Inflammatory Bowel Disease (IBD)

1. Epidemiology

• IBD peaks between ages 15-30 (CD) and 20-40 (UC), with a smaller second peak in the 6th-7th decade for both.
• Sex distribution: CD affects females slightly more (F:M = 1.2:1); UC affects both sexes equally.
• Incidence is highest in Western, industrialized nations; it is increasing in newly industrialized countries, implicating environmental factors.
• Smoking is paradoxically protective against UC but worsens CD.

2. Pathogenesis

Genetics

• NOD2 (chromosome 16) was the first gene associated with CD - three common polymorphisms (Arg702Trp, Gly908Arg, Leu1007fsX1008). NOD2 senses muramyl dipeptide (MDP) from bacterial cell walls and activates NF-κB signaling.
• ATG16L1 (autophagy-related gene) is another key variant affecting the innate immune response in CD.
• Other relevant SNPs: CARD9, IL18RAP, SLC11A1.
• Over 200 IBD susceptibility loci have been identified by GWAS.

Immune Mechanisms

• CD is characterized by a defective innate immune response to luminal antigens, resulting in exaggerated adaptive Th1/Th17 responses. Key cytokines: TNF-α, IL-12, IL-23, IFN-γ, IL-17.
• UC involves predominantly a Th2-like response with elevated IL-4, IL-5, IL-13.
• Regulatory T cells (Tregs) are impaired in IBD, removing normal brakes on inflammation.

Microbiome

• Dysbiosis (imbalance of gut microbiota) is central; IBD patients show reduced Firmicutes and Bacteroidetes and increased Proteobacteria.
• Polymorphisms in NOD2 reduce clearance of intracellular bacteria, promoting dysregulated inflammatory responses.
• Antibiotics can modify disease course, supporting a microbial role in pathogenesis.

3. Differentiating CD vs. UC

4. Clinical Features

Crohn Disease

• Terminal ileum is affected in ~70% of cases; pure ileal disease in 30%, ileocolonic in 40%.
• Symptoms: right lower quadrant pain, diarrhea, hematochezia, fatigue, fever, weight loss.
• Obstructive symptoms (distension, nausea) occur with stricturing disease.
• Upper GI involvement (esophageal, gastroduodenal) in <5%; associated with dysphagia, chest pain.
• Fistulae occur in 20-40%: enterocutaneous, rectovaginal, enterovesicular, perianal.
• Perianal disease (fissures, abscesses, skin tags, fistulae) in up to 30%.

Ulcerative Colitis

• Disease starts in the rectum and extends proximally in a continuous pattern.
• At diagnosis: pancolitis in 14-37%, disease beyond the rectum in 36-41%, proctosigmoiditis in 44-49%.
• Symptoms: hematochezia, diarrhea, tenesmus, mucus in stool, urgency, abdominal pain.
• With severe disease: weight loss, fever, hypoalbuminemia, anemia.
• "Backwash ileitis" = spillover inflammation into terminal ileum, not true ileal involvement.

5. Extraintestinal Manifestations

6. Diagnosis

Endoscopy

• Colonoscopy (including terminal ileum) is the initial test for lower GI symptoms.
• UC: diffuse mucosal erythema, granular mucosa, loss of vascular pattern, friability, continuous ulceration starting from rectum. Pseudopolyps in chronic disease.
• CD: cobblestone mucosa, discrete ulcers, skip lesions, aphthous ulcers.
• Histology: crypt distortion (both); non-caseating granulomas (CD only).

Radiology

• CT enterography / MRI enterography: gold standard for small bowel CD; identifies strictures, fistulae, abscesses.
• Capsule endoscopy: useful when other tests are non-diagnostic (contraindicated with known strictures; use patency capsule first).
• MRI is preferred over CT for pelvic/perianal disease (less radiation).

Laboratory

• CBC: anemia (iron, B12, folate deficiency), leukocytosis in active/complicated disease.
• ESR, CRP: elevated in active disease (non-specific).
• Fecal calprotectin: elevated in active disease, useful for monitoring.
• Hypoalbuminemia: marker of malnutrition and severe disease.
• Vitamin B12 deficiency: with >100 cm ileal resection or ileal disease.

Serologic Markers

• ASCA (anti-Saccharomyces cerevisiae antibodies): positive in 40-70% of CD, <15% of UC. High ASCA IgA + IgG specificity for CD = 89-100%.
• pANCA: positive in 55% of UC, 20% of CD (colon-predominant).
• ASCA+/pANCA- = high sensitivity for CD; pANCA+/ASCA- = more specific for UC.

7. Treatment

Step 1: 5-Aminosalicylates (5-ASAs)

• Mesalamine (5-ASA): mainstay for mild-moderate UC (induction and maintenance). Topical (suppository/enema) for proctitis/distal disease.
• Sulfasalazine: effective for ileocolonic/colonic CD (response rates 45-55% in mild-moderate disease) but not proven to heal mucosa.
• 5-ASAs are NOT effective for small bowel CD alone.

Step 2: Corticosteroids

• Prednisone (40-60 mg/day): effective for moderate-severe IBD flares; not appropriate for long-term maintenance.
• Budesonide (9 mg/day enteric-coated): preferred for distal ileal/right colonic CD; ~70% response rate at 8 weeks; superior to mesalamine for distal ileal/right colonic disease.

Step 3: Immunomodulators

• Azathioprine (2-3 mg/kg/day) or 6-mercaptopurine (1.5 mg/kg/day): maintenance of remission; slow onset (months).
• Methotrexate (25 mg IM/SC weekly for 16 weeks for active CD; 15-25 mg weekly for maintenance): used for CD, and as combination therapy with biologics to reduce immunogenicity.
• Monitor: CBC, LFTs regularly. Side effects: myelosuppression, hepatotoxicity, pancreatitis, lymphoma risk.

Step 4: Biologics

Anti-TNF-α Agents

• Infliximab (IgG1 chimeric mAb): IV infusion - 5 mg/kg at 0, 2, 6 weeks, then every 8 weeks. Used in moderate-severe CD and UC.
• Adalimumab (fully humanized mAb): SC injection; for moderate-severe CD and UC.
• Certolizumab pegol: pegylated anti-TNF; CD only (US).
• Golimumab: SC injection; UC only.

Anti-integrins (gut-selective)

• Vedolizumab: humanized mAb against α4β7 integrin; blocks lymphocyte recruitment to intestinal mucosa via MAdCAM-1. 300 mg IV at 0, 2, 6 weeks, then every 8 weeks. Approved for moderate-severe CD and UC. Gut-selective = favorable safety profile.

Anti-IL-12/23

• Ustekinumab: fully humanized mAb against the p40 subunit shared by IL-12 and IL-23; prevents Th1 and Th17 activation. IV loading dose (260-520 mg, weight-based), then 90 mg SC every 8 weeks. Approved for moderate-severe CD and UC.

Anti-IL-23 (Selective p19)

• Risankizumab: targets IL-23 p19 subunit selectively; approved for moderate-severe CD and UC.

Antibiotics (CD-specific)

• Metronidazole (10-20 mg/kg/day) and/or ciprofloxacin (500 mg twice daily), 4-8 weeks: primary therapy for perianal fistulae in CD. NOT effective for luminal CD or UC as primary therapy.

Surgery

• UC: colectomy is curative. Indication: medically refractory disease, toxic megacolon, dysplasia, cancer.
• CD: surgery is palliative (not curative). Indications: obstruction, fistulae/abscesses, perforation, refractory disease. Bowel-sparing procedures preferred to avoid short bowel syndrome.

8. Cancer Risk

• UC: CRC risk begins after 7-10 years of disease; rises ~10% per decade; up to 18-34% at 30 years (depends on extent).
  • Risk is highest with universal colitis > left-sided colitis > proctitis.
  • Surveillance colonoscopy with biopsies every 1-2 years starting after 8-10 years of disease.
• CD: CRC risk is 4-20x the general population, especially with colonic involvement.
• Dysplasia (low-grade to high-grade) is the precursor lesion - characterized by crypt architectural distortion, nuclear enlargement, pseudostratification.
• Aminosalicylate "chemoprevention" is NOT routinely recommended.

9. Recent Evidence (2024-2025)

• Goldman-Cecil Medicine, 26th ed. - Chapter 127
• Yamada's Textbook of Gastroenterology, 7th ed. - Chapter 62
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Chapter 15
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease - Chapter 127