The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis.

In the seventies, the molecule subsequently termed IL-1 was among the first cytokines to attract the attention of rheumatologists due to its biological role in tissue destruction and bone resorption. In the mid-eighties, cachectin/tumor necrosis factor was found to share some of these biological activities, and a strong synergism between the two cytokines became evident. While IL-1 appeared to be more important at the local level, TNF played a more prominent part at the systemic level. In 1984, we became aware of the existence of an antagonist to IL-1 - subsequently termed IL-1Ra (interleukin-1 receptor antagonist) - in urine of febrile patients; its mechanism of action was elucidated in 1987 and the molecule cloned in 1990. The natural inhibitors of TNF were identified in 1996/97 by different investigators and proved to be soluble fragments of the TNF receptor. A concept commonly accepted at present is that disease activity and clinical outcome are controlled by the balance between agonistic and antagonistic cytokines, and at present the principal goal is to understand the underlying mechanisms. This concept is illustrated by observations in numerous animal models. The control of IL-1 and TNF is strongly dependent on the contact between activated lymphocytes and monocytes, the main source of these cytokines. Inhibiting this interaction by interfering with ligands and counter-ligands may be a useful approach if it is possible to maintain the production of the cytokine antagonist. Apolipoproteins A-I and A-II as well as beta2-integrins are molecules that block ligand/counter-ligand interaction. According to animal experiments and clinical data, blocking either IL-1 or TNF, or both, is beneficial. However, to determine not only the benefit but also the side effects of combination therapy in the human system, long-term clinical trials will be required.