Inflammatory Bowel Disease (IBD): A Comprehensive Overview

1. Definition and Overview

2. Types of IBD

A. Crohn's Disease (CD)

• Can affect any part of the GI tract from mouth to anus
• Most commonly involves the terminal ileum and ileocecal region (~70%)
  • Primary ileal: 30%
  • Ileocolonic: 40%
  • Isolated colonic: 25%
• Characterized by transmural inflammation with "skip lesions" (areas of normal bowel between affected segments)
• Female-to-male ratio: 1.2:1

B. Ulcerative Colitis (UC)

• Confined strictly to the colon and rectum
• Starts at the rectum and extends proximally in a continuous, uninterrupted pattern
• Inflammation is mucosal only (not transmural)
• Distribution at diagnosis:
  • Proctosigmoiditis: 44-49%
  • Left-sided colitis: 36-41%
  • Pancolitis: 14-37%
• Sex ratio: 1:1

Comparison Table (Goldman-Cecil Medicine)

3. Gross & Endoscopic Features

Crohn's Disease - Gross Features

• Aphthous ulcers are the earliest mucosal change - small, superficial mucosal erosions
• As disease progresses, ulcers deepen and become round, linear, or serpiginous
• Cobblestone appearance: intersecting longitudinal and transverse deep ulcers with intervening islands of edematous normal mucosa ("stones")
• Skip lesions: diseased segments alternating with normal bowel
• Mural thickening with "creeping fat" (mesenteric fat wrapping around bowel wall)
• Strictures (fibrotic narrowing from transmural healing)
• Fistulae (enteroenteric, enterocutaneous, rectovaginal, enterovesicular)
• Noncaseating granulomas on histology (pathognomonic when present, but found in only ~30% of biopsies)

Crohn's disease: cobblestoning pattern on colonoscopy - Goldman-Cecil Medicine, Fig. 127-1

Ulcerative Colitis - Gross Features

• Early disease: diffuse mucosal erythema, loss of normal vascular pattern, granular/edematous mucosa
• Moderate disease: mucosal friability, contact bleeding (bleeds on touch), superficial ulceration
• Severe disease: confluent ulceration, spontaneous bleeding, mucosal sloughing
• Pseudopolyps: islands of regenerating epithelium surrounded by ulceration in long-standing disease - marker of more severe disease
• Inflammation is continuous from the rectum, going proximally
• "Backwash ileitis" may occur as a spillover from the cecum (not true ileal involvement)
• In chronic disease, the colon may shorten and narrow ("lead-pipe colon") with loss of haustrations

Ulcerative colitis: diffuse erythema and granularity on colonoscopy - Goldman-Cecil Medicine, Fig. 127-3

Histopathology of Ulcerative Colitis

UC histology: crypt distortion (irregular, branched crypts) with dense lymphocytic infiltrate in the lamina propria - Goldman-Cecil Medicine, Fig. 127-2

4. Clinical Manifestations

Crohn's Disease

• Right lower quadrant pain (most common - reflects terminal ileal disease)
• Diarrhea (may be non-bloody if small bowel disease; bloody if colonic)
• Hematochezia in colonic disease
• Obstructive symptoms: colicky pain, distension, nausea/vomiting (strictures)
• Malabsorption/steatorrhea: fat-soluble vitamin deficiencies (A, D, E, K), vitamin B12 deficiency from terminal ileal disease
• Dysphagia/odynophagia: upper GI Crohn (rare, <2%)
• Perianal disease (20-30%): fistulas, abscesses, fissures, skin tags, rectal stricture

• Enteroenteric (internal)
• Rectovaginal - fluid/gas per vagina
• Enterovesicular - pneumaturia, recurrent UTIs
• Enterocutaneous - external drainage
• Perianal

Ulcerative Colitis

• Bloody diarrhea (cardinal symptom) - blood mixed with stool
• Tenesmus (painful urge to defecate with feeling of incomplete evacuation)
• Mucus in stool (excessive)
• Urgency to defecate
• Abdominal cramping/pain
• Proctitis/proctosigmoiditis may paradoxically present with constipation (hard stool proximal, inflamed distal segment)
• Weight loss, fever, fatigue in extensive or severe disease
• Nausea/vomiting from pain
• Peripheral edema from hypoalbuminemia in severe disease

Extraintestinal Manifestations (Both)

5. Diagnosis

• Colonoscopy with biopsy - gold standard; must reach terminal ileum
• CT/MRI enterography - preferred for small bowel assessment; detects strictures, fistulae, abscesses
• Capsule endoscopy - used when above tests non-diagnostic (contraindicated in strictures)
• Histopathology: noncaseating granulomas (CD), crypt distortion + continuous mucosal inflammation (UC)
• Lab markers: CRP, ESR (activity markers), fecal calprotectin (elevated in active disease), CBC (anemia, leukocytosis), albumin
• Serologic markers:
  • ASCA (IgA + IgG) positive: 40-70% of CD, highly specific when combined (89-100%)
  • pANCA positive: 55% of UC, 20% of CD

6. Treatment and Management

Step 1 - Aminosalicylates (5-ASA)

• Mechanism: Topical anti-inflammatory action on the colonic mucosa; inhibition of NF-kB, prostaglandin synthesis, and free radical scavenging
• Use: Mild-to-moderate UC (first-line); also used for maintenance of remission in UC
• Dosing: Mesalamine 2.4-4.8 g/day orally; rectal forms (suppositories, enemas) for distal disease
• Sulfasalazine requires colonic bacteria to cleave the 5-ASA from its sulfapyridine carrier
• Limited role in CD: 5-ASA has minimal proven benefit in Crohn's disease
• Side effects of sulfasalazine: dose-dependent nausea, headache, oligospermia (reversible); hypersensitivity reactions (sulfa allergy)

Step 2 - Corticosteroids

• Mechanism: Broad immunosuppression - inhibit NF-kB, reduce cytokine production, suppress neutrophil/macrophage function
• Use: Induction of remission in moderate-to-severe UC or CD; NOT used for maintenance (long-term toxicity)
• Prednisone/Prednisolone: 40-60 mg/day orally, tapered once response achieved
• IV Methylprednisolone: 40-60 mg/day for hospitalized severe disease
• Budesonide: first-pass hepatic metabolism limits systemic toxicity; used for ileal/right-colon CD; 9 mg/day orally
• Side effects: osteoporosis, avascular necrosis of hip, Cushing's syndrome, hyperglycemia, hypertension, infection risk, adrenal suppression

Step 3 - Immunomodulators (Thiopurines & Methotrexate)

• Mechanism of thiopurines: Converted to 6-thioguanine nucleotides that incorporate into DNA and inhibit purine synthesis, suppressing lymphocyte proliferation
• Mechanism of methotrexate: Inhibits dihydrofolate reductase; anti-inflammatory effects at low doses
• Use: Steroid-sparing agents; maintenance of remission; often combined with anti-TNF biologics to reduce immunogenicity
• AZA: 2-2.5 mg/kg/day; 6-MP: 1-1.5 mg/kg/day; onset of action 3-6 months
• Thiopurine methyltransferase (TPMT) testing required before initiation (gene variant = myelosuppression risk)
• Side effects: myelosuppression (most serious), hepatotoxicity, pancreatitis (6-MP/AZA), increased lymphoma risk (EBV-related), nausea
• Methotrexate: 15-25 mg IM/SC weekly for CD; requires folate supplementation; teratogenic

Step 4 - Biologic Therapies

Anti-TNF-alpha Agents (First-line Biologics)

• Mechanism: Bind and neutralize TNF-alpha, a central pro-inflammatory cytokine; some induce apoptosis of activated T cells
• Infliximab (chimeric IgG1): IV infusion 5 mg/kg at weeks 0, 2, 6, then every 8 weeks maintenance; effective in CD (including fistulizing) and UC
• Adalimumab (fully human): SC injection 160 mg, then 80 mg at week 2, then 40 mg every 2 weeks
• Golimumab: SC injection; approved for moderate-to-severe UC
• Side effects: reactivation of latent TB (screen before starting), hepatitis B reactivation, serious infections (bacterial, fungal), demyelinating disease, lymphoma, worsening CHF
• Combination therapy (anti-TNF + thiopurine) shown superior to monotherapy (SONIC trial data) in CD

Anti-Integrin Agents

• Mechanism: Humanized monoclonal antibody that binds the alpha-4-beta-7 integrin on lymphocytes, preventing their binding to MAdCAM-1 on intestinal vascular endothelium - gut-selective (does not affect CNS trafficking, so lower PML risk than natalizumab)
• Dosing: 300 mg IV at weeks 0, 2, 6, then every 8 weeks maintenance
• Use: Moderate-to-severe CD and UC; approved for both
• Side effects: headache, hypersensitivity, arthralgia, nasopharyngitis, fatigue
• Note: Anti-TNF drugs may enhance adverse effects of vedolizumab

• Chimeric anti-alpha-4 integrin; approved for moderate-severe CD; associated with progressive multifocal leukoencephalopathy (PML) risk due to JC virus reactivation - requires JC virus antibody testing before use

Anti-IL-12/23 Agent

• Mechanism: Fully humanized IgG1 monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23, blocking signaling through IL-12Rβ1 and IL-23R on T cells and NK cells
• Dosing: Initial single IV dose (weight-based: 260-520 mg), then 90 mg SC every 8 weeks for maintenance
• Use: Moderate-to-severe CD (approved); also approved for UC
• Side effects: Upper respiratory infections, headache, arthralgia, nasopharyngitis; long half-life (up to 120 days) - must discontinue 15 weeks before live vaccines

JAK Inhibitors (Small Molecules)

• Mechanism: Block Janus kinase (JAK) signaling, which is used by multiple cytokine receptors (IL-2, IL-6, IFN-gamma, etc.), broadly suppressing inflammatory cytokine pathways
• Use: Moderate-to-severe UC; oral agents offering an alternative to biologics
• Side effects: Serious infections (herpes zoster, VZV reactivation), lipid elevations, potential cardiovascular/thrombotic events, MACE risk (class warning in older patients)

Step 5 - Surgical Management

• Total proctocolectomy with ileal pouch-anal anastomosis (IPAA / J-pouch) is curative - UC is the only IBD that can be surgically cured
• Indications: Medically refractory disease, toxic megacolon, perforation, high-grade dysplasia/CRC, severe hemorrhage
• Complication: "Pouchitis" (inflammation of the J-pouch) in 50% of patients over time; treated with metronidazole or ciprofloxacin

• Surgery is not curative; reserved for complications
• Indications: Bowel obstruction from stricture, fistulae not responsive to medical therapy, abscesses, perforation, failure of medical management
• Strictureplasty: bowel-conserving procedure for fibrotic strictures
• High rate of post-surgical recurrence (endoscopic recurrence in >70% at 1 year without prophylaxis); anti-TNF maintenance recommended post-operatively

Additional Management Principles

• Nutritional support: Elemental/polymeric enteral nutrition can induce remission in CD (especially pediatric); TPN for severe disease with gut failure
• Antibiotics: Metronidazole and/or ciprofloxacin for perianal CD, intra-abdominal abscesses; no role in luminal UC/CD activity
• Cancer surveillance: Colonoscopy every 1-2 years after 8-10 years of pancolitis (UC); risk increases ~10% per decade
• Thromboprophylaxis: IBD patients have significantly elevated DVT/PE risk, especially during hospitalizations for active disease
• Bone health: DEXA scan; calcium + vitamin D supplementation; bisphosphonates for steroid-induced osteoporosis
• Vaccinations: Live vaccines contraindicated in patients on immunosuppression; pneumococcal, influenza, HPV, hepatitis B vaccines recommended

7. Summary - Treatment Ladder

MILD DISEASE
    ↓
5-ASA agents (UC) / Budesonide (ileal CD)

MODERATE DISEASE
    ↓
Corticosteroids (induction only) + Immunomodulators (maintenance)

MODERATE-SEVERE / STEROID-DEPENDENT
    ↓
Anti-TNF biologics ± Immunomodulator (combination)
    or
Vedolizumab (gut-selective)
    or
Ustekinumab (anti-IL-12/23)
    or
JAK inhibitors (tofacitinib/upadacitinib - UC)

REFRACTORY / COMPLICATIONS
    ↓
Surgery (curative in UC; palliative in CD)

• Goldman-Cecil Medicine, 26th ed. - Ch. 127, Clinical Characteristics, Symptoms, Extraintestinal Manifestations, Diagnosis & Treatment
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. - Ch. on Monoclonal Antibodies: Vedolizumab, Ustekinumab, Anti-TNF mechanisms
• Sleisenger and Fordtran's GI and Liver Disease - IBD and CRC surveillance