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OP0010 Neutralisation of il-18 activity is a disease-modifying therapy in the murine collagen-induced arthritis model
  1. C Plater-Zyberk1,
  2. LA Joosten2,
  3. MA Helsen2,
  4. P Sattonnet-Roche1,
  5. C Siegfried1,
  6. S Alouani1,
  7. AJ Van de Loo2,
  8. P Graber1,
  9. E Lubberts2,
  10. CA Dinarello3,
  11. WB Van den Berg2,
  12. Y Chvatcko1
  1. 1Experimental Biology and Pharmacology, Serono Pharmaceutical Research Institute, Geneva, Switzerland
  2. 2Rheumatology Research Laboratory, University Medical Center St-Radboud, Nijmegen, The Netherlands
  3. 3Department of Medicine, University of Colorado Health Sciences Center, Denver, USA

Abstract

Background Interleukin-18 (IL-18) is a member of the interleukin-1 cytokine family. In vivo IL-18 has been demonstrated as promoting the development of a TH1 response in synergy with IL-12. Patients with rheumatoid arthritis (RA) have in their joints significant levels of IL-18 and IL-12.

Objectives This study was aimed at studying the effect of neutralising endogenous IL-18 in vivo in collagen-induced arthritic (CIA) mice, to define the therapeutic potentials of IL-18 blockade for the treatment of patients with RA.

Methods Two distinct IL-18 neutralising strategies were used, i.e. a recombinant human IL-18 binding protein (rIL-18BP) and a polyclonal rabbit anti-mouse IL-18 IgG, 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; 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.

Conclusion These results clearly demonstrate that neutralising endogenous IL-18 is therapeutically efficacious in the CIA model and support the use of IL-18 neutralisation as a novel cartilage and bone sparing 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.

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