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New Treatments for Inflammatory Bowel Disease

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, and 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.

Inflammatory bowel disease seems to be a western disease. Highest incidence areas cover North America, Europe, Australia and South Africa. These are fairly common diseases. Crohnís disease is less common than ulcerative colitis. The ratio is about 3:10 to 8:10. Incidences of 5:8 per 100,000 population per year for UC, 5:6 for Crohnís.

Heredity in inflammatory bowel disease is a great concern for patients and their families and indeed there is a 10% to 25% occurrence of inflammatory bowel disease in relatives of those affected. Pathology is something we all waded through in medical school but itís terribly important for the understanding of these diseases, in fact I would say itís the key to understanding whatís going on in your IBD patients. Ulcerative colitis, if you look at it macroscopically, itís a continuous disease starting at the rectum.

Pseudopolyps are a non-malignant phenomenon. They are an inflammatory phenomenon.

Crohnís disease is very different, as I said. It can occur anywhere from the mouth to the anus. But the commonest sites of involvement particularly are the ileocolonic region with almost half of patients having involvement here. A third will have small bowel alone and about a fifth will have colonic disease alone. Perineal complications are typical of Crohnís disease and characteristic and occur in about a third of patients. Here we can see a perianal fistulae and abscess formation. This is a cross-section of the rectum and the anus, external skin tag here, with a sinus and fistula tract formation and an abscess. Itís important to remember that Crohnís disease is transmural and this explains a lot of its complications. Here we have the mucosa, a cross-section all the way through to the serosa and see that there is deep ulceration but in a focal distribution. Thereís a sinus tract in here and thereís a fistulous tract all the way to the serosa as well as inflammatory cells within the layers of the bowel. This is the endoscopic appearance of Crohnís disease. Typically you can see aphthous ulcers which are very discreet, small, 1 mm or 2 mm ulcerationís which actually occur over a lymphoid aggregates. Then you get larger ulcerationís which are typically stellate or longitudinal so thereís deep ulceration here with intervening normal mucosa around the ulcer. You may also get pseudo-polyps in Crohnís disease due to the exuberant inflammatory response.

Obstruction, because of the transmural nature of Crohnís disease, is common. This is terminal ileitis. Hereís the cecum and the appendix. You can see intense narrowing here with dilatation in between due to inflammation and possibly fibrosis in the bowel wall. This is fistula formation. This is aortoenteric fistula in Crohnís disease where a tract has burrowed out from the mucosa to the serosa, attached itself to another loop of bowel.

So to summarize features of UC versus Crohnís, very important features are the site. Ulcerative colitis is colonic, Crohnís involves the small bowel and the colon, although it may be exclusively colonic. The pattern here is continuous from the rectum, whereas in Crohnís there will be skipped areas. The inflammation is mucosal in ulcerative colitis and continuous, whereas it is transmural and focal in Crohnís disease. Perianal disease is uncommon in UC, common in Crohnís. Fistulae do not occur in UC, they do in Crohnís. Strictures are relatively uncommon in UC and quite common in Crohnís.

If you look at the acute complications of inflammatory bowel disease, exsanguinating hemorrhage is certainly a risk. Toxicity and perforation, obstruction -whether itís due to benign strictures or malignant complications. Abscess formation which may be abdominal, perianal or perirectal. Hereís an illustration of toxicity in the colon.

There are complications of inflammatory bowel disease related to chronic inflammation, and the systemic complications are glomerulonephritis and amyloidosis related to the elevated inflammatory proteins and immune complexes. This is relatively uncommon now that we have better treatments. Local complications are still common.

Systemic complications of inflammatory bowel disease can be related to the inflammatory activities so that if you control the inflammatory bowel disease, you control these manifestations; including aphthous stomatitis, episcleritis and uveitis, arthritis which is typically monoarticular and peripheral and is not destructive. The vascular complications, such as thrombophlebitis, erythema nodosum and pyoderma gangrenosum, the chronic skin lesions. There are systemic complications that do not resolve with treatment of the underlying inflammatory bowel disease, and important among these is the central or axial arthritis which is related HLA B-27 positivity. Here you can see an extensive ankylosis of the spine and the surgical clips from the colectomy, which did not help the spine.

Similarly, liver and bile duct lesions tend to follow their own course and can include anything from fatty change to chronic active hepatitis, sclerosing cholangitis and cholangiocarcinoma.

There are complications related to the small bowel pathology, and clearly if you have Crohnís disease you have the potential to malabsorb. And once malabsorption becomes chronic, youíre at risk for gallstones and also renal stones.

Colorectal cancer is one of the most feared complications of inflammatory bowel disease and this slide illustrates the risk of colorectal cancer in ulcerative colitis. This is cumulative incidence by decade of disease.

In Crohnís disease thereís in increased risk of gastrointestinal cancers, but the incidence of this is somewhat unclear and debated. Two-thirds of the malignancies will occur in the diseased bowel and one-third will occur in the

So how does inflammatory bowel disease present to you, the practicing physician? Importantly, one of the commonest presentations is with proctocolitis and unfortunately this is a lesion that can have many different causes, including ulcerative colitis, Crohnís disease, radiation, ischemia, infections, antibiotics and other rarer causes.

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.

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 two of them when you use this drug. Five-ASA drugs, as Iíve mentioned, are used for maintenance of remission.

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 side-effects, including allergic reactions all the way through to the severity of Stevens-Johnson; hemolysis, agranulocytosis and severe organ toxicities are all a concern. The common side-effects, however, are the patients main concern. And these are nausea and dyspepsia, anorexia, headaches which may be of a migraine-type, mild hemolysis, folate deficiency and importantly reversible male infertility. Now we have the other option of mesalamine.