IL-18 blockade is a potential disease-modifying therapy for rheumatoid arthritis

Introduction

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).

Aim

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.

Methods

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.

Results

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.

Conclusions

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.