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Inflammatory Bowel Disease (IBD): Crohn's Disease & Ulcerative Colitis

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1. DEFINITION & OVERVIEW

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2. EPIDEMIOLOGY

• Prevalence >0.3% in North America, Oceania, and most of Europe
• Highest recorded prevalences: UC - 505/100,000 (Norway); CD - 322/100,000 (Germany)
• USA: 2.39 million Americans diagnosed with IBD; UC up to 286/100,000; CD up to 319/100,000 (Canada)
• Incidence rising rapidly in newly industrialized countries (Brazil: +11.1%/year for CD, +14.9%/year for UC; Taiwan: +4-4.8%/year)
• Peak age: 2nd-4th decade; 78% of CD and 51% of UC cases peak at ages 20-29. A second rise occurs in the 7th-9th decades.
• Gender: Not strongly gender-specific (female:male ratio 0.34-1.65 for CD; 0.51-1.58 for UC)
• Pediatric IBD: ~20-25% of all IBD; ~5% are <10 years old
• Very-early-onset IBD (VEO-IBD) (<6 years): colon-predominant, therapy-resistant, strong family history; up to 10% have rare single-gene Mendelian mutations
• Higher prevalence in urban > rural, high > low socioeconomic class, and in White > Latinx/Black/Asian populations (though rising in all groups)

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3. PATHOLOGY

Ulcerative Colitis - Macroscopic Features

• Confined to the colon and rectum
• Disease begins in the rectum (always involved) and extends proximally in a continuous manner
• Proctitis: disease limited to rectum
• Left-sided colitis: up to splenic flexure
• Pancolitis: entire colon
• Mucosa is granular, erythematous, friable with loss of normal vascular pattern
• Pseudopolyps (inflammatory polyps) result from mucosal regeneration
• No skip lesions

Ulcerative Colitis - Microscopic Features

• Inflammation confined to mucosa and submucosa (superficial)
• Crypt abscesses: polymorphonuclear infiltration into crypts - pathognomonic
• Cryptitis and crypt architectural distortion
• Goblet cell depletion (mucin depletion)
• Chronic changes: crypt atrophy, branching, basal plasmacytosis
• No granulomas

Crohn's Disease - Macroscopic Features

• Can affect any part of the GI tract from mouth to anus
• Distribution:
  • Terminal ileum alone: ~30%
  • Colon alone: ~25%
  • Ileocolon: ~45%
  • Small bowel: any segment
• Transmural inflammation (all layers of bowel wall)
• Skip lesions (segmental involvement with normal intervening bowel)
• Cobblestone mucosa: submucosal edema + linear ulcers creating cobblestone appearance
• Creeping fat: mesenteric fat wrapping around the bowel wall
• Strictures from fibrosis - can cause obstruction
• Fistulas and sinuses - internal (enteroenteric, enterovesical, enterovaginal) and external (perianal, enterocutaneous)

Crohn's Disease - Microscopic Features

• Transmural chronic inflammation
• Non-caseating granulomas (in ~50% of cases) - pathognomonic but not always present
• Lymphoid aggregates throughout all layers
• Fissuring ulcers extending deep into submucosa/muscularis
• Submucosal fibrosis

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4. CLINICAL FEATURES

Ulcerative Colitis

• Mild: <4 stools/day, minimal bleeding, no systemic signs, ESR <20
• Moderate: 4-6 stools/day, moderate bleeding, mild systemic signs
• Severe: >6 bloody stools/day, fever >37.5°C, HR >90, Hb <10.5 g/dL, ESR >30
• Fulminant/toxic megacolon: >10 bloody stools/day, fever, HR >90, abdominal distension, colonic dilation >6 cm on X-ray

Crohn's Disease

• B1 - Inflammatory (non-stricturing, non-penetrating)
• B2 - Stricturing
• B3 - Penetrating (fistulizing)
• +p - Perianal modifier

• L1 - Ileal
• L2 - Colonic
• L3 - Ileocolonic
• L4 - Upper GI (modifier)

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5. EXTRAINTESTINAL MANIFESTATIONS

• Peripheral arthritis (large joints - knees, ankles, elbows)
• Erythema nodosum (tender, red nodules on shins)
• Episcleritis

• Axial arthropathy / ankylosing spondylitis (HLA-B27 associated)
• Pyoderma gangrenosum (painful, undermined ulcer)
• Uveitis / iritis (requires urgent ophthalmology)
• Primary sclerosing cholangitis (PSC) - more common in UC; associated with high risk of cholangiocarcinoma and colorectal cancer

• Oxalate kidney stones (fat malabsorption in CD → excess enteric oxalate absorption)
• Uric acid stones (from dehydration/chronic diarrhea)
• Gallstones (bile acid malabsorption from terminal ileal CD)
• Osteoporosis (from corticosteroids, malabsorption, chronic inflammation)
• Amyloidosis (rare, with chronic active disease)

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6. DIAGNOSIS & INVESTIGATIONS

Laboratory

• CBC: anemia (iron deficiency, B12/folate, anemia of chronic disease), leukocytosis, thrombocytosis
• CRP and ESR: elevated with active disease; useful for monitoring
• Fecal calprotectin: sensitive marker of intestinal inflammation; useful for differentiating IBD from IBS and for monitoring mucosal healing
• ANCA (pANCA): positive in ~60-70% UC; ASCA (anti-Saccharomyces): positive in ~60-70% CD - useful when diagnosis is uncertain but not definitive
• Stool cultures, C. difficile toxin: to rule out infection

Endoscopy

• Colonoscopy with ileoscopy: gold standard; allows biopsy, assessment of extent and severity
• UC: continuous mucosal inflammation from rectum; loss of vascular pattern, granularity, ulceration, pseudopolyps
• CD: aphthous ulcers (earliest lesion), linear ulcers, cobblestoning, strictures, skip lesions

Imaging

• CT enterography / MR enterography: preferred for small bowel CD assessment; evaluates transmural involvement, strictures, fistulas, abscesses
• MRI pelvis (Fig. 337-11): gold standard for perianal CD - evaluates fistula anatomy (intersphincteric/transsphincteric), abscesses
• CT/MRI abdomen: for complications (abscess, obstruction, perforation)
• Small bowel follow-through (SBFT): string sign of Kantor (narrow terminal ileum in CD stricture)
• Capsule endoscopy: for suspected small bowel CD when other tests negative (contraindicated if stricture suspected)

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7. DISEASES THAT MIMIC IBD (Table 337-6)

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8. MEDICAL TREATMENT

Step 1: Aminosalicylates (5-ASA)

• Sulfasalazine (5-ASA + sulfapyridine carrier): effective for mild-moderate UC; less effective for CD
• Mesalamine (oral, enema, suppository forms): first-line for mild-moderate UC
• Mechanism: inhibit prostaglandin synthesis, scavenge free radicals, inhibit NF-kB
• Useful for maintaining remission in UC
• Limited efficacy in CD (not recommended for small bowel CD)
• Side effects of sulfasalazine: nausea, headache, oligospermia (reversible), hemolytic anemia, hypersensitivity - due to sulfapyridine moiety

Step 2: Glucocorticoids

• Prednisone 40-60 mg/day for moderate-severe active disease
• Budesonide: high first-pass metabolism; effective for mild-moderate ileocecal CD with fewer systemic side effects
• IV hydrocortisone/methylprednisolone: for severe/hospitalized disease
• Not for maintenance - cannot use long-term (osteoporosis, adrenal suppression, cushingoid features)
• ~50% of patients who respond initially become steroid-dependent or steroid-refractory

Step 3: Immunomodulators

• Azathioprine (AZA) 2-2.5 mg/kg/day or 6-Mercaptopurine (6-MP) 1-1.5 mg/kg/day
• Prodrug → 6-TGN (active) via TPMT enzyme
• Check TPMT activity before starting (low/absent TPMT → risk of severe myelosuppression)
• Slow onset (3-6 months); used for steroid-sparing and maintenance
• Side effects: nausea, hepatitis, pancreatitis, bone marrow suppression, increased risk of lymphoma (especially with EBV), non-melanoma skin cancer
• Monitor CBC regularly

• 25 mg IM/SC weekly for induction; 15 mg/week for maintenance of CD
• Effective in CD; not proven effective in UC
• Supplement with folic acid
• Side effects: hepatotoxicity (cirrhosis with long-term use), pneumonitis, teratogenicity (Category X - stop 3 months before conception)

• 2-4 mg/kg/day IV; salvage therapy for acute severe UC (steroid-refractory)
• Rapid onset; bridge to thiopurine maintenance
• Side effects: nephrotoxicity, hypertension, neurotoxicity, opportunistic infections
• Tacrolimus: similar mechanism, 100x more potent, better oral absorption (useful in proximal CD); use decreasing with biologic expansion

Step 4: Biologic Therapies

• Combination therapy (infliximab + azathioprine) more effective than either alone in moderate-severe CD and UC
• Infliximab dosing: 5 mg/kg IV at 0, 2, 6 weeks (induction), then every 8 weeks (maintenance)
• Hospitalized acute severe UC: intensive (accelerated) infliximab dosing due to protein-losing enteropathy lowering drug levels
• ADA: 40 mg SC every other week; dose escalation to weekly improves remission rates
• Certolizumab pegol crosses placenta by passive diffusion only - minimal fetal exposure

• Vedolizumab (anti-α4β7 integrin): gut-selective; blocks lymphocyte trafficking to intestinal mucosa; approved for moderate-severe CD and UC; favorable safety profile (no systemic immunosuppression)

• Ustekinumab: anti-p40 subunit shared by IL-12 and IL-23; IV loading dose then SC maintenance; effective for moderate-severe CD and UC

• Tofacitinib: JAK1/3 inhibitor; oral; approved for moderate-severe UC
• Upadacitinib: JAK1 inhibitor; oral; approved for CD and UC
• Ozanimod: S1P receptor modulator; oral; for UC
• Contraindicated in pregnancy (tofacitinib, upadacitinib) - teratogenic; washout 4 weeks before conception

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9. SURGICAL MANAGEMENT

Ulcerative Colitis

• Surgery is curative in UC (unlike CD)
• Indications: medically refractory disease, fulminant colitis/toxic megacolon, perforation, severe hemorrhage, dysplasia/carcinoma, growth retardation in children
• Procedure of choice: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) ("J-pouch")
• Complications of IPAA: pouchitis (most common long-term complication; treated with metronidazole or ciprofloxacin), pouch failure (~10%)
• Three-stage surgery: (1) subtotal colectomy + ileostomy, (2) IPAA creation, (3) ileostomy reversal - used in acute/severe presentations

Crohn's Disease

• Surgery is not curative - disease recurs at anastomosis; lifetime risk of surgery ~80%
• Indications: obstruction (stricture), fistula/abscess, perforation, refractory disease, growth failure
• Strictureplasty: for short strictures - preserves bowel length
• Segmental resection: for longer strictures or fistulas
• Perianal disease: seton placement for high fistulas; anti-TNF therapy preferred over surgery
• Post-surgical recurrence prophylaxis: metronidazole post-op, then immunomodulator or anti-TNF

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10. CANCER SURVEILLANCE IN IBD

Ulcerative Colitis

• Colorectal cancer (CRC) risk: 1.5-2x higher than general population
• Risk increases with duration and extent of disease
• Historical risk: ~2% at 10 years, 8% at 20 years, 18% at 30 years - decreasing with better inflammation control
• Surveillance colonoscopy: annual or biennial after 8-10 years of extensive colitis (>1/3 of colon), or after 12-15 years of proctosigmoiditis
• Chromoendoscopy recommended by international guidelines for dysplasia surveillance (enhances mucosal surface visualization)
• PSC + UC: CRC risk dramatically higher; annual colonoscopy from time of PSC diagnosis

Crohn's Disease

• Similar CRC risk if colon involved
• Small bowel adenocarcinoma: rare but increased risk (especially in areas of long-standing CD)
• Lymphoma risk slightly increased (may be partly from thiopurine use)

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11. IBD IN SPECIAL SITUATIONS

Pregnancy

• Active IBD increases risk of premature birth, low birth weight, IUGR - disease control is paramount
• Safe in pregnancy: 5-ASA, corticosteroids (short-term), azathioprine/6-MP (generally considered safe), anti-TNF agents (no increased risk of stillbirth/miscarriage in large prospective studies)
• IgG1 biologics (infliximab, ADA, vedolizumab, ustekinumab) actively transported across placenta in late 2nd/3rd trimester; infant serum levels persist up to 1 year - avoid live vaccines until 12 months
• Certolizumab pegol: crosses placenta by passive diffusion only; minimal infant levels - preferred biologic if biologic needed in 3rd trimester
• Avoid: MTX (teratogenic, stop 3 months before conception), tofacitinib, upadacitinib (animal teratogenicity data; 4-week washout)
• Do not switch drugs during pregnancy unless medically required
• Surgery (colectomy/IPAA): only for emergencies; total colectomy + ileostomy carries 50% risk of spontaneous abortion; if surgery needed, best in 2nd trimester

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12. KEY DIFFERENCES: UC vs. CD SUMMARY TABLE

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