INFLAMMATORY BOWEL DISEASE

I. General

1. Two distinct conditions, UC and Crohn's (CD), though 10-20% of IBD can't be characterized as one or the other
2. Prevalence UC 4-15/100k; CD 0.2-8.0/100k
3. Usually presents 2nd or 3rd decade of life
4. Crohn's more common with juvenile onset; UC more common with adult onset
5. More common in Ashkenazi Jews

II. Etiology

1. Unclear for both UC and CD; probably multifactorial
2. Mycobacterium avium paratuberculosis may play a role in CD
3. Genetic: 10-12% have family hx; risk to 1st degree relatives 20-30%; identical twins show concordance rate 6.3% with UC and 58% with CD
4. Bacterial gastroenteritis may be a risk factor (BMJ 318:565, 1999--JW)
5. Smoking can causes relapses in CD, but may make UC better

III. Clinical characteristics

1. Crohn's Disease

1. Insidious presentation; consequently, often delayed dx
2. Waxing and waning course; tends to progress with time

1. May be worsened by dietary simple sugars, tylenol, NSAIDs

3. Transmural bowel inflammation; characteristic granulomas on bx
4. May be isolated to one segment of bowel (esp ileum) or may involve multiple segments separated by nl bowel ("cobblestone" pattern)

1. With exclusive involvement of terminal ileum (30% of cases), 60% will resolve and not recur

5. Can involve from mouth to anus
6. In adults, chronic diarrhea with or w/o blood may occur; also weight loss, abd pain
7. In children, may present with growth failure (resolves with nutritional support), anorexia, fever
8. In elderly, us. just diarrhea; tends to be less fulminant and involve the colon more
9. Complications:

1. Malabsorption and consequent electrolyte imbalance, anemia, vitamin deficiancies, malnutrition
2. Bila acid malabsorption causes gallstones (30% of pts) and oxalate kidney stones
3. Hypertrophic osteoarthropathy (occurs in 15-33%)

1. Digital clubbing, periostitis, synovitis, new bone formation

4. Ocular, derm manifestations (see under UC)
5. Hepatobiliary-80% have hepatomegaly from fatty liver
6. Higher risk for small bowel and colon cancer
7. Aphthous ulcers
8. Fistulae and sinus tracts
9. Abcesses

2. Ulcerative colitis

1. Continuous area of inflammation (no skip areas), limited to colon
2. Limited to mucosal layer
3. Can sometimes see "backwash ileitis"
4. In adults, bloody diarrhea and abd. pain more common than with CD; also weight loss, fever, and tenesmus (if rectal involvement-45% of cases)
5. In kids, almost always have rectal involvement, with tenesmus
6. In elderly, may present only with extraintestinal symptoms; more likely than younger pts to present with toxic megacolon, but overall course tends to be more benign
7. Complications:

1. Perforation
2. Toxic megacolon (a surgical emergency)
3. Adenocarcinoma of colon

1. Risk doubled compared with general population
2. Tends to be higher grade than general population
3. Uniformly dist'd in colon
4. Arises from flat mucosa so hard to dx on BE
5. Screen with Ba enema/colonoscopy Q6mo-1y starting 10y after sx onset
6. UC + Ca = worse 1-yr prognosis than non-UC pts (50-60% 1yr survival); afterward no diff.

4. Mucosal hemorrhage and consequent anemia
5. Arthritis (seen in 20-25% of pts)

1. The most common extraintestinal manifestation in kids
2. Hips, ankle, wrist, elbow in that order
3. Similar sx to RA
4. Resolve completely after proctocolectomy

6. Ocular manifestations

1. episleritis, uveitis, cataracts, keratopathy, corneal ulcers, retinopathy
2. 4-10% of IBD pts; 30% if have arthritis

7. Derm probs: 10% of IBD pts, inc. erythema nodosum, pyoderma gangrenosum
8. Hepatobiliary: chronic active hepatitis, pericholangitis, bile duct cancer (1-5%)
9. Increased risk for kidney stones
10. Maybe increased risk of thrombotic events

8. Criteria of Truelove and Witts for evaluating severity of UC (BMJ 2:1041, 1955):

3. "Ulcerative Proctitis" (i.e. ulcerative colitis confined to the rectum)
   1. In a retrospective study of 341 pts with ulcerative proctitis c/w 575 pts with more extensive UC, followed for avg. 64mos, 27 pts with UP developed proximal extension of the disease; in multivariate analysis, only predictor of proximal extension was "refractory disease" (>2 relapses/yr, chronic active disease, or need for steroids or immunosuppressants) (Am. J. Gastroent. 95:469, 2000--JW)

IV. Diagnostic approach

1. Clinical features play a significant role in diagnosis
2. To rule out alternative diagnoses:
   1. Stool studies to r/o infection
3. Blood work to explore possibility of complication, e.g. biliary function, anemia
4. KUB-useful during acute flare. Colon > 6cm = toxic megacolon; look also for signs of perforation or obstruction
5. Ba enema-can cause perf or toxic megacolon if done during an attack
6. UGI/SBFT-useful to look for CD or backwash ileitis with UC
7. Endoscopy-Facilitates both visual examination and tissue diagnosis
8. Serum antibody markers for inflammatory bowel disease
   1. Anti-Neutrophil Cytoplasmic Antibodies (ANCA) are associated with UC and can be seen in patients with CD as well
   2. Anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with Crohn's
   3. Anti-CBir (an antibody against flagellin) is associated with Crohn's but not UC; seen in about 40% of pts with CD who are ASCA-negative
   4.  

V. Treatment

1. General principles

1. Evaluation of different treatments hampered by no animal models, no pathognomonic features of disease, and no clearly definable therapeutic endpoints. In addition, many pts with IBD also have irritable bowel syndrome which clouds the picture.
2. In general, goal of treatment is to first induce then maintain remission
3. Assessing reponse to treatment: in UC, use the Truelove and Witts criteria (see above); in Crohn's, more difficult b/c of more heterogeneous sx in general, and the "Crohn's Disease Activity Index" hasn't been useful in clinical practice so I didn't copy it here.
4. Dietary changes: fish oil in large doses can reduce need for steroids in UC
5. During acute flares: bowel rest, nutritional support with elemental formulas or TPN if needed; elemental diets and TPN more helpful in Crohn's than UC.
6. Can treat diarrhea and cramping with antidiarrheals and antispasmodics as long as sx are mild and no fvr/abd tenderness

2. Aminosalicylates-used to treat mild or moderately active UC and Crohn's and to maintain remission; sulfasalazine and mesalamine seem to be OK for kids and pregnant or breastfeeding women

1. Sulfasalazine (Azulfadine)

1. Consists of 5-ASA (active moiety), aka "mesalamine" bound to sulfapyridine, a sulfa antibiotic which keeps the 5-ASA from being absorbed in small bowel; bond cleaved by bacteria in distal ileum, so little effect in small bowel.
2. Unclear mechanism of action
3. Not as effective as steroids in moderate or severe flares
4. In Crohn's, was effective at inducing remission with colonic BUT NOT WITH SMALL-BOWEL DISEASE; not effective at maintaining remission with either type of involvement
5. Many pts can't tolerate b/c of vomiting, dyspepsia, headache, anorexia, fatigue (dose-related) or hypersensitivity to sulfa component; 80% of men get hypermotility of sperm
6. Impairs absorption of folic acid and some recommend folate supplementation for pts on it

2. Other aminosalicylates

1. Mesalamine = 5-ASA (Asacol, Pentasa)
   1. Rectal use (suppositories and enemas)--Effective for mild-moderate active disease and maintenance
   2. Oral use--Formulated with coating that break down in distal ileum for delivery to colon where it won't be absorbed; used for mild-mod active disease and maintenance in both UC and Crohn's.
   3. 60 pts with mild-mod distal UC randomized to x mesalamine enemas 4g HS, mesalamine PO 400mg TID, or both x 6wks. At 6wks, greater improvement in Disease Activity Index, rectal bleeding as reported by pts, and physician ratings of improvement, with combination tx than w/other 2 groups (Am. J. Gastroent. 92:1867, 1997--AFP)
2. Olsalazine (Dipentum)
   1. A dimer of mesalamine, cleaved in the colon to 2 molecules of mesalamine.
   2. May be less effective than other agents for active disease
3. Balsalazide (Colazal)
   1. A prodrug of mesalamine, metabolized to mesalamine in the colon
   2. Associated with higher remission rates than delayed-release mesalamine in active ulcerative colitis and at least as effective in maintaining remission (Med. Lett. 43:63, 2001)
4. Side effects: Headache, dyspepsia, nausea, abdominal pain, diarrhea, and rarely, interstitial nephritis, hypersensitivity pericarditis, leukopenia, thrombocytopenia, pancreatitis, hepatitis, and allergic pulmonitis.
5. Occasional hypersensitivity reactions, including pneumonitis, pancreatitis, hepatitis, nephritis, and worsening of colitis.
6. There's a dose-response relationship with the aminosalicylates, so if no response or relapse during remission, can try increasing dose before changing to different meds.

3. Corticosteroids

1. Effective for acute flares in UC and Crohn's when used orally, parenterally, or rectally

1. When used IV for acute flares, us. 7-10d of 40-60mg/d of methylprednisolone or equivalent
2. Budesonide slow-release has topical activity against Crohn's with less systemic effect than other steroids

2. Not as effective for maintaining remission, though many pts are steroid-dependent and get worsening of sx when steroids are tapered
3. Relative importance of local vs. systemic effects are unclear
4. Newer formulations maximize local and minimize systemic effects

1. Prednisone and prednisolone conjugated with esters that minimize absorption, e.g. metasulfobenzoate
2. Newer steroids with more rapid presystemic metabolism, e.g. beclomethasone and budesonide
3. Steroid suppositories or enemas can be used as first-line in active UC or Crohn's with left-sided colonic involvement or as an adjunct to parenteral steroids in severe flares
4. Slow-release budesonide (Entocort) 9mg QD for mild-mod Crohn's of ileum and/or ascending colon
   1. Extensive first-pass metabolism gives it a high ratio of local-to-systemic anti-inflammatory effect
   2. Coating requires pH > 5.5 to dissolve preventing release in the stomach
   3. In comparison with. slow-release mesalamine (2g BID) was ass'd with sig. higher remission rates (62% vs. 36%) and sig. less withdrawal b/c of worsening Crohn's but no diff. in incidence of adverse events in a 16wk randomized trial of 182 pts with mild-moderately active Crohn's disease of terminal ileum, ascending colon, or both. There was evidence of adrenal axis suppression at end of trial in budesonide users (NEJM 339:370, 1998--JW)
   4. In a meta-analysis of 4 randomized trials comparing conventional corticosteroids to budesonide for active Crohn's disease, clinical remission @ 8wks was sig. more common in pts on conventional corticosteroids (60% vs. 52%) (Aliment. Pharm. Ther. 14:1419, 2000--Med. Lett.)
   5. For maintaining remission, may be as effective as conventional corticosteroids (Gut 48:186, 2001--Med. Lett.)

6. Some use ACTH but not in kids
7. Keep in mind toxic effects of steroids--See above link for more info

4. Antibiotics

1. Metronidazole may be useful in acute CD but not UC; peripheral neuropathy can result from prolonged use
2. 40 pts with mild-mod Crohn's flares randomized to Cipro 500 BID vs. mesalazine 2g PO BID x 6wks; at end of tx period; similar remission rate in the 2 groups (56% w/Cipro and 55% w/mesalazine (Am. J. Gastroent. 94:674, 1999--JW)
3. 134 pts (mean age 32yo) with moderately active Crohn's of the ileum randomized to 8wks of (ciprofloxacin + metronidazole) vs. placebo; all pts also received steroids.  Remission rates were not sig. different in the 2 groups at 8wks (Gastroent. 123:33, 2002--JW)

5. Immunosuppressives-have sig. toxicity but may allow tapering of steroids in UC and Crohn's

1. 6-mercaptopurine 2.0-2.5 mg/kd/d or Azathioprine 1.0-1.5 mg/kg/d (rapidly converted to mercaptopurine in RBC's)

1. Used as long-term therapy for steroid-dependent or steroid-unresponsive UC or Crohn's pts
2. Unclear mechanism of action; impedes DNA synthesis and T-lymphocyte function
3. Requires 3-6mos of Rx before clinical response is seen
4. Pancreatitis occurs in 3-15% of pts, usually after sev. weeks of Rx, resolves when drug is d/c'd; recurs if it's restarted
5. Bone marrow suppression, esp. neutropenia; must check CBC Q3mos
6. Some concern re: carcinogenicity and teratogenicity; this is probably low (Lancet 343:1249, 1993-cited in NEJM rvw)
7. In a randomized study comparing 6-MP (50mg/d) vs. mesalamine (3g/d) vs. placebo for prevention of Crohn's recurrence after resection and ileocolic anastomosis in 131 pts, over 24mo f/u, 6-MP, but not mesalamine, was ass'd with sig. lower incidence than placebo of both clinical (50% vs. 77%) and endoscopic (43% vs. 64%) recurrence (Gastroent. 127:723, 2004--abst)
8. In a randomized study comparing azathioprine 2mg/kg/d vs. mesalamine 3g/d x 24mos in 142 pts s/p conservative surgery for Crohn's, there was no sig. diff. in incidence of clinical or surgical relapse, though a significant benefit was seen in the subgroup of pts with prior intestinal resections (Gastroent. 127:730, 2004--abst)

2. Cyclosporine: used in acute, severe, refractory UC or Crohn's; IV effective; PO probably less so; cn cause renal insufficiency (decreased GFR and interstitial nephritis), neurotoxicity and sz, immunosuppression and opportunistic infections
3. Methotrexate
   1. Weekly IM injections can reduce steroid dependency
   2. Maintenance weekly methotrexate 15mg IM in pts with Crohn's and methotrexate-induced remission was, in one study of 76 pts, ass'd with sig. longer remission than placebo (NEJM 342:1627, 2000--JW)

6. Anti-TNF monoclonal antibodies, e.g. Infliximab
   1. Better relapse and remission c/w placebo (NEJM 337:1029, 1997 Am. J. Gastroent. 92:1746, 1997--Med. Lett.)
   2. Better efficacy at healing fistulas in Crohn's Disease c/w placebo (NEJM 340:1398, 1999--JW and NEJM 350:876, 2004--AFP)
   3. Infliximab over 6wks + azathioprine x 1y associated with higher rates of steroid-free remission over 1y (40% vs. 22%) compared with azathioprine alone in a randomized study in 113 pts with Crohn's, on prednisone x > 6mos (Gastroent. 130:1054, 2006--JW)
   4. In a study in 299 pts with moderate-to-severe Crohn's randomized to adalimumab (at one of 3 doses) vs. placebo x 4wks, the 2 highest dosing regimens had sig. higher rates of remission at 4wks than placebo (24% and 36% vs. 12%), with no sig. diff. in incidence of adverse reactions. (Gastroent. 130:323, 2006--JW)
   5. In a study in 362 adults with mod-to-severe active ulcerative colitis (Mayo disease activity score > 5 and active disease on sigmoidoscopy)  randomized to infliximab vs. placebo x 46wks, 8wk clinical response rates were sig. higher in the active-tx group (69% vs. 37%) and at 46wks (NEJM 353:2462, 2005--JW)

8. Anti-Integrin medications
   1. Integrins: Dimeric proteins that regulate cell movement and adhesion
   2. Natalizumab-An antibody against alpha-4 integrin, which is involved in cell adhesion in the intestinal tract.
   3. MLN02-An antibody that blocks the beta-7 subtype of the alpha-4 integrin receptor
      1. In a study in 181 adults with actuve ulcerative colitis but no severe disease randomized to MLN02 Q28d x 2 doses vs. placebo, the 6wk incidence of clinical remission was sig. higher in the MLN02 group (32% vs. 14%)
         
9. Thalidomide (inhibits of TNF-alpha)
   1. 22 pts with Crohn's refractory to steroids & other immunosuppressives ass'd with high rates of clinical remission and reduced steroid need (Gastroent. 117:1271, 1999--JW)

9. Growth hormone
   1. May decrease intestinal permeability
   2. 37 pts randomized to growth hormone (daily SQ injections) vs. placebo; at 4mo f/u, sig. less sx in GH group than placebo group (NEJM 342:1633, 2000--JW)

10. IL-1, alpha-interferon, IgG, omega-3-fatty acids, nicotine, amtisense polypeptides--under investigation
11. Surgery-only for intractable disease, steroid dependency, or complications requiring it; complications more frequent than for intestinal surg. for other indications