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A. Epidemiology navigator

  1. More common in colder areas of Northern Hemisphere
  2. In USA, East > West; Jews > Non-Jews
  3. Age Peaks: 18-25 (major) and 60 (minor)
  4. Whites > Blacks >> Asians and Hispanics
  5. Higher incidence of IBD in families
  6. Smoking associated with increased Crohn's disease (CD), reduced ulcerative colitis (UC)

B. Etiology [1,2,3]navigator

  1. Genetic influence
    1. Twin concordance 37% in CD and 10% in UC
    2. Associations with 12 genetic loci reported
  2. Lower incidence in developing nations versus developed suggest environmental factors
  3. Clear Immune Dysregulation
    1. Trigger includes bacterial antigens, at least in animal models
    2. Innate immune system and intestinal epithelium interaction play key role
    3. Abnormal handling of normally tolerogenic bacterial antigens
    4. Dysregulation of dendritic cells (abnormal antigen presentation) may be central
    5. Reduced generation of regulatory T cells (Tr1, Th3) implicated
    6. Crohn's Disease (CD) appears to be a Th1 T helper cell predominant disease
    7. Ulcerative colities (UC) appears to be a Th2 T helper cell predominant disease
  4. Inflammatory Mediators
    1. Elevated local levels of interleukin-1 (IL-1) and TNF-alpha
    2. Many cytokines, chemokines, and other bioactive molecules elevated
    3. Dendritic cells normally play a role in stimulating T regulatory cells; these are reduced
    4. Reduced levels of transforming growth factor (TGF) ß, key regulatory cytokine
    5. Role of prostaglandins is under study; some appear protective, others are aggrevators
    6. Nitric oxide synthetase induced locally; both detrimental and protective roles found [5]
  5. Mouse Models of IBD
    1. Mice with interferon receptor, interleukin-2 (IL-2), or IL-10 deletions develop IBD
    2. Mice with transgenic human HLA-B27 develop arthritis and IBD
    3. Mice raised in a germ-free (bacteria negative) environment do not develop IBD
  6. Inciting Factors [1]
    1. Gut epithelial barrier leaky in IBD patients
    2. Disturbances of innate immune system
    3. Antigen recognition, processing and presentation abnormal
    4. Atypical antigen presenting cells become potent T-cell activators in IBD
    5. Disturbed clearance of autoreactive or over-reactive T cells
    6. Balance of regulatory cells versus effector cells is abnormal
    7. Psychosocial stressors may trigger or augment inflammation

C. Symptomsnavigator

  1. Crampy abdominal pain
  2. Diarrhea - may be bloody or watery
  3. Weight Loss
  4. Fever
  5. Extra-intestinal Manifestations
    1. Arthritis [6]
    2. Eye Problems - anterior uveitis, episcleritis
    3. Skin - pyoderma gangrenosum, erythema nodosum
    4. Liver disease - especially sclerosing cholangitis
    5. Osteopenia - increased in IBD; associated fracture risk increased 40% [7]
  6. Increased incidence of pancreatitis (acute/chronic) with IBD
  7. Triggers of IBD Flares [8]
    1. Infection - viral upper respiratory infection most commonly; bacteria, other viruses [19]
    2. Diet - excess fructose and sorbitol intake
    3. Disease progression - new fistula development
    4. Small bowel bacterial overgrowth - gastric antisecretory therapy
    5. Antibiotics inducing Clostridium difficile outgrowth
    6. Nonadherence - patient stops or tapers medication
    7. Drug interactions - 5-ASA and mercaptopurine, cholestyramine blocking drug absorption

D. Classification of Diseases [1]navigator

  1. CD
    1. Full thickness inflammation anywhere in gastrointestinal tract
    2. Typically anti-Saccharomyces ceriviseae antibody (ASCA) positive and pANCA (periplasmic antineutrophil cytoplasmic antibody) negative
    3. Sensitivity and specificity of ASCA+/pANCA- for CD are 50% and 95% respectively [9]
  2. UC [3]
    1. Inflammation of superficial layers of large intestine
    2. May be continuous from rectum
    3. Typically ASCA negative and pANCA positive
    4. Sensitivity and specificity of ASCA-/pANCA+ for UC are 50% and 97% respectively [9]
  3. Microscopic Colitis Syndromes [10]
    1. Account for ~10% of chronic diarrhea at referral centers
    2. Lymphocytic Colitis
    3. Collagenous Colitis (see below)
    4. Nondescript macroscopic appearance; diagnosis on histopathology of biopsy
    5. Biopsy finding s very similar between to conditions
  4. Lymphocytic Colitis
    1. Collections of lymphocytes without granulomas
    2. Biopsy specimens show lymphocytic inflammation
    3. Generally responds to moderate dose glucocorticoids
  5. Diagnosis is clinical but requires tissue biopsy for confirmation and classification

E. Collagenous Colitisnavigator

  1. Persistent watery diarrhea with blood
  2. Average age ~60 with female to male ratio 4 to1
  3. Diagnostic Pathology
    1. Biopsy required for diagnosis, usually optained by flexible sigmoidoscopy
    2. Deposition of dense band of collagen in subepithelial zone of the colon or rectum
    3. Excess collagen is Type III, the kind of collagen found usually in inflammatory areas
    4. Lymphocytes, plasma cells, and few eosinophils found in lamina propria
    5. Fecal leukocytes occur in ~55% of patients and help with diagnosis
  4. Differential Diagnosis
    1. UC
    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
  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

F. Overview of Medical Therapy for IBD navigator

  1. Treatment divided into acute therapy and maintenance of remission
  2. Acute Moderate to Severe Exacerbation
    1. Usually in patients with known disease, now active
    2. Essential to rule out underlying infection, fistula, perforation, other pathology
    3. Glucocorticoids are often given IV: suggest hydrocortisone or methylprednisolone
    4. Patients are usually made NPO (nothing by mouth) and given intravenous (IV) fluids
    5. Broad spectrum antibiotics (including metronidazole) are given
    6. Parenteral nutrition may be required (institute within 2-3 days of NPO)
    7. Sulfasalazine or related compounds have little efficacy in severe acute flares
    8. Intravenous cyclosporine may be used after 7-10 days if responses are poor
  3. 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 and generally well tolerated
    3. Metronidazole (or ciprofloxacin) is effective in CD ileitis but not in UC
    4. Low dose glucocorticoids are not recommended for chronic therapy

G. Medications [13]navigator

  1. Agents
    1. Sulfasalazine
    2. Olsalazine
    3. Mesalamine
    4. Balsalazide
    5. Glucocorticoids - oral, enemas
    6. Azathioprine / 6-Mercaptopurine
    7. Cyclosporine
    8. Antibiotics
    9. Methotrexate
    10. Specific Cytokine Inhibitors / Antibodies
  2. 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
  3. 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
  4. Mesalamine (mesalazine; Rowasa® enema, Asacol®, Pentasa®) [11]
    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 UC
    5. Available as enemas (Rowasa®) as well as oral form (250mg tabs)
    6. 2gm po qd 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
  5. 6-Mercaptopurine (6-MP, Purinethol®) [12]
    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
  6. Azathioprine (AZA, Imuran®) [12]
    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
  7. Methotrexate [12]
    1. 20-25mg/week given im in refractory CD
    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
  8. Cyclosporine (CsA) [12]
    1. Good response initially to IV form, usually within 48 hours
    2. Relapses common when drug is stopped
    3. Continues IV CsA 2-4mg/kg/day rapid onset of activity in glucocorticoid refractory UC
    4. Reduces need for surgical resection in fulminant UC
    5. Low doses of CsA do not prevent attacks; are generally ineffective
    6. Dose is usually 4mg/kg IV qd initially (adjust for renal function)
    7. Oral dose is typically 2-3X higher, 8-12mg/kg/day, and must be monitored closely
  9. Antibiotics
    1. Effective in "backwash" ileitis (UC), pouchitis, ileocolonic CD
    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
  10. Tumor Necrosis Factor alpha (TNFa) Blockade [13]
    1. Good activity in induction and maintenance in CD
    2. Excellent activity for healing fistulae in CD
    3. Modest to good activity in induction and maintenance in UC [14]
    4. Useful for induction in glucocorticoid-refractory UC exacerbations

H. Indications for Surgerynavigator

  1. Bleeding - more common in UC
  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

I. Novel Therapies [13]navigator

  1. Adhesion Molecule Blockade [15]
    1. Anti-alpha4beta7 integrin Abs [18]
    2. Anti-Madcam Abs
  2. Other Immunosuppressive Agents
    1. Rapamycin
    2. FK506 and other immunosuppressives
    3. CTLA-4Ig blocks T cell activation, approved for rheumatoid arthritis
    4. Anti-IL12 antibody (see below)
  3. 5-Lipoxygenase Inhibitor - Zileuton 600mg po qid has shown some efficacy in CD
  4. Fish Oil
    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
  5. Interferon alpha
    1. Some reduction in disease symptoms in early studies
    2. No effect on endoscopic appearance
  6. Sargramostim (GM-CSF) - maintains intestinal barrier integrity, stimulates leukocytes [16,17]

References navigator

  1. Baumgart DC and Carding SR. 2007. Lancet. 369(9573):1627 abstract
  2. Podolsky DK. 2002. NEJM. 347(6):417 abstract
  3. Bamias G, Nyce MR, De La Rue SA, Cominelli F. 2005. Ann Intern Med. 143(12):895 abstract
  4. Farrell RJ and Peppercorn MA. 2002. Lancet. 359(9303):331 abstract
  5. Kubes P and McCafferty DM. 2000. Am J Med. 109(2):150 abstract
  6. Khan MA. 2002. Ann Intern Med. 136(12):896 abstract
  7. Bernstein CN, Blanchard JF, Leslie W, et al. 2000. Ann Intern Med. 133(10):795 abstract
  8. Greenberger NJ. 2000. Ann Intern Med. 133(7):545 (Synopsis)
  9. Rutgeerts P and Vermeire S. 2000. Lancet. 356(9248):2117 abstract
  10. Schiller LR. 2000. Lancet. 355(9211):1198 abstract
  11. Mesalamine Study Group. 1996. Ann Intern Med. 124(2):204 abstract
  12. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 129(1):49 abstract
  13. Baumgart DC and Sandborn WJ. 2007. Lancet. 369(9573):1641 abstract
  14. Rutgeerts P, Sandborn WJ, Feagan BG, et al. 2005. NEJM. 353(23):2462 abstract
  15. Westermann J, Engelhardt B, Hoffmann JC. 2001. Ann Intern Med. 135(4):279 abstract
  16. Dieckgraefe BK and Korzenik JR. 2002. Lancet. 360(9344):1478 abstract
  17. Korzenik JR, Dieckgraefe BK, Valentine JF, et al. 2005. NEJM. 352(21):2193 abstract
  18. Feagan BG, Greenberg GR, Wild G, et al. 2005. NEJM. 352(24):2499 abstract
  19. Babyatsky MW, Keroack MD, Blake MA, et al. 2007. NEJM. 357(20):2068 (Case Record) abstract