[Present importance of direct immunologically based intervention strategies using anticytokines in rheumatoid...

Rheumatoid arthritis (RA) is a chronic inflammatory multisystemic autoimmune disease of unknown origin. RA is clinically characterized by recurrent inflammation of joints, synovialitis, progressive destruction of cartilage or bone tissue and multiorgan involvement. Today all established therapies of RA are still unable to stop or even cure the disease. In most cases these therapies can only reduce progression. Furthermore, these therapies have substantial side effects, which can contribute to the increased mortality of disease. Therefore more effective therapies with fewer side effects are needed. In this context direct immunological intervention strategies increasingly gained interest to inhibit proinflammatory cytokines. In vivo and in vitro studies as well as experimental therapies documented the important role of the proinflammatory cytokines TNFalpha and IL-1 in RA. The therapy with TNFalpha-antibodies or receptor fusion proteins as well as IL-1 receptor antagonists proved to be clinically as well as immunologically highly effective as therapy of RA. The single dose treatment is associated with mild side effects only. In addition, trials using combined TNFalpha-antibody and methotrexate therapy gave promising results. However, potential severe side effects may occur after repeated therapy cycles or may be discovered after prolonged time of observation only (e.g., allergic reactions, induction of autoantibodies or malignancies). Therefore, at present these therapy options can only be recommended for selected patients, who are included into controlled clinical trials. In addition, repeated courses of therapy seem to lead to reduced therapeutical efficacy (especially in TNFalpha-antibody therapy). Further controlled studies with cytokine antagonists should especially address these problems and focus in particular on potential inductions of autoantibodies or malignancies as well as on additional long-term side effects. In contrast to direct inhibition of TNFalpha or IL-1 several further therapies indirectly influence these cytokines by interference with their synthesis or by alteration of the respective receptors. The importance of these therapeutical options has to be determined as well as the possibility of combination of established therapies with immunological intervention strategies.