The rationale for the current boom in anti-TNF alpha treatment. Is there an effective means to define therapeutic targets for drugs that provide all the benefits of anti-TNF alpha and minimise hazards?

Progress in understanding mechanisms of disease are necessary to usher in m ajor changes in treatment. A new era in rheumatoid arthritis (RA) and relat ed chronic autoimmune/inflammatory diseases is now beginning, with a variet y of anti-TNF alpha treatments licensed for use in both RA and Crohn's dise ase. The rationale for this new treatment lies in an understanding that cyt okines are critical, rate limiting molecules lying at the heart of the chro nic autoimmune/inflammatory disease process. This understanding was develop ed from the critical evaluation of a hypothesis that was proposed Linking c ytokines, antigen presentation and autoimmunity in 1983. Detailed analysis focusing on the major site of the disease, the rheumatoid synovium was esse ntial to developing indications that blockade of TNF alpha might be efficac ious. This clue was validated using anti-TNF alpha treatment of an animal m odel of RA, murine collagen induced arthritis, and by immunohistochemical d emonstration of upregulated TNF and TNF-R expression in the synovium. With this three pronged rationale, the authors were able to convince Centocor, I nc, which had developed a chimaeric anti-TNF alpha antibody for use in seps is, to work with them to test the concept that TNF alpha blockade would be beneficial in RA. With the success of that first trial, other companies hav e subsequently tested their anti-TNF strategies successfully. Current inter ests extend to understanding the processes that regulate TNF production in the rheumatoid joint. Progress in this area is discussed, using adenoviruse s to infect normal macrophages and rheumatoid synovium.