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Ulcerative Colitis

The topics that Iíd like to cover include the definitions, the etiology and the epidemiology of inflammatory bowel disease. The pathology, the complications, the presentation, and therapy and prognosis will also be discussed.

There is a spectrum of presentations in inflammatory bowel diseases. The major ones are ulcerative colitis and Crohnís disease. There are minor ones, such as microscopic colitis. Ulcerative colitis is a mucosal disease and effects the colon only, whereas Crohnís disease is a transmural disease, with inflammation through all the layers of the bowel, associated with ileitis, ileocolitis, ulcerative colitis, ulcertive colitis, ulsertive colitis, ulserative colitis

The etiology of inflammatory bowel disease really is unknown, but there are several lines of evidence involving disordered immune regulation, stimulation of the bowel by intestinal luminal antigens, particularly bacterial, altered permeability of the intestinal epithelium and the generation of soluble mediators of inflammation. This area has been the greatest area of expansion in our knowledge of recent times. The cytokines are deeply involved in the pathogenesis of inflammatory bowel disease and our knowledge of cytokines has exploded in the last few years. There are several pairs of cytokines, pro-inflammatory and anti-inflammatory pairs. So IO-1 is the pro-inflammatory cytokine of the two. IO-1 receptor antagonist is anti-inflammatory and so you can match them across here with TNF IL8 and TGF beta. Our knowledge of these has been expanded greatly by the use of transgenic mice, where

We move on now to the therapy of inflammatory bowel disease, and clearly the major categories are: medical, surgical, supportive - such as nutritional and stoma - and social and psychological support, which is very important.

If you look at the 5- ASA drugs, sulfasalazine is the mainstay that has been with us for many years, and the cheapest. Itís an oral formulation. Olsalazine is used less now because of its side-effects. Itís also an oral formulation. Mesalamine is really the drug of choice now for remission reduction for mild and moderate disease and it comes in oral and enema form, and para-aminosalicylic acid is available overseas but not here.

This is an illustration of the structure of sulfasalazine just to remind you that really the part that works is the aminosalicylate and the part that gives the side-effects is the sulfapyridine, and unfortunately you are stuck with the

This is an illustration of the effect of 5-ASA in active ulcerative colitis. Here you can see a nice dose response curve where the 4.8 grams a day causes improvement in 50% and remission in 25%, and so on down to placebo, where you have very low rates of improvement. Itís important to remember that this is a lot of pills for the patient to take, but it may well be worthwhile. Sulfasalazine is still very widely used because of its low cost and has major

Systemic glucocorticoids are used in IBD. These include prednisone and prednisolone. All are IV. They induce remission in acute IBD, they reverse life-threatening colitis. They are not helpful for maintenance of remission and can be hard to taper. They glucocorticoids, as you know, have wide ranging side-effects including these; salt and

If you want to move on to stronger immunosuppression, the most commonly used drug is mercaptopurine or azathioprine as precursor. Here you can see the effects of azathioprine in active Crohnís disease, in achieving steroid typhi, inhaling fistulae and in overall clinical improvement as far superior to placebo.

Cytokine therapies are new are certainly not available on the market yet, but the most exciting development in the last few years in IBD, and this is the clinical application of all that knowledge we gained on cytokines in research models. The ones being used are monoclonal antibodies to TNF alpha, recombinant IO-10, recombinant IO-11 and anti-sense molecule to ICAM-1. The recent study in the New England Journal showed a dramatic response of Crohnís disease to a chimerical monoclonal antibody called CA-2 tumor necrosis factor alpha. This is looking at

Antibiotics, as I said, can be useful and the classic one used in IBD is metronidazole. The indications are mostly in Crohnís disease, for perianal disease, mild to moderate colitis, ileocolitis and possibly ileitis. It does have toxicities, including nausea and orexia, diarrhea, furry tongue, monilial infections, puerperal neuropathy is the one I would point out to you that this is almost inevitable on chronic maintenance metronidazole therapy and patients must be warned