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Inflammatory Bowel Disease (IBD)             IBD2009.pdf  |  Crohn's Disease   |   Ulcerative Colitis

There is a spectrum of IBDs, encompassing various types and degrees of intestinal inflammation that must be distinguished from inflammations caused by infections, drugs, ischemia, and radiation.
UC  (Ulcerative Colitis) and CD (Crohn's Disease) are the most common and best understood of these idiopathic diseases; their etiologies, however, remain elusive.  No single etiologic infectious agent has been associated with UC or CD

There are two major clues to etiology:

  1. The first is the primary familial association of IBD, which suggests a genetic predisposition.
  2. The second etiologic clue is the curious relationship of cigarette smoking with UC and CD. Cigarette smoking is well established to decrease the risk of UC; however, smoking is strongly associated with CD.

Classification of Inflammatory Bowel Disease

  1. Crohn's Disease (CD)  - full thickness inflammation anywhere in gastrointestinal tract
  2. Ulcerative Colitis (UC) - inflammation of superficial layers, continuous from rectum
  3. Lymphocytic Colitis - collections of lymphocytes without granulomas
  4. Collagenous Colitis - collagenous deposition in subepithelial zone, rectum and colon
  5. Diagnosis is clinical but requires tissue biopsy for confirmation and classification

Symptoms  

  1. Crampy abdominal pain; Diarrhea - may be bloody or watery       
  2. Weight Loss; Fever - may be major manifestation
  3. Extra-intestinal Manifestations: Arthritis; Eye Problems - anterior uveitis, episcleritis; Skin - pyoderma gangrenosum, erythema nodosum; Liver disease - especially sclerosing cholangitis

Medical Therapy Overview of IBD  -  Treatment divided into acute therapy and maintenance of remission  
[ Management of Inflammatory Bowel Disease - AFP 1998  ]

  1. Acute Moderate to Severe Exacerbation - Usually in patients with known disease, now active
    1. Essential to rule out underlying infection, fistula, perforation, other pathology
    2. Diet restriction:  Patients are usually made NPO (nothing by mouth) and given intravenous fluids
    3. Parenteral nutrition may be required (institute within 2-3 days of NPO)
    4. Glucocorticoids are often given, eg. hydrocortisone or methylprednisolone continuous iv
    5. Broad spectrum antibiotics (including metronidazole) are given
    6. Sulfasalazine or related compounds have little efficacy in severe acute flares
    7. Intravenous cyclosporine may be used after 7-10 days if responses are poor
  2. Chronic Therapy (Remission Maintenance)      
    1. Agents based on 5-aminosalicylate are the mainstay of therapy
    2. Azathioprine, 6-mercaptopurine (6-MP) and methotrexate are steroid sparing
    3. Metronidazole (or ciprofloxacin) is effective in CD ileitis but not in UC
    4. Low dose glucocorticoids are not recommended for chronic therapy

   
Medications for Inflammatory Bowel Disease

Sulfasalazine, Olsalazine, Mesalamine, Glucocorticoids - oral, enemas, Azathioprine/6-Mercaptopurine, Cyclosporine, Antibiotics, Methotrexate

  1. Sulfasalazine (Azulfidine®)
    1. First line therapy in most patients with acute or chronic IBD
    2. Congener of sulfapyridine and 5-aminosalicylic acid linked by an azo bond
    3. Attenuates inflammation in the large bowel only
    4. Compound is cleaved to composite groups by colonic bacteria (azoreductase)
    5. Requires 5-28 days for efficacy
    6. Contradindicated in patients with sulfa allergy; 15% of patients will discontinue drug
    7. Side effects: cytopenias, pancreatitis, hepatitis, rash, diarrhea, male infertility
    8. Dose maximum is 1gm qid po; usually begin at 500mg po bid and increase q week
    9. Use of larger initial doses associated with severe diarrhea
    10. Maintenance therapy is usually 1gm po bid
    11. Monitor blood counts, liver functions and amylase q 1-2 months
  2. Olsalazine (Dipentum®)
    1. Dimer of 5-ASA linked by azo bond which is split by colonic bacteria
    2. Contraindicated in patients with salicylate allergy; no sulfa moiety
    3. Main side effect is diarrhea (~25% of patients)
    4. Main use is in patients who cannot tolerate sulfasalazine
    5. Appears to be as effecive as sulfasalazine for mild to moderate IBD
  3. Mesalamine (mesalazine; Rowasa® enema, Asacol®, Pentasa®)
    1. Delayed release 5-ASA (ie. coated with acrylic-based resin) dissolves at pH 6
    2. Mainly released in distal ileum and colon;
    3. Pentasa® is slow release mesalmine (ethylcellulose coated) for delivery to proximal small intestine with activity in proximal Crohn's Disease
    4. Appears effective in exacerbations of Crohn's Disease as well as in ulcerative colitis
    5. Available as enemas (Rowasa®) as well as oral form (250mg tabs)
    6. 2gm. po lowers rate of relapses in patients with remissions lasting <3 months
    7. 0.8-1.6gm per po each day reduced exacerbations in UC patients over 6 months study
  4. 6-Mercaptopurine (6-MP, Purinethol®)
    1. Effective in prevention of relapses and possibly in active disease
    2. Most patients require >17 weeks to begin working, however
    3. Recommended in Crohn's patients with chronic fistulae, obstruction, etc.
    4. Dose is 50mg/day po initially, increase to maximum 2-2.5mg/kg/day
    5. 6-MP and AZA are effective in 50-70% of patients with IBD
    6. Side effects include bone marrow suppression and pancreatitis, hepatitis
    7. ~0.5% of population deficient in thiopurine methyltransferase leading to toxicity
  5. Azathioprine (AZA, Imuran®)
    1. Begin 50mg/day; may increase to maximal 2.5mg/kg/day
    2. Side Effects: Pancreatitis (~5%), Bone marrow suppression (~2%), hepatitis
    3. Mildly effective as single agent, does prevent flares of disease and maintain remissions
    4. Usually permits reduction in glucocorticoid dose required for suppression of disease
    5. Useful in steroid refractory exacerbations and to prevent remissions
    6. Note that AZA is metabolized to 6-MP
  6. Methotrexate
    1. 20-25mg/week given im in refractory Crohn's disease disease
    2. Clear benefit in patients on >20mg/day prednisone
    3. Extremely well tolerated without notable side effects > placebo
    4. Allowing lowering of steroid doses and control of disease
    5. Recommended now in nearly all patients requiring higher dose prednisone
  7. Cyclosporine
    1. Good response initially to iv form, usually within 48 hours
    2. Relapses common when drug is stopped
    3. This agent shows most rapid onset of activity in steroid refractory disease
    4. Reduces need for surgical resection in fulminant UC
    5. However, low doses do not prevent attacks and may be generally ineffective
    6. Dose is usually 4mg/kg iv qd initially (adjust for renal function)
    7. Oral dose is typically 2-3X higher, eg. 8-12mg/kg/day and must be monitored closely
  8. Antibiotics
    1. Effective in "backwash" ileitis, pouchitis, ileocolonic Crohn's Disease
    2. Metronidazole is usually used, 250mg po or iv tid-qid initially; qd or qod or q3d chronic
    3. Ciprofloxacin 500mg po bid or iv may also be used
    4. Clarithromycin, cephalosporins, tetracyclins are being tested
    5. Anti-tuberculous therapy - mixed results, still experimental
    6. Broad spectrum agents should be used in "toxic" patients, toxic megacolon, perforation
  9. Tumor Necrosis Factor Alpha (TNFa) Blockade
    1. Activity predicted on the basis of certain animal models
    2. Has good activity in Crohn's Disease, including fistula healing

Indications for Surgical Treatment for IBD        

  1. Bleeding - usually in Ulcerative Colitis
  2. Obstruction
    1. More common in Crohn's Disease
    2. Acute obstruction with edema is contraindication to operate
  3. Perforation / Fistula / Peritonitis / Abscess
  4. Failed medical therapy
  5. Remove grossly involved bowel; ~50% of CD patients recur
  6. For UC, removal of entire colon completely eradicates the intestinal disease


Novel Therapies for IBD

  1. Specific Cytokine Blockers
    1. IL-1 receptor antagonist (IL-1RA)
    2. TNFa blockers (see below)
  2. Other immunosuppressive agents may be effective
    1. Cyclosporine is being evaluated in specific settings
    2. Rapamycin
    3. FK506 and other immunosuppressives
    4. CTLA-4Ig blocks T cell activation, is being evaluated in various autoimmune diseases
  3. 5-Lipoxygenase Inhibitor - Zileuton 600mg po qid has shown some efficacy in CD
  4. Fish Oil [3]
    1. May reduce production of inflammatory leukotrienes and thromboxanes
    2. Suppresses IL-1 and TNF production
    3. Free Radical Scavanger activity
    4. High dose enteric coated (2.7gm/d) reduced CD exacerbations at 1 year [10]
  5. Interferon alpha
    1. Some reduction in disease symptoms in early studies
    2. No effect on endoscopic appearance)

   
OTHER INFLAMMATORY BOWEL DISEASES

A.  Lymphocytic Colitis

  1. Biopsy specimens show lympocytic inflammation
  2. Generally responds to moderate dose glycocorticois

B.  Collagenous Colitis  

  1. Persistent watery diarrhea with blood
  2. Average age ~60 with female to male ratio 4 to1
  3. Biopsy required for diagnosis, usually optained by flexible sigmoidoscopy
    1. Deposition of dense band of collagen in subepithelial zone of the colon or rectum
    2. Excess collagen is Type III, the kind of collagen found usually in inflammatory areas
    3. Lymphocytes, plasma cells, and few eosinophils found in lamina propria
    4. Fecal leukocytes occur in ~55% of patients and help with diagnosis [37]
  4. Differential Diagnosis
    1. Ulcerative Colitis
    2. Microscopic (Lymphocytic) Colitis
    3. Ischemic Colitis
    4. Radiation Colitis
    5. Systemic Sclerosis
    6. Infectious Colitis
    7. May be related to collagenous sprue, where abnormal collagen is found in small intestine
    8. Celiac sprue infrequently occurs in these patients [37]
  5. Treatment
    1. Sulfasalazine initially 1gm/day, increase to 2-3gm/day
    2. Mesalazine also effective in patients intolerant of sulfasalazine
    3. Glucocorticoids are used in resistant and severe disease
    4. Combination therapies may be used

NIDDK- NIH   Ulcerative Colitis Information  

American Gastroenterological Association Info on IBD

Crohn's & Colitis Foundation

Ref:
Outlines in Clinical Medicine  on Physicians' Online 1999

       

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