Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role for interleukin-I.
Chronic arthritis is characterised by persistent joint inflammation and concomitant joint destruction. Although joint swelling is a major clinical feature, destruction of bone and cartilage may be dissociated from inflammation. It is therefore important to understand fully all elements of the destructive process. Tumour necrosis factor (TNF) and interleukin-I (IL-I) are considered pivotal cytokines in the process of human rheumatoid arthritis (RA), with a claimed cascade of TNF inducing most of the IL-I production. Studies in experimental models have revealed that TNF is indeed a pivotal cytokine in acute joint swelling, yet IL-I beta is the dominant cartilage destructive cytokine and its production may occur independently of TNF alpha. This was found with anti-TNF/IL-I neutralising antibodies and the observations were recently supported by similar findings in arthritis models in TNF and IL-I knock-out mice. In RA, early clinical studies suggested a correlation between levels of IL-I beta and measures of joint damage. In vitro studies have also demonstrated regulatory effects of IL-I beta on both cartilage degradation and cartilage invasion by synoviocytes. A randomised clinical trial has suggested a significant reduction in the rate of joint damage following IL-I beta inhibition by IL-I receptor antagonist. Clinical trials of TNF alpha blockade have demonstrated a marked reduction in the clinical manifestations of inflammation but, to date, an effect on the rate of joint damage awaits confirmation.
van den Berg
W B
WB
Department of Rheumatology, University Hospital Nijmegen, The Netherlands.
Bresnihan
B
B
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha