Tocilizumab: The First Interleukin-6-Receptor Inhibitor

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]

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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]

Am J Health Syst Pharm. 2008;65(15):1413-1418. © 2008  American Society of Health-System Pharmacists

Cite this: Tocilizumab: The First Interleukin-6-Receptor Inhibitor - Medscape - Aug 01, 2008.