Inflummcrtory zyxwvutsrqponm Bowel Diseuse.@ zyxwvutsrqponm 6(2):137-139 zyxwvutsrqponmlk 0 zyxwvutsrqpo 2000 zyxwvutsrqpon Crohn’s & Colitis zyxwvutsrqpon Foundation of America, Inc. Anti-TNF Therapy for Crohn’ s Disease: A Perspective (Infliximab Is Not the Drug We Have Been Waiting For) Fergus Shanahan Department zyxwvuts qf Medicine, University College Cork, National University of Ireland, Cork, Ireland The immune substances ... in the munner of magic bullets, seek out the enemy. -Paul Ehrlich One should treat as many patients as possible with a new drug while it still has the power to heal. -Sir William Osler Most debaters would prefer to modify the motion for debate to suit their arguments, as truth and reality usually lie somewhere between polarized viewpoints. To the question, Is infliximab a significant or even a major ad- vance in the management of Crohn’s disease?-the an- swer is yes. The introduction of anti-TNF (tumor necro- sis factor) therapy has been satisfying for clinicians, a godsend for some patients, gratifying for immunologists and those who pursued immune mechanisms of tissue injury in this disease, and proof that investment and per- sistence with basic research pays dividends in terms of therapeutic advances. But, to the question, Is infliximab the drug that we have been waiting for?-the answer must be not quite. To claim that anti-TNF therapy is some form of latter- day magic bullet or finality that patients and their phy- sicians have been waiting for is, at best, premature and simplistic. The clinical pharmacology of anti-TNF therapy in Crohn’s disease (CD) has been reviewed else- where (l), and its merits are detailed in the accompany- ing article by Rutgeerts. Evidence for the efficacy of anti-TNF therapy in moderate-to-severe CD resistant to conventional therapy (2), and in patients with fistulas (3), is well established and not at issue. However, the most compelling argument for more restrained enthusiasm for anti-TNF is that it only tackles part of the immunopatho- genesis of CD. Crohn’s disease is a syndrome represent- Received January 12, 2000; accepted January 17, 2000. Address correspondence and reprint requests to Dr. F. Shanahan, Department of Medicine, Clinical Sciences Building, Cork University Hospital, Cork, Ireland. ing the outcome of three interacting elements that in- clude genetic predisposing factors, environmental modi- fiers, and immune-mediated tissue damage (4). Most current drug therapies, including anti-TNF, suppress or block the host immunoinflammatory response. The other variable, environmental priming of the mucosal inflam- matory response, is not addressed by these forms of therapy. The enteric bacterial flora is the most important local environmental factor priming the mucosal inflammatory response. Evidence implicating the enteric flora in the pathogenesis of CD disease includes: 1) the purported efficacy of antibiotics in some patients with CD, 2) thera- peutic efficacy of diversion of the fecal stream, 3) clini- cal evidence for disease recurrence on restoration of the fecal stream, 4) experimental induction of mucosal in- flammation after luminal installation of bacterial mate- rial in susceptible subjects, 5) evidence for loss of im- munologic tolerance to enteric flora in humans, 6) at- tenuation of mucosal inflammation in germ-free animal models of enterocolitis, and 7) preliminary evidence for therapeutic efficacy of probiotic organisms in animal models of enterocolitis. Long-term remission of chronic relapsing disorders, such as CD, is unlikely to be attained by any form of therapy that ignores one of the major contributors to the immunopathogenesis. The situation is reminiscent of the management of peptic ulcer disease in an earlier era. Effective drugs causing gastric acid suppression were hailed as major advances in the management of duodenal ulceration and did, indeed, heal ulcers, but did not prove to be the drugs we were waiting for. Acid suppression dealt with only one factor in the pathogenesis of peptic disease, and it was not until the role of the gastric mi- croflora (Helicobacter pylori) was recognized that long- term cure of peptic ulcer disease was achieved. This should be a sobering lesson for those involved in the 137