title: Recent advances in neutralizing the IL-6 pathway in arthritis.
abstract: Recent advances in understanding the mechanism(s) of how IL-6trans-signaling regulates immune cell function and promotes inflammation in autoimmune arthritis are critically reviewed. Serum and/or synovial fluid (SF) IL-6 is markedly elevated in adult and juvenile rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and osteoarthritis (OA). IL-6, in concert with IL-17, determines the fate of CD4+lymphocytes and therefore TH17cell differentiation. IL-6 also plays a critical role in modulating B-lymphocyte activity. The recognition that IL-6trans-signaling regulates inflammation resulted in the development of tocilizumab, a fully humanized monoclonal antibody that neutralizes the biological activity of the IL-6-receptor (IL-6R). Significant clinical benefit was demonstrated as well as reduced serum IL-6 levels with suppression of X-ray progression of disease in several clinical trials in which juvenile or adult RA patients were treated with tocilizumab monotherapy or tocilizumab plus methotrexate. However, levels of serum and/or SF IL-6 cytokine protein superfamily members, adiponectin, oncostatin M, pre-B-cell colony enhancing factor/visfatin and leukemia inhibitory factor are also elevated in RA. Additional studies will be required to determine if anti-IL-6trans-signaling inhibition strategies with tocilizumab or recombinant soluble IL-6R reduce the level of these cytokines.
authors: Division of Rheumatic Diseases, Case Western Reserve University, School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Charles J
authors: CJ
authors: Malemud
keywords: JAK/STAT pathway; SAP/MAPK pathway; interleukin-6; interleukin-6/interleukin-6 receptor/glycoprotein 130; osteoarthritis; rheumatoid arthritis