One-year inhibition of tumor necrosis factor-α:: a major success or a larger puzzle?

The concept suggesting the involvement of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha in the pathogenesis of rheumatoid arthritis (RA) has been demonstrated by several clinical trials targeting TNF-alpha. In addition to reduction of pain and swelling, a dramatic effect of TNF blocking therapies on the progression of joint destruction was shown. Nevertheless, complete remissions of the disease are rare even with these powerful therapeutic agents, and the optimal doses and dosage intervals of TNF blockers remain to be determined. Some insights into the pathogenesis of RA are provided by studying the effects of therapeutic TNF blockade on the biology of the disease. The fact that inflammation is not completely halted and destruction is ongoing in some patients suggests that other mechanisms may also be involved, including other cytokines such as interleukin-l and interleukin-6. In addition to the necessity of understanding the pathogenic events proximal to TNF-alpha induction, pharmacologic intervention with small molecules in the TNF signaling pathways may constitute a promising strategy. (C) 2001 Lippincott Williams & Wilkins, Inc.