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CROHN'S DISEASE (CD)

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It can involve anywhere from mouth to anus can be affected:  
Isolated Ileal disease 30%;  Ileocolic disease 50%;  Isolated colonic disease 15%

Pathology     

  1. Full thickness bowel wall inflammation in "skip lesion" areas
  2. Inflammation is usually focal, but can be extensive
  3. 25-40% with true non-necrotizing granulomas on biopsy
  4. ANCA  (Anti-neutrophil cytoplasmic antibodies) may be present; these patients often have vasculitis

SX:  

  1. Crampy abdominal pain - spasms, smooth muscle contraction, reflex contractions painful
  2. Diarrhea - hyperperistalsis
  3. Bacterial overgrowth in stagnant area (proximal to obstruction)
  4. Bacteria deconjugate bile; deconjugated bile is a potent secretogogue in colon
  5. Weight Loss: decreased eating due to increased pain on eating (eat-pain cycle)
  6. Chronic, indolent disease
  7. Malabsorption common (especially with ileal disease and/or bowel resection)
  8. Relapses are common, with 25-80% of patients relapsing within 12 months of remission

DX:

  1. Contrast Studies: Small Bowel Series, Barium Enema
  2. Upper or Lower Endoscopy if lesions accessible; Biopsy is usually required

Complications of Crohn's Disease  

  1. Strictures
    1. May occur at any part of GI tract
    2. Should be considered in evaluation of esophageal stricture
  2. Perforation
  3. Penetration
  4. Fistula Formation: Enterovesicular, Enterocolic, Enterovaginal, Enterocutaneous
  5. Arthritis, Spondylitis (especially in HLA-B27 persons)
  6. Toxic Megacolon in 1-2% of patients
  7. Myelodysplastic syndromes
    1. Possible association in minority of patients; usually in elderly
    2. Chromosome 20 abnormalities implicated

RX: Medical                

  1. Evaluation
    1. A thorough evaluation of flares must be carried out to rule out underlying complications
    2. Gastroenteric infections, fistula formation, microperforations can all occur
    3. Glucocorticoids are often used in severe exacerbations, but will worsen fistulae
    4. Severe flares should usually be treated with bowel rest as described above
  2. Antibiotics
    1. Use metronidazole 250mg po bid-qid; may increase to 500mg qid as needed
    2. Ciprofloxacin 500-750mg po bid may be effective in pouchitis and ileitis
  3. Sulfasalazine
    1. Most efficacious for large bowel involvement
    2. Begin at 500mg po bid - tid then increase to maximum 1.5gm tid or 1gm qid
  4. Glucocorticoids      
    1. Mainstay of treatment for Crohn's Disease
    2. Rapid onset of action and usually effective for flares
    3. Topical hydrocortisone or other agents (enemas) in distal proctocolitis (to ~40cm)
    4. Effective for flared disease usually in IV form with bowel rest (~1mg/kg)
    5. Chronic use in aspirin-derivative resistant cases, adjunctive therapy
    6. All patients develop side effects with chronic use
    7. Budesonide (~9mg/d) may have less absorption, may be better for chronic use
    8. Ileal release budesonide more effective for inducing remissions than mesalamine
  5. Olsalazine (Dipentum®)
    1. Appears to have mild steroid sparing ability in moderate disease
    2. Use in patients with intolerance to sulfasalazine for chronic suppression
  6. Mesalamine (mesalazine; Rowasa®, Pentasa®)
    1. Pentasa® is a slow release form recommended for ileitis, ileocolitis
    2. Appears effective in exacerbations of Crohn's Disease as well as in UC
    3. Available as enemas (Rowasa®) as well as oral form (250mg tabs)
    4. 500mg qid lowers rate of relapses in patients with remissions <3 mo. (but not >3 mo)
    5. Rowasa® suppositories recommended for proctitis (<12cm)
    6. Rowasa® enemas recommended for proctosigmoiditis (to ~40cm)
  7. 6-Mercaptopurine (6-MP)
    1. Effective in prevention of relapses
    2. Requires several months to begin working, however
    3. Dose is typically 1.5mg/kg and can be used similar to AZA
    4. About 55% of patients with Crohn's flare respond to 6-MP or AZA
    5. 6-MP and AZA maintains remissions in 40-50% of patients with Crohn's
  8. Azathioprine (AZA, Imuran®)
    1. Begin 50mg/day; may increase to maximal 2.5mg/kg/day
    2. Side Effects: Pancreatitis (~5%), Bone marrow suppression (~2%)
    3. Allows reduction in glucocorticoid dose required for suppression of disease
    4. Useful in steroid refractory exacerbations and to preserve remissions
    5. Clearly reduces relapse rate for up to 4 years of therapy, then effect wanes
    6. AZA is metabolized to 6-MP
  9. Methotrexate
    1. 20-25mg/week given im in refractory disease
    2. Clear benefit in patients on >20mg/day prednisone
    3. Fairly well tolerated; side effects were not much greater than placebo
    4. Allowing reduction in steroid doses and control of disease with reduced symptoms
    5. Recommended now in nearly all patients requiring higher doses of prednisone
  10. Cyclosporine (CsA, Sandimmune®)
    1. Good responses are seen when drug is initiated
    2. Relapses very common when drug is stopped
    3. This agent shows most rapid onset of activity in steroid refractory disease
    4. May reduce need for surgical resection and permits fistula closure
    5. However, low doses do not prevent flares and are generally ineffective or harmful
    6. Low dose CsA has no role in the treatment of Crohn's Disease
    7. Higher doses (eg. >3mg/kg/d) are likely required in patients who fail other therapies
  11. Tumor Necrosis Factor Alpha Blockers
    Infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor-a (TNF-a), was the first biologic agent approved by the Food and Drug Administration for the treatment of Crohn's disease. A double-blind dose-ranging study found that a single 5 mg/kg infusion of infliximab induced clinical improvement in 80% of patients with Crohn's disease refractory to steroids, aminosalicylates, antibiotics, and azacitidine (AZA) and 6-mercapto-purine (6-MP). Nearly half of the Crohn's disease patients achieved remission lasting approximately 8 to 12 weeks.  Reinfusion of infliximab at 8-week intervals sustained the response for up to 44 weeks. Infliximab administered in three doses of 5 mg/kg at 0, 2, and 6 weeks induced clinical response in approximately 50% of refractory Crohn's disease fistulas for approximately 12 weeks. Infliximab has generally been safe, with common side effects similar to those of placebo.   
    1. One to several doses has 1-3 month therapeutic benefits in ~70% of patients
    2. Anti-TNFa Antibodies are typically used
    3. Effective in some patients with resistant disease and/or fistulae
    4. Generally well tolerated

Remissions of Cronh's Disease (CD) 

  1. CD is notable for very frequent relapses
    1. 6-mercaptopurine and azathioprine have been shown to reduce relapses
    2. Mean time to response to 6-MP was 3.1 months
    3. Mesalamine [9] and Fish Oil [10] also appear to reduce relapse rates 20-40%
    4. In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate 15 mg IM weekly  for 40 weeks maintains remission. (N Engl J Med June 1, 2000;342:1627-32.-  Brian G. Feagan )
  2. Surgery often required for resistant disease
    1. Cyclosporine may reduce need for surgery and can heal fistulas
    2. Glucocorticoids should be combined with other agents before surgery is undertaken
    3. However, fistula formation, bacteremia / sepsis, etc. are indications for resection
  3. Complications of surgery
    1. Short bowel syndrome - diarrhea      
    2. Malabsorption       
    3. Vitamin B12 deficiency       

Ref:
Outlines in Clinical Medicine  on Physicians' Online 1999  
Scientific American Medicine  - October 1999

         

2009