Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis

Abstract

Chronic arthritis is characterised by chronic joint inflammation and concurrent joint erosion and destruction. The inflammatory cytokine interleukin 1 (IL1) has been shown to be a key mediator in the autoimmune disease rheumatoid arthritis (RA). Interleukin 1 mediates bone resorption and cartilage destruction, but may not play as dominant a part in joint swelling and inflammation. Interleukin 1 receptor antagonist (IL1Ra) selectively inhibits the effects of IL1 by competing for the IL1 receptor on all surfaces of the synovium. In a randomised controlled trial in 472 patients with active disease, IL1Ra 30 mg/day, 75 mg/day or 150 mg/day given by subcutaneous injection significantly reduced the signs and symptoms of RA at 24 weeks. An American College of Rheumatology (ACR) 20% response was seen in 43% of the patients treated with 150 mg/day at 24 weeks. IL1Ra was well tolerated; injection site reactions were the most common adverse event. In another trial, in 419 patients with active RA treated concomitantly with methotrexate, there were ACR 20% responses after 24 weeks in 42% of the patients treated with 1 mg/kg/day by subcutaneous injection and in 35% of those treated with 2 mg/kg/day. I1Ra offers a unique selective, targeted mechanism of action to block the IL1 mediated effects of RA.

Figure 1

IL1Ra binds to IL1 receptor type I but does not activate the cell.²

Figure 2

Plasma concentrations of IL1β in controls and patients with active RA.⁷

Figure 3

Cytokine regulation of osteoclast differentiation and activation. OPG, osteoprotogerin; PGE₂, prostaglandin E₂. (Courtesy of M H Schiff).

Figure 4

Clinical response at week 24 in European Monotherapy Study.³³

Figure 5

Erythrocyte sedimentation rates (ESRs) (A), inhibition of structural damage by IL1Ra (B) and swollen joint counts (C) in European Monotherapy Study.³²

Figure 6

Erythrocyte sedimentation rates (ESRs) in Extension Study of European Monotherapy Study.³³

Figure 7

Assessment of joint damage in Extension Study of European Monotherapy Study.³³