Interleukin-18 (IL-18) has been demonstrated as promoting the development of a TH1 response in vivo in synergy with IL-12. Significant levels of IL-18 and IL-12 have been detected in the joints of patients with rheumatoid arthritis (RA).

To define the therapeutic potentials of IL-18 blockade in RA by investigating the effect of neutralising endogenous IL-18 in the experimental CIA mouse model.

Two distinct IL-18 neutralising strategies, i.e., a recombinant human IL-18 binding protein (rIL-18BP) and a polyclonal anti-IL-18 IgG, were used to treat CIA mice in a therapeutic protocol (after disease onset). The effect on disease severity (visual scores) as well as parameters of cartilage and bone destruction were evaluated.

Clinical scores were significantly reduced after IL-18 blockade (rhIL-18BP 1 mg/kg, P < 0.001, n = 13; rhIL-18BP 0.25 mg/kg, P < 0.05, n = 7; anti-IL18 IgG, 2 mg, P < 0.05, n = 9, Mann Whitney test, treated versus placebo groups). Histological examination showed cartilage protection (decrease erosion scores, P < 0.05) that was accompanied by significantly reduced levels of serum cartilage oligomeric matrix protein (an indicator of cartilage turnover) and VDIPEN expression (a neoepitope present after digestion by matrix metalloproteinases). X-ray analysis of joints provided evidence of reduced bone erosion. Serum IL-6 levels were diminished in the treated animals.

These results clearly demonstrate that blocking endogenous IL-18 is therapeutically efficacious in the CIA model and support the use of IL-18 neutralisation as a novel cartilage and bone protective therapy for the treatment of destructive arthritis. Recombinant hIL-18BP could therefore represent a new disease-modifying anti-rheumatic drug that warrants testing in clinical trials in patients with rheumatoid arthritis.