Pathogenic roles of IL-6 and IL-6 blocking therapy on rheumatoid arthritis

Background

In rheumatoid arthritis (RA), chronic inflammation followed by the destruction of joints and systemic symptoms is constructed and progressed with a continuous inflammatory and immunological hyperactivity. IL-6 is considered a proinflammatory cytokine produced in inflammatory synovium in RA, and to participate in the lymphocyte activation, synovial cell growth, angiogenesis, cartilage and bone destruction, and generation of AA amyloidosis. However, precise functions of IL-6 in RA are still unknown.

Objective

To know the actual pathogenic roles of IL-6 in RA and to develop IL-6 blocking therapy on RA, a humanized anti-IL-6 receptor antibody (MRA) has been used for the treatment of RA as a specific blockade of IL-6 function.

Method

To evaluate the therapeutic effects of MRA to patients with RA, three clinical studies have so far been performed in Japan: a pilot study of 11 severe patients, an open-labeled, dose-escalating, multidose clinical study of 15 patients, and a randomized, placebo-controlled trial of a multidose study on 163 patients. In most clinical trials in Japan, 2–8 mg/kg MRA was administered intravenously every 4 weeks.

Results

The treatment was well tolerated at all doses. The clinical efficacy of MRA evaluated by ACR criteria seems to be same as or more than those of tumor necrosis factor alpha blockades. MRA treatment also improved the abnormal laboratory findings observed in active RA patients. In most MRA-treated patients, elevated levels of acute phase proteins, such as C-reactive protein, fibrinogen and SAA, were rapidly normalized after first administration, and thrombocytosis, anemia and hypoalbuminemia were improved within 2 months. Rheumatoid factor levels were gradually decreased.

Conclusion

These therapeutic effects and improvements of abnormal findings by MRA treatment confirm that IL-6 is one of the key cytokines in the pathogenesis of RA arthritis, and IL-6 blocking therapy is a cytokine-specific, safe and effective therapy for patients with RA.