INFLAMMATORY BOWEL-DISEASE - CURRENT CONCEPTS IN PATHOGENESIS AND THERAPY

Current drug therapy of inflammatory bowel disease comprises predominantly drugs with multiple actions and, for some, multiple adverse effects. Advances in the understanding of disease pathogenesis has only in recent years led to the application of new therapies targeted to specific pathogenic pathways considered of importance. Observation of events occurring early in the pathogenesis of Crohn's disease have pointed to T cell activation in response to a specific luminal antigen or a group of antigens as the major immunopathological event. These antigen(s) are not adequately eradicated because of: (a) their nature; (b) deficiencies in macrophages; or (c) abnormalities in the regulation of interaction between macrophages and T cells. In contrast, abnormalities of large bowel epithelium represent the most likely event early in the pathogenesis of ulcerative colitis. Mucosal inflammation results largely from responses to luminal macromolecules that penetrate a deficient epithelial barrier. Whether autoimmune, luminal or genetic factors underlie the epithelial abnormalities is unresolved. Late pathogenic events in both disease groups have much in common and are responsible for the majority of clinical manifestations. Knowledge of the effectors of tissue injury and repair is increasing, but our understanding of their effects on the target tissues - epithelial, endothelial, mesenchymal and neural - is less well developed. Recent advances in therapy have come mainly from pharmacological refinements in the use of established drugs such as corticosteroids and sulfasalazine. However, there is increasing focus on agents with more specific anti-inflammatory properties and more powerful suppressive actions on T cells. Therapies directed specifically towards protecting the targets of injury are only starting to gain serious attention. Only through continued intense investigation of pathogenic mechanisms in inflammatory bowel disease will novel therapies offering efficacy with minimal adverse effects be rationally developed.