activation of T cells and the differentiation of B cells. IL-6 has also demonstrated a protective role in disease processes. For example, in a septic shock model, IL-6 protected mice against death by suppressing acute neutrophil accumulation caused by intratracheal administration of endotoxin.[22] IL-6 produces many other effects throughout the human body, both locally and systemically ( Table 2 ).[19]

Cells producing interleukin-6 (IL-6) and the actions of IL-6 in the body. Ig = immunoglobulin, CRP = C-reactive protein, SAA = serum amyloid A protein. Reprinted, with permission, from reference 21.

Many laboratory test value abnormalities associated with RA have been linked to IL-6. For instance, severe RA is commonly associated with thrombocytosis, hypergamma-globulinemia, and elevated erythrocyte sedimentation rate (ESR) and CRP levels. Such abnormalities tend to rise in parallel with plasma and synovial levels of IL-6.[23] Persistently elevated levels of CRP predict a very poor outcome for RA patients.[24] Systemic and periarticular bone loss, common in severe disease, is highly correlated with IL-6 levels in bone marrow.[25,26] Consistent with these data, therapeutic studies in which the effects of IL-6 are blocked have noted improvements in clinical and laboratory variables.[16,27]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.