.

     

    Introduction

    • Symptoms to suspect IBD:
      • Nocturnal symptoms
      • W/D from social/work activities
      • Bloody diarrhea
      • Weight loss, abdo fullness/mass
      • Extra-intestinal manifestations of IBD
        • Organ Manifestation
          Eyes Episcleritis, Uveitis, Iritis
          Oral Aphthous ulcers (Crohn's)
          Joints

          Arthritis (symmetric, large + small joints)

          ankylosing spodilitis / sacroilitis (if HLA-B27 positive)

          Skin

          Erythema Nodosum (Painful nodules, on extensor surface of leg)

          Pyoderma Gangrenosum

          Liver Primary Sclerosing Cholangitis (Ulcerative Colitis)
      • Bloodwork:
        • Elevated CRP.
        • No role of antibody
        • Little interest in pANCA for screening (not definite)
        • Stool biomarkers: Calprotectin (abundant cytosolic protein in activated neutrophils)
          • If <50, IBD less likely.

     

    • Lesion Crohn's Disease Ulcerative Colitis
      Thickened Bowel Wall Typical Uncommon
      Luminal Narrowing Typical Uncommon
      "Skip" Lesions Common Absent
      Right Colon Predominance Typical Absent
      Fissures/Fistulas Common Absent
      Circumscribed Ulcers Common Absent
      Confluent Linear Ulcers Common Absent
      Pseudopolyps Absent Common
      MICROSCOPIC    
      Transmural Inflammation Typical Uncommon
      Submucosal Fibrosis Typical Absent
      Fissures Typical Rare
      Granulomas Common Absent
      Crypt Abscesses Uncommon Typical

     

     

    Investigations/Diagnosis

    • Endoscopic biopsy is gold standard
      • Often hard to distinguish CD from UC.
      • Also could be chronic infections (TB, Yersinia), NSAID-induced colitis, small bowel lymphoma.
      • Cultures, NSAID avoidance important!
    • CT enterography - recent prominent role.
      • Small bowel follow-through important to look at small bowel disease (cannot get with scope)
        • MRI used more b/c high radiation exposure in these patients.
    • Serologic Markers:
      • Helpful in indeterminate colitis (UC vs. Crohn's)
      • Not powerful enough to make diagnosis without scope.
      • Often mimics extent of disease.
    • For flares:
      • Stool studies (enteric pathogens, O&P, C. difficile) [C.diff important in IBD patients even without abx use]
      • Patients with colitis (UC/CD) that is refractory to steroids should undergo colonoscopy + bx  to evaluate for CMV infection (30% of patients undergoing colectomy have CMV).
      • If obstructive symptoms, severe pain, fever, (CT/ MRI) required to rule out complications.

     

    Crohn's Disease

    • Abbreviated as CD.

    Clinical Features

    • Abdominal pain and diarrhea (75%) and recurrent fever (50%).
    • Usually more indolent onset than UC.
    • Other symptoms depend on area of involement.
      • Small Bowel - Malabsorption, malnutrition
      • Colon - Colonic Bleeding, Diarrhea
      • Peri-anal Disease - Abscesses, Fistulas, Fissures - 25%
    • Complications
      •    
        Intestinal Obstruction Malabsorption, malnutrition
        Fistulas

        - Peri-anal Fistulas, enteral-enteral, entero-vesicular,

          entero-vaginal, entero-cutaneous

        - Painless --> to abscess formation.

        Perforation Uncommon
        Abscesses Pain, fevers
        Polyps Can have clusters
    •  
    • Defining Features:
      • Transmural Inflammatory Disease
        • Involves all layers of the bowel wall. (Thickened bowel).
      • Discontinuous Involvement
        • Inflammation areas are separated by areas of normal bowel.
      • Other Features:
        • Mesenteric lymph nodes are frequently enlarged
        • Intestinal lumen is narrowed by inflammation and fibrosis.
        • Nodular swelling, firbosis, and mucosal ulceration lead to "cobblestone" apperance. 
        • Since inflammation is transmural, fustulas can form, and can fistulize with blatter, bowel, uterus, vagina, skin.   Lesions at distal rectum and anus can form perianal fistulas. 
        • Noncaceating granulomas often form in submucosa.  
               (Presence of granulomas = strong predictor for CD, but half of CD doesn't have it.)
    • Involement:
      • Anywhere mouth to rectum.
      • Location  
        Ileum and Cecum 50%
        Only Small intestine 15%
        Only Colon 20%
        Mainly Anorectal Region 15%
        Upper GI <10%
    • Increases small bowel cancer 3-fold, and predisposes to colorectal cancer.
    • Complications:
      • Liver disease (Scerosing Cholangitis)
      • Cholelithiasis
      • Renal oxalate stones
      • Amyloidosis.
      • Eye (episcleritis, uveitis)
      • Medium-sized joints (Arthritis)
      • Skin (erythema nodosum)

    Treatment

    • Remission
    1. Symptomatic Therapy (loperamide, acetaminophen)
    2. Diet
      • Some role , need to be highly motivated.  Can help stunt growth, and puberty.
    3. 5-ASA (mesalamine)
      • 5-ASA usually no role... maybe if really really mild case, can work. 
      • More helpful in UC (only affects mucosa, not transmural inflammation)
      • Most Crohn's is terminal ilium
    4. Corticosteroids (budesonide, prednisone)
      • Only for remission (acute setting)
      • Usually steroid + immunomodulator, then taper steroid. 
    5. Thiopurines
      • Azathioprine, 6-MP
      • Methotrexate + 1mg folic acid
        • If cannot tolerate thiopurines (i.e. pancreatitis, etc..)
        • Only effective in CD
    6. Biologics
      • TNF-antagonists (infliximab, adalimumab)
        • Big push to start Anti-TNF therapy early (alone or with thiopurines) for flares [SONIC Study]
          • Classically usually started if steroids and immunomodulators aren't effective.
        • For flares and maintenance
      • Natalizumab (blocks lymphocyte recruitment to bowel)
        • If Anti-TNF therapy unsuccessful (or contraindicated).
        •  (not used often due to fear of progressive multifocal leukoencephalopathy due to JC virus infection).
        • Considered more aggressive than TNF-alpha
    7. Experimental/ Surgery
    8. Cipro+Flagyl  (Adjunctive Therapy)
      • Usually only if abscess or wound infection. (In past used very often)
      • Especially for colonic and peri-anal disease.
    9. Surgery (last resort)
      • For refractory disease to resect diseased segment of bowel.
      • Consider if very focal area of bowel involved.
      • Peri-anal disease -> surgical drainage, and seton placement (rubber band through fistula orifice and out through anus to prevent further abscesses and heal fistula).
        • Anti-TNF very effective for peri-anal disease
    • Remission Maintenance
      • Biologics (TNF-alpha inhibitors)
        • Excellent for remission maintenance
        • SONIC study --> clinical outcomes were better with mod-to-severe Crohn's treated aggressively with anti-TNF therapy (+/- azathioprine or 6MP) vs. azathiprine/6MP alone.
      • Aminosalicylates
      • Antibiotics (for fistulizing disease)
    • Treatments:
      • Treatment Notes
        Lifestyle/Diet
        • Smoking cessation
        • - Enteral diet
          • (aids in remission, but no change in natural hx)
        • If excessive small bowel resection/involvement
          • replace VitD, Ca, Mg, Zinc, Fe, B12
        • Loperamide (Immodium) > diphenoxylate (Lomotil) > codeine (cheap, works additive)
        • avoid during flare-ups of colitis (toxic megacolon risk)
        5-ASA
        • Most evidence for mild colonic disease (controversial)
        • Sulfasalazine (Salazopyrin): 5-ASA bound to sulfapyridine

                    (Intestinal bacterial hydrolyzes, releases 5-ASA -- efficady dose dependent)

        • Mesalamine (Pentasa): coated 5-ASA releases 5-ASA in ileum and colon
        Antibiotics
        • For perianal Crohn's (metronidazole, cipro), relapses when stopped.
        Corticosteroids
        • Prednisone: 40mg OD for acute exacerbations, IV methylpred for severe

                   (No evidence for maintaining remission, masks intra-abdo sepsis)

        Immunosuppression
        • Most common:
          • 6-mercaptopurine
          • Azathioprine (Imuran)
          • Methotrexate (less often)
        • For maintenance (steroid sparing)
        • Not for active flare
        • Response in ~3mo
        • Helps heal fistula (only simple ones), decrease disease activity.
        Biologics
        • Infliximab IV (Remicade)
        • Adalimumab SC (Humira)
        • Effective in fistulae and refractory CD.
        • STUDY: first line infliximab+azathioprine more effective for remission than either alone.
        Surgery
        • For fistulae, obstruction, abscess, performation, bleeding, refactory.
          • If <50% or <200cm of intestine --> short gut syndrome.
        • Complications:
          • <100cm resected --> watery diarrhea (impared bile salt absorption
            • Tx: cholestyramine, andi-diarrheals (loperamide)
          • >100cm resected --> steatorrhea (cannot absorb, bile salt deficiency)
            • Tx: fat restriction, medium chain TGs

    Evidence Base

    • Starting with immunosuppressives + immunomodulators ("bottom-up approach") is more popular
      • Lancet 2008; 371;660-667
    • Azathioprine + infliximab --> highest remission rate (NEJM 2010;362; 1383-1395)

    Ulcerative Colitis

    • Defining Features:
      • Diffuse Disease
        • Extends from most distal part of rectum for variable distance proximally.
        • Sparing or rectum or R colon involvement is RARE  (Query Crohn's)
      • Generally limited to colon and rectum
        • Stomach, small bowel or esophagus is RARE
      • Essentially Mucosal Disease
        • Involvement of deeper layers is very uncommon. (unless fulminant or toxic-megacolon).
    • Presentation:
      • Often 1 week of diarrhea
      • NOTE: Abdominal pain is RARE (think toxic megacolon, or other complications)
        • Tolic megacolon: diarrhea, tachycardic, hypotensive, febrile, peritoneal finding son exam
        • Abdo Xray STAT, look for colon dilation >6cm
    • Extrainstestinal Manifestations
      • Manifestation Rate
        Arthritis 25%
        Uveitis and Skin 10%
        Erythema Nodosum  
        Pyoderma Gangrenosum  
        Liver D. (Primary Sclerosing Cholangitis) 4%
        Thromboembolic phenomena (DVT) 6%

         
    • Colorectal cancer:
      • Risk higher than general population.
    • Treatment
      • Remission Induction (obtain in 3 days as inpatient, and 1 week in o/p)
        • 5-ASA - Aminosalicylates (oral, rectal - works too!)
          • Respond very well to 5-ASA
          • 2.4g is minimal.
          • For proctitis or L-colitis --> 5-ASA suppositories/enemas (or hydrocortisone enemas).
          • Dose that takes into remission is the dose that maintains remission
        • Corticosteroids (IV, oral)
          • If requires multiple steroid therapy --> Use thiopurines (Aza, 6-MP)
        • 6MP / Azathioprine (Thiopurines)
          • Note: Methotrexate not effective in UC
        • Cyclosporine - not used as much anymore. (death rate increases)
        • Anti-TNF --> if fails thiopurines
        • (NOTE: In hospital can use infliximab or cyclosporine for steroid-refractory patients)
          • After that continue infliximab for maintenance, and bridge cyclosporine to thopurines maintenance.
        • Surgery:
          • Colectomy with end-ileostomy or ileal pouch-anal anastomosis (J-pouch) considered last resort.
          • (20% of pts will need colectomy in lifetime).
      • Remission
        • Aminosalicylates (oral, remission) --> Keep dose that established remission
        • 6MP/Azathioprine  --> only if steroid dependent (steroid sparing).
        • Anti-TNF
      • Monitor:
        • CRP >45 = bad
        • BMs/day (>4/day is higher risk).

     

    Other Long-Term Therapy

    • Osteopenia/Osteoporosis monitoring.
    • Calcium, Vitamin D supplementation + baseline DEXA scan.
    • Pneumococcal and yearly influenza vaccines (ACIP guidelines).
      • Avoid live vaccines (MMR, varicella, intranasal influenza) if immunosuppressed.
    • Colorectal Cancer Screening (UC [except if only proctitis], Crohn's with 1/3 of colon involved) high risk >8yrs of disease.
      • Colonoscopy q1-2 yrs. (look for flat dysplasia - discuss prophylactic colectomy).
    • Monitor malabsorption syndromes
    • STOP smoking
    • STOP NSAID use
    • IF HOSPITALIZED --> VTE prophylaxis is important (high risk).

    Extraintestinal Manifestations

    • 15% had extraintestinal symptoms:
      • Eyes: episcleritis, iritis, uveitis
      • Rheumatologic: enteropathic arthritis (symmetric, large and small joints).
        • Sacroiliitis and Ankylosing Spondylitis  (HLA-B27 positive)
      • Dermatologic:
        • Erythema Nodosum (painful nodules often on extensor surface of leg)
        • Pyoderma Gangrenosum (ulcers on skin mimicing cellulitis)
      • Biliary:
        • Primary Sclerosing Cholangitis (UC patients)

    Notes on Therapies

     

    Medical Therapy for Inflammatory Bowel Disease

     

    Medication

    Indication

    Side Effects/Adverse Events

    5-ASA

    (sulfasalazine, olsalazine, balsalazide, mesalamine: oral, rectal)

     

    - In special matrix - hydrates and sticks to colon (DOES NOT cause GI bleeding

    - 2.4g is minimal

    - Dose that takes into remission maintains remission

    Acrylate-coated mesalamine

    UC: induction/maintenance

    CD (mild) involving the colon: induction/maintenance

     

    For proctitis or L-colitis --> 5-ASA suppositories/enemas

    Interstitial nephritis (rare)

    Diarrhea (olsalazine)

    Antibiotics (metronidazole, ciprofloxacin)

    CD: perianal and colonic disease

    Metronidazole: peripheral
    neuropathy, metallic taste,
    antabuse effect

    Ciprofloxacin: arthropathy,
    tendon injury, sun sensitivity

    Corticosteroids (oral, intravenous, rectal)

    UC/CD: induction, not maintenance

    Acne, moon facies, truncal obesity,
    osteoporosis, osteonecrosis,
    diabetes mellitus, hypertension,
    cataracts, infection

    Budesonide

    CD (ileal/right colon): induction

    Minimal corticosteroid effects

    Methotrexate

    CD: induction/maintenance

    Nausea, fatigue, hepatotoxicity,
    pneumonitis

    6-MP, azathioprine

    - Azathioprine is converted to 6-PM in

    RBC's, but also releases lots of

    emetogenic substances. (feel nauseous)

    If lots of photo-damage - look at skin.

    UC/CD: corticosteroid withdrawal, maintenance

    - Monitor blood counts often, and periodically look at liver enzymes.

    Pancreatitis, fever, infection,
    leukopenia, hepatotoxicity, lymphoma

    Anti-TNF-α (adalimumab, certolizumab pegol, infliximab)

    UC/CD: induction/maintenance

    Infusion/injection-site reaction,
    tuberculosis reactivation, demyelination, infection, heart failure, lymphoma

    Cyclosporine

     

    - Extremely Toxic, rarely used.

    UC: corticosteroid refractory

    Nephrotoxicity 24%

    Infection 20%

    Sezure 4%

    Death 1%

     

    Hypertension, nephro- and
    neurotoxicity

    Natalizumab

    CD: induction/maintenance for disease refractory to anti-TNF agents

    Progressive multifocal
    leukoencephalopathy

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