title: Anti-TNFalpha therapy of rheumatoid arthritis: what can we learn about chronic disease?
abstract: The importance of tumour necrosis factor (TNF)alpha in rheumatoid arthritis (RA) was initially proposed on the basis of analysis of cytokine gene regulation at the local site of the disease, the synovium. This was then verified in animal models and established in an extensive series of clinical trials, culminating in now 250000 treated patients with either of two approved TNF inhibitors, antibody or fusion protein. The degree and magnitude of clinical benefit has enabled analyses of the mechanism by which anti-TNF benefits, and hence insights into important steps in the disease process. It was found that essentially all aspects of RA were ameliorated, and important mechanisms of benefit involved diminution of multiple pro-inflammatory cytokines, adhesion molecules and chemokines, leading to reduced cell trafficking, reduced angiogenesis and most importantly halting of joint destruction. What of the problems? Safety is better than prior drugs, but there is a small increase in severe infections, smaller than might have been anticipated. Cost is the major drawback limiting greater use. In view of the central pathological processes down-regulated, and their role in many diseases, the early clinical success of anti-TNF in RA led to subsequent successful trials and registration in Crohn's disease and juvenile rheumatoid arthritis, and successful trials in ankylosing spondylitis, psoriasis and psoriatic arthritis. The era of anti-cytokine therapeutics is just dawning.
authors.affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, London W6 8LH, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Fionula M
authors.initials: FM
authors.lastname: Brennan
authors.forename: Ewa
authors.initials: E
authors.lastname: Paleolog
authors.forename: Andrew
authors.initials: A
authors.lastname: Cope
authors.forename: Peter
authors.initials: P
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Jim
authors.initials: J
authors.lastname: Woody
authors.forename: Ravinder N
authors.initials: RN
authors.lastname: Maini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000378:metabolism; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D000069285:Infliximab; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept