TNFa as Therapeutic Target: New Drugs, More Applications

TNFα is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune diseases. With the introduction of infliximab and etanercept, two injectable biologic TNFα blocking drugs are now available. Both are effective in the treatment of rheumatoid arthritis, reducing clinical inflammation and damage to bones. In addition, infliximab is FDA-approved for the treatment of Crohn's disease. More recent controlled trials have shown effectiveness for TNFα blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Further trials are underway in diverse inflammatory conditions including including uveitis, sarcoidosis, Behcet's syndrome, and graft versus host disease. Although the safety profile has been generally excellent, the rare development of reactivation tuberculosis, anti double-stranded DNA antibodies, or a demyelination syndrome point out the need for further close follow-up of treated patients. New formulations of recombinant anti-TNFαbiologics undergoing clinical trials use modifications to reduce antigenicity, increase the half-life, and maintain or extend the efficacy of these agents. Future development of TNFα antagonists is turning to small molecule inhibitors. The inhibition of the TNFα signaling cascade is under study using blockers of the p38, JNK, and ERK kinases, and by antagonists of transcription factor NF-κB activation. The goal of this approach is to develop compounds that are orally available, have increased selectivity compared to generalized blockade of TNFα, yet are therapeutically useful for a range of chronic inflammatory diseases.