Overview of the safety of TNF inhibitors

Among the most dramatic therapeutic advances in medicine in recent years has been the development of novel biologic therapeutics. In autoimmune disease, the introduction of biologic therapeutics, particularly recombinant proteins and monoclonal antibodies (mAbs), has been driven largely by three factors: (1) a growing recognition of the unmet clinical need for potent therapeutic agents in various disease states; (2) a clearer delineation of the molecular pathogenesis of diverse autoimmune conditions, allowing the identification of specific components of the dysregulated immune response that could serve as relevant therapeutic targets; and (3) advances in biopharmaceutical development, allowing the creation of agents capable of altering the function of specific targets. While a number of biologic agents targeting diverse components of the immune system have been introduced for several autoimmune conditions, the greatest clinical success to date has been achieved with inhibitors of the key proinflammatory cytokine tumor necrosis factor (TNF)-α. Through 2006, more than 1.2 million patients worldwide have received therapy with one of the three approved recombinant macromolecule TNF inhibitors. The three are infliximab, a chimeric IgG1 mAb specific for TNF-α; etanercept, a dimeric soluble type-II TNF receptor (CD120b)IgG Fc fusion protein that binds -α as well as lymphotoxin (TNF-β); and adalimumab, a human IgG1 mAb specific for TNF-α. Based on impressive results from a number of controlled clinical trials, these agents have been approved for use in rheumatoid arthritis (RA), Crohn’s disease, psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis, juvenile idiopathic arthritis, and ulcerative colitis. They are under study in a variety of other diseases as well. As reviewed elsewhere, the TNF inhibitors have achieved remarkable clinical efficacy, both in terms of substantially improving the signs and symptoms of disease, and in improving quality of life and maintaining or improving functional status, a key outcome for arthritis patients. Moreover, TNF inhibitors have been shown to prevent the progression of structural damage in RA and other conditions, including PsA.