Molecular targets in immune-mediated diseases: the case of tumour necrosis factor and rheumatoid arthritis.
Rheumatoid arthritis is a common autoimmune condition in which, for unknown reasons, synovial joints become the target of a sustained immune response. For many years, rheumatoid arthritis was in the 'too hard basket' in terms of understanding disease mechanisms and providing rational therapy. This has changed dramatically over the last 10 years and rheumatoid arthritis is now at the forefront of biotechnology. In this review, we outline one of the most exciting recent developments, namely antagonists of the cytokine TNF. The preclinical evaluation of TNF in animal models of rheumatoid arthritis, and subsequent clinical trials of TNF inhibitors in patients, provides insight into the 'bench to bedside' paradigm. We therefore briefly review rheumatoid arthritis, animal models of rheumatoid arthritis, the biology of TNF, the pivotal clinical trials of TNF antagonists and the emerging data on side-effects. Tumour necrosis factor inhibitors in rheumatoid arthritis represent the first attempt to achieve sustained blockade of a single cytokine in a human disease. Whilst this approach has been even more successful than might have been predicted, we suggest it is only the beginning of what has become a new therapeutic era.
Campbell
Ian K
IK
Reid Rheumatology Laboratory, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Roberts
Lynden J
LJ
Wicks
Ian P
IP
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006099:Granuloma / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011817:Rabbits; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha