The future role of anti-tumour necrosis factor-alpha products in the treatment of Crohn's disease.

Tumour necrosis factor-alpha (TNF alpha) is thought to play a central role in the immunopathology of Crohn's disease, particularly since its levels are raised in all types of cells, tissues and secretory fluids of these patients and in animal models of the disease. In addition, TNF alpha has been found to modulate a number of different processes within the network of inflammatory reactions and therefore has become a target molecule for intervention studies. In the past few years several compounds have been developed which neutralise or impair the production of TNF alpha, e.g. monoclonal antibodies [infliximab (cA2), CDP-571], TNF receptor p75-Fc fusion protein, pentoxifylline (oxpentifylline), p65 antisense oligonucleotides and metalloproteinase inhibitors, thereby counteracting the deleterious effects of this proinflammatory cytokine. At present, successful treatment of active 'refractory' and fistulising Crohn's disease has been reported with anti-TNF alpha antibodies; more clinical studies are in progress or will be performed with substances that intervene in the activation, production and processing of TNF alpha. Although important aspects of this type of immune-intervention therapy still need to be elucidated, e.g. long term effects, mechanism(s) of action, identification of responders and nonresponders, etc., it is obvious that the integration of basic and clinical research brings us to a new era of specific cytokine-directed therapy in Crohn's disease.