• rheumatoid arthritis
• clinical trials
• infliximab

Cytokines play a central part in the human immune response and can generally be categorised as proinflammatory or anti-inflammatory cytokines in nature. Tumour necrosis factor α (TNFα) is a proinflammatory cytokine and is a key mediator of inflammation. It has been shown to be pivotal early in the inflammatory cascade. Its effect on upregulation of inflammatory events within the joints makes it an appropriate pharmacological target in rheumatoid arthritis (RA). Infliximab, an anti-TNF treatment, has been successful in clinical trials in reducing TNFα induced production of other inflammatory mediators, thereby reducing the signs and symptoms of RA.

Infliximab is a chimeric monoclonal antibody that is 75% human and 25% mouse protein.1 The mouse portion contains a variable region binding site while the human portion is responsible for effector function. Infliximab binds to soluble TNFα as well as membrane bound TNFα. It has also been shown to lyse TNFα producing cells in vitro, although this has not been studied in vivo.2 The antibody binds with high affinity, avidity and specificity to human TNFα. It does not bind to TNFβ, otherwise known as lymphotoxin-α. This high specificity decreases the potential for non-specific effects on other biological pathways. There is a dose proportional neutralisation of TNFα at doses ranging from 0.01 to 10 mg/kg in subjects with increased TNFα levels after endotoxin challenge. Because infliximab is a protein, it is not metabolised by cytochrome P-450 enzymes providing additional advantages. For example, the genetic polymorphisms of P-450 isoenzymes and the consequent variability in metabolism leading to different toxic or inactive metabolites are less of an issue. Also, the likelihood of complex drug interactions are decreased in comparison with small molecules.

Infliximab has also been studied in inflammatory bowel disease, specifically Crohn's disease. TNFα seems to play a central part in the inflammatory …