Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role for interleukin-I

Chronic arthritis is characterised by persistent joint inflammation and con comitant joint destruction. Although joint swelling is a major clinical fea ture, destruction of bone and cartilage may be dissociated from inflammatio n. It is therefore important to understand fully all elements of the destru ctive process. Tumour necrosis factor (TNF) and interleukin-1 (IL-1) are co nsidered pivotal cytokines in the process of human rheumatoid arthritis (RA ), with a claimed cascade of TNF inducing most of the IL-1 production. Stud ies in experimental models have revealed that TNF is indeed a pivotal cytok ine in acute joint swelling, yet IL-1 beta is the dominant cartilage destru ctive cytokine and its production may occur independently of TNF alpha. Thi s was found with anti-TNF/IL-1 neutralising antibodies and the observations were recently supported by similar findings in arthritis models in TNF and IL-1 knock-out mice. In RA, early clinical studies suggested a correlation between levels of IL-1 beta and measures of joint damage. In vitro studies have also demonstrated regulatory effects of IL-1 beta on both cartilage d egradation and cartilage invasion by synoviocytes. A randomised clinical tr ial has suggested a significant reduction in the rate of joint damage follo wing IL-1 beta inhibition by IL-1 receptor antagonist. Clinical trials of T NF alpha blockade have demonstrated a marked reduction in the clinical mani festations of inflammation but, to date, an effect on the rate of joint dam age awaits confirmation.