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Inflammatory Bowel Disease (IBD)

1. Definition and Overview

• Crohn Disease (CD) - transmural inflammation that can affect any segment of the GI tract from mouth to anus
• Ulcerative Colitis (UC) - mucosal/submucosal inflammation confined to the colon and rectum

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2. Epidemiology

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3. Etiopathogenesis

3.1 Genetic Factors

• NOD2 (CARD15) - most strongly associated with Crohn disease; encodes an intracellular pattern recognition receptor for bacterial muramyl dipeptide. NOD2 variants increase CD risk but are protective in UC.
• PTPN22 - increases CD risk, protective in UC
• ATG16L1 and IRGM - involved in autophagosome formation; autophagy defects impair clearance of intracellular pathogens
• IL10, IL10RA, IL10RB - mutations cause very early onset (infantile) monogenic IBD; IL-10 is a key anti-inflammatory cytokine
• HLA variants - associated with specific extraintestinal manifestations (arthropathy, uveitis, PSC)

3.2 Immune Dysregulation

• Activation of Th17 and Th1 cells (predominant in CD)
• More limited Th2 activation (relatively more prominent in UC)
• Reduced regulatory T cell (Treg) function
• Defective mucosal barrier integrity allowing luminal bacteria to trigger abnormal immune responses

3.3 Environmental/Microbial Factors

• Intestinal dysbiosis: Reduced microbial diversity, decreased short-chain fatty acid (SCFA)-producing bacteria (e.g., Firmicutes), increased Proteobacteria
• Infectious trigger: Infectious enteritis may precede onset in some patients; it is hypothesized that enteritis triggers mucosal immune activation and microbial changes in susceptible individuals
• Antibiotics: Altered microbiome composition
• Appendectomy: Protective against UC
• Oral contraceptives and NSAIDs: May trigger flares

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4. Pathology

4.1 Crohn Disease - Pathological Features

• Can involve any region from esophagus to anus
• Skip lesions: Diseased segments interspersed with normal mucosa
• Early lesions: Aphthous ulcers (small, superficial mucosal ulcers)
• Advanced lesions: Deep longitudinal and transverse ulcers creating a cobblestone appearance (normal mucosa = "stones", ulcers = "mortar")
• Transmural inflammation: Thickened bowel wall, narrowed lumen
• Creeping fat: Mesenteric fat wraps around the bowel wall (fat wrapping)
• Strictures and fistulae due to transmural disease
• "String sign" on barium studies due to strictures

• Transmural inflammation extending through all layers of the bowel wall
• Non-caseating epithelioid granulomas (pathognomonic when present; found in ~50% of resected specimens)
• Lymphoid aggregates in all layers
• Focal crypt architectural irregularity
• Submucosal fibrosis and neural hyperplasia

4.2 Ulcerative Colitis - Pathological Features

• Continuous involvement starting from the rectum extending proximally (rectum always involved)
• Disease is confluent - no skip lesions
• Granular, red, friable mucosa with contact bleeding
• Pseudopolyps (inflammatory polyps): Islands of regenerating mucosa surrounded by denuded areas
• Disease is limited to mucosa and submucosa (no transmural involvement)
• No fistulae, no strictures (in contrast to CD)

• Crypt abscesses: Neutrophils accumulate within crypt lumina - hallmark of active UC
• Crypt architectural distortion: Branching, shortening, and irregular spacing of crypts
• Diffuse lymphoplasmacytic infiltrate in the lamina propria
• Goblet cell depletion
• Pseudopyloric and Paneth cell metaplasia in chronic disease
• No granulomas (unless a complication is present)
• Inflammation confined to mucosa and superficial submucosa

4.3 Comparison Table: CD vs. UC

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5. Clinical Features

5.1 Crohn Disease

• Terminal ileum disease (70%) - most common; right lower quadrant pain, diarrhea (usually non-bloody), weight loss, fatigue
• Ileocolonic disease (40%)
• Primary ileal disease (30%)
• Perianal disease (30%): Fissures, fistulae, skin tags, abscesses
• Colonic disease (25%): Diarrhea, hematochezia (less frequent than UC)
• Upper GI disease (~5%): Dysphagia, odynophagia, heartburn, epigastric pain

• Enteroenteric
• Rectovaginal
• Enterovesicular (pneumaturia, fecaluria)
• Enterocutaneous
• Perianal

5.2 Ulcerative Colitis

• Proctitis (limited to rectum): Tenesmus, rectal urgency, bloody discharge; systemic symptoms uncommon
• Left-sided colitis (to splenic flexure): Bloody diarrhea, lower abdominal cramps
• Pancolitis: Profuse bloody diarrhea, severe abdominal pain, fever, weight loss

• 14-37% have pancolitis
• 36-41% have disease up to the splenic flexure
• Remaining have proctitis or proctosigmoiditis

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6. Extraintestinal Manifestations

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7. Investigations

7.1 Laboratory Tests

• CBC: Anemia (from blood loss, chronic disease, or B12/folate deficiency), leukocytosis in active disease/abscess
• CRP and ESR: Elevated in active disease; useful for monitoring
• Fecal calprotectin: Elevated in active disease, lower in remission - useful marker of mucosal inflammation
• Albumin: Low in severe/prolonged disease - indicates malnutrition
• Serum B12: Low with >100 cm distal ileum disease or resection (CD)
• Iron studies: Iron deficiency from blood loss

7.2 Serologic Markers

7.3 Endoscopy

7.4 Imaging

• CT/MR Enterography: Best for evaluating small bowel extent, fistulae, abscesses, and complications in CD
• Barium follow-through: "String sign" (severe luminal narrowing) in CD strictures
• Abdominal X-ray: Used in acute settings; detects toxic megacolon (transverse colon diameter >6 cm with systemic toxicity)
• MRCP/ERCP: For PSC evaluation
• Capsule endoscopy: For small bowel CD (contraindicated with known strictures)
• Pelvic MRI: Gold standard for perianal fistula mapping in CD

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8. Complications

8.1 Crohn Disease Complications

• Fistulae: Enterocutaneous, enterovesicular, rectovaginal, enteroenteric
• Intra-abdominal abscesses: From penetrating disease or blind-ending fistulae
• Strictures leading to bowel obstruction
• Perianal disease: Fissures, abscesses, skin tags
• Malabsorption and nutritional deficiencies (B12, fat-soluble vitamins, zinc, iron)
• Gallstones: Impaired bile acid reabsorption from terminal ileum disease
• Oxalate renal stones: Increased colonic oxalate absorption
• Short bowel syndrome: Following extensive resections
• Colorectal carcinoma: Risk 4-20x general population; often mucinous type, commonly in bypassed/strictured colon segments

8.2 Ulcerative Colitis Complications

• Toxic megacolon: Occurs in up to 10% of UC patients. Defined as total or segmental colonic dilatation (>6 cm on AXR) with systemic toxicity (fever >38.6°C, HR >120, leukocytosis, anemia). Medical emergency - antidiarrheal and anticholinergic medications are contraindicated. Requires IV corticosteroids; surgery if not responsive
• Massive hemorrhage: From sustained blood loss
• Bowel perforation: Often at the site of deepest ulceration
• Colorectal carcinoma (CRC): Major long-term complication
  • Risk begins after 7 years of disease duration
  • Rises approximately 10% per decade
  • Reaches as high as 34% at 30 years (in some series; population-based data suggests 15-18% at 30 years)
  • Greatest risk with pancolitis (universal colitis)
  • Left-sided disease: Risk begins ~10 years later than pancolitis
  • Proctitis alone: Minimal increased risk
  • Dysplasia is the precursor lesion - graded as low-grade or high-grade
  • Colonoscopic surveillance programs recommended starting 8-10 years after diagnosis

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9. Treatment

9.1 Categories of Medical Therapy

A. 5-Aminosalicylates (5-ASA)

• Sulfasalazine: Combination of sulfapyridine (carrier) + 5-ASA (active component). Active moiety released in the colon by bacterial action. Dose: 3-6 g/day. Side effects: Headache, nausea, oligospermia, hemolytic anemia, agranulocytosis.
• Mesalamine (5-ASA): pH-dependent release in the small intestine/colon. Fewer systemic side effects.
• Olsalazine, Balsalazide: Azo-bonded prodrugs, colon-specific delivery

• First-line for mild-to-moderate UC (induction and maintenance)
• Effective for ileocolonic and colonic CD (sulfasalazine: 45-55% response rate for mild-moderate disease)
• Not effective for small bowel CD alone

B. Corticosteroids

• Oral prednisone: 40-60 mg/day for moderate-severe active IBD
• Enteric-coated budesonide (9 mg/day): For distal ileal/right colonic CD; ~70% response rate at 8 weeks; lower systemic side effects due to high first-pass metabolism. Significantly more effective than mesalamine for distal ileal/right colonic CD.
• IV hydrocortisone: For severe/fulminant disease requiring hospitalization

• Not for maintenance therapy - cause significant side effects with prolonged use (osteoporosis, hyperglycemia, adrenal suppression, Cushingoid features)
• Used for induction only

C. Immunomodulators (Thiopurines and Methotrexate)

• Azathioprine (2-2.5 mg/kg/day) and 6-mercaptopurine (6-MP, 1-1.5 mg/kg/day):
  • Purine antimetabolites - inhibit lymphocyte proliferation
  • Used for maintenance of remission and steroid-sparing
  • Slow onset of action (3-6 months to full effect)
  • Side effects: Pancreatitis, hepatotoxicity, myelosuppression, increased risk of lymphoma (especially in males <35 years with thiopurines)
  • Check TPMT enzyme activity before starting (enzyme deficiency increases toxicity risk)
• Methotrexate (15-25 mg/week IM):
  • Alternative immunomodulator, especially in patients intolerant of thiopurines
  • Preferred in males <35 years in place of azathioprine (lower lymphoma risk)
  • Side effects: Hepatotoxicity, pulmonary toxicity, teratogenicity - requires folate supplementation and contraception
• Ozanimod: Sphingosine-1-phosphate (S1P) receptor modulator - prevents lymphocyte egress from lymph nodes; newer oral small molecule for UC

D. Biologics

• Combined infliximab + azathioprine is superior to monotherapy for both induction and maintenance
• Up to 50% of patients eventually lose response to anti-TNF therapy
• Meta-analysis: Adalimumab, infliximab + azathioprine, or ustekinumab are the three most effective therapies for induction and maintenance in CD

• Vedolizumab: Humanized monoclonal antibody targeting the α4β7 integrin. Blocks binding of lymphocytes to MAdCAM-1 (mucosal addressin cell adhesion molecule-1) on gut venular endothelium - preventing lymphocyte recruitment to intestinal mucosa. Gut-selective mechanism means lower systemic immunosuppression.
  • Dose: 300 mg IV at 0, 2, 6 weeks, then every 8 weeks
  • Approved for moderate-severe CD and UC
  • Side effects: Headache, arthralgia, nasopharyngitis, hypersensitivity reactions
• Natalizumab: Chimeric anti-α4 integrin antibody. Blocks both gut and CNS lymphocyte trafficking. Restricted use due to risk of Progressive Multifocal Leukoencephalopathy (PML) from JC virus reactivation. Only for CD patients negative for JC virus antibody.

• Ustekinumab: Fully humanized monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23. Prevents activation of IL-12Rβ1 and IL-23 receptors on CD4+ T cells and NK cells, suppressing Th1 and Th17 responses.
  • Induction: IV 260-520 mg (weight-based), then SC 90 mg every 8 weeks for maintenance
  • T½ up to 120 days - discontinue 15 weeks before live vaccines
  • Approved for moderate-severe CD and UC
  • Side effects: Upper respiratory infections, headache, arthralgia

• Risankizumab (targets IL-23 p19 subunit only): Approved for moderate-severe CD; used for upper GI and systemic CD

• Tofacitinib (JAK1/3 inhibitor): Oral agent for moderate-severe UC; blocks cytokine signaling
• Side effects: Increased risk of infections, VTE, cardiovascular events - use with caution in patients >50 years with cardiovascular risk factors

E. Antibiotics

• Metronidazole and ciprofloxacin: Used for perianal fistulae, intra-abdominal abscesses, and bacterial overgrowth in CD
• Not recommended as primary therapy for UC

9.2 Treatment Strategy by Severity and Disease

UC Treatment Algorithm

• First-line: Oral + rectal 5-ASA (combined is more effective than oral alone)
• Add oral corticosteroids if no response after 2-4 weeks

• Oral corticosteroids (prednisone 40-60 mg/day) ± 5-ASA
• If steroid-dependent/refractory: Add immunomodulator (azathioprine/6-MP) or escalate to biologics
• Biologics (infliximab, adalimumab, vedolizumab, ustekinumab) for moderate-severe disease refractory to conventional therapy

• IV corticosteroids (hydrocortisone 300-400 mg/day or methylprednisolone 60 mg/day)
• Cyclosporine IV (2-4 mg/kg/day) or infliximab (5 mg/kg) as rescue therapy for steroid-refractory disease
• Evaluate for toxic megacolon - strict avoidance of antidiarrheal/anticholinergic agents
• Surgery if no response to 3-5 days of IV steroids or complications arise

CD Treatment Algorithm

• Budesonide (9 mg/day) for distal ileal/right colonic disease
• Sulfasalazine for colonic/ileocolonic disease (limited efficacy)

• Systemic corticosteroids (prednisone 40-60 mg/day) for induction
• Add immunomodulator (azathioprine or methotrexate) for maintenance
• Biologics: Infliximab, adalimumab (± azathioprine), ustekinumab for high-risk/severe disease
• Early combined immunosuppression (anti-TNF + antimetabolite) is more effective than conventional stepwise therapy

• NPO, IV fluid resuscitation
• IV corticosteroids
• Surgical consultation for abscesses, obstruction, perforation

• Metronidazole + ciprofloxacin (symptomatic relief)
• Infliximab or adalimumab (60-80% closure rates for perianal fistulae)
• Drainage of abscesses before biologic therapy

9.3 Surgical Treatment

Ulcerative Colitis

• Fulminant colitis/toxic megacolon not responding to medical therapy
• Massive hemorrhage
• Perforation
• Colonic dysplasia or carcinoma
• Chronic refractory disease

Crohn Disease

• Bowel obstruction from strictures
• Intra-abdominal abscesses
• Fistulae not responding to medical therapy
• Malignancy
• Growth retardation (pediatric)

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10. Surveillance for Colorectal Carcinoma

• Colonoscopic surveillance should begin 8-10 years after diagnosis of UC and IBD-associated colitis
• Annual or biennial colonoscopy with multiple random biopsies
• Dysplasia (low-grade or high-grade) is the target lesion; high-grade dysplasia = indication for colectomy
• Chromosomal alterations (p53 overexpression, 18q LOH), high MSI, and specific miRNA methylation may precede histologic dysplasia
• CRC in UC is associated with a similar survival to sporadic CRC when matched controls are used
• PSC co-existing with UC significantly increases CRC risk

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11. Key Differentiating Points: CD vs. UC (Summary)

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12. Special Situations

Pregnancy

• IBD does not significantly impair fertility when in remission
• Active disease increases risk of preterm birth, low birth weight, miscarriage
• 5-ASA agents are generally safe
• Methotrexate: Absolutely contraindicated (teratogen) - must discontinue ≥3 months before conception
• Azathioprine/6-MP: Generally continued if benefits outweigh risks
• Anti-TNF agents: Held after 24-32 weeks to reduce neonatal immunosuppression (certolizumab pegol has minimal placental transfer)
• Corticosteroids: Used when essential

Pediatric IBD (Very Early Onset IBD)

• Can be monogenic - mutations in IL10, IL10RA, IL10RB
• More than 100 genes encode monogenic IBD
• Standard treatments often less effective; genetic testing warranted

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13. Prognosis

• UC: Relapsing-remitting course; >50% have mild disease; colectomy rate has fallen sharply with modern biologics; surgery is curative for intestinal disease
• CD: Chronic progressive disease with risk of bowel damage and surgical resection accumulating over time; surgery is not curative; average of 2-3 bowel resections over a lifetime in severe cases
• Both: Significantly reduced quality of life during active disease; extraintestinal manifestations and psychological comorbidities (anxiety, depression) are common

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