Transcending conventional therapies: the role of biologic and other novel therapies.
Biologic and other novel therapies targeted to specific pathogenic processes offer the potential for improved treatment outcomes in patients with Crohn's disease and alteration of the course of the disease. Therapies targeted to tumor necrosis factor alpha (TNF-alpha) include anti-TNF-alpha monoclonal antibodies (infliximab and CDP-571), TNF-binding neutralizing fusion proteins (etanercept), and TNF-alpha production inhibitors (thalidomide). In placebo-controlled trials, infliximab has rapidly induced clinical response and remission in patients with moderately to severely active Crohn's disease refractory to conventional therapy and patients with fistulizing Crohn's disease, with minimal toxicity; retreatment with infliximab in patients who experienced an initial response maintained their clinical improvement. Clinical experience suggests that infliximab may also be effective when administered as corticosteroid-sparing therapy. Infliximab is the only anti-TNF-alpha therapy currently available in clinical practice for the treatment of active Crohn's disease. Controlled trials of the investigational anti-TNF-alpha agent CDP-571 show benefit for induction of clinical improvement and steroid-sparing, but further investigation is needed. A pilot study of etanercept suggested a beneficial effect, but its efficacy was not confirmed in a controlled trial. In open-label trials, thalidomide has demonstrated efficacy in patients with refractory Crohn's disease; however, the therapeutic potential of thalidomide may be severely limited by the high incidence of drug-induced side effects. Other novel agents, including anti-alpha4 integrin antibodies, interleukin (IL)-10 and IL-11, and the immunomodulators tacrolimus and mycophenolate mofetil have been evaluated as treatment in patients with severely active or fistulizing Crohn's disease in open-label and controlled trials, with varied results reported to date. The development of these new therapies is an exciting advance that promises to improve the management of Crohn's disease and expand current knowledge of underlying pathophysiologic mechanisms.
Sandborn
W J
WJ
Mayo Medical School, Rochester, Minnesota 55905, USA.
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000187:drug effects; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000627:therapeutic use; D015507:Drugs, Investigational; D000068800:Etanercept; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007074:Immunoglobulin G / Q000627:therapeutic use; D007155:Immunologic Factors / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D000069285:Infliximab; D039441:Integrin alpha4; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D013792:Thalidomide / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D016207:Cytokines; D015507:Drugs, Investigational; D005765:Gastrointestinal Agents; D007074:Immunoglobulin G; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D039441:Integrin alpha4; C402162:CDP 571; D013792:Thalidomide; D000069285:Infliximab; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D000068800:Etanercept; D016559:Tacrolimus