Inflammatory Bowel Disease (IBD) - A Comprehensive Overview

1. Epidemiology

• Goldman-Cecil Medicine, p. 1479-1480

2. Pathobiology

Genetics

• 5-20% of IBD patients have a first-degree relative with IBD; first-degree relatives carry a 10-15x increased risk.
• Identical twin concordance for CD is ~50%; for UC it is somewhat lower.
• Over 200 gene susceptibility loci have been linked to IBD; at least 30 are specific to CD, 20+ to UC.
• NOD2/CARD15 (chromosome 16q12): expressed in Paneth cells, macrophages, and dendritic cells. Senses muramyl dipeptide (a component of gram-positive bacterial cell walls). A mutation in the leucine-rich domain fails to activate NF-kB and is strongly associated with CD.
• ATG16L1 and IRGM genes (involved in autophagy) are linked to CD susceptibility - they impair the cell's ability to process intracellular pathogens.
• IL-23 receptor polymorphisms confer varied risk for both UC and CD.
• HLA-DR class II polymorphisms increase risk for UC.
• ADCY7 missense mutations cause excessive inflammatory responses predisposing to UC.
• IBD is also associated with Turner syndrome, Hermansky-Pudlak syndrome, ankylosing spondylitis, psoriasis, primary sclerosing cholangitis, and multiple sclerosis.

Microbiome and Immune Dysregulation

• Goldman-Cecil Medicine, p. 1480

3. Pathology: Key Differences

Histopathology - Crohn Disease

• Early: acute inflammatory infiltrate in the lamina propria, cryptitis, crypt abscesses
• Late: crypt architectural distortion, lymphocytic infiltrate with branching/shortening of crypts
• Noncaseating granulomas confirm the diagnosis when present alongside classic features
• Surgical specimens show transmural inflammation and fat creeping (fat wrapping) on the serosal surface

Histopathology - Ulcerative Colitis

• Early: epithelial necrosis, acute inflammatory infiltrate, cryptitis, crypt abscesses
• Chronic: predominantly lymphocytic infiltrate, marked crypt architectural distortion
• Goldman-Cecil Medicine, p. 1421, 1429-1431

4. Clinical Manifestations

Crohn Disease

• Ileal only (ileitis): 30%
• Ileocolonic: 40%
• Colonic only: 25-30%
• Upper GI (gastric, duodenal, jejunal): uncommon

Ulcerative Colitis

• Proctitis (rectum only): ~40-50%
• Left-sided colitis (distal to splenic flexure): ~30-35%
• Pancolitis (extensive colitis): ~20%

• Goldman-Cecil Medicine, p. 1481-1482

5. Endoscopic Appearances

Crohn Disease - Cobblestoning

• Early: superficial aphthous ulcers
• Progressive: deeper round, linear, or serpiginous ulcers
• Advanced: cobblestone appearance from intersecting longitudinal and transverse ulcers; "skip areas" of normal mucosa between diseased segments

Ulcerative Colitis

• Mild: granular, edematous, erythematous mucosa with loss of vascular pattern
• Moderate-severe: friable mucosa, contact bleeding, ulceration
• Chronic: pseudopolyps, loss of haustral folds, "lead pipe" colon
• Goldman-Cecil Medicine, p. 1560, 1576-1585

6. Extraintestinal Manifestations (EIMs)

7. Diagnosis

Laboratory Findings

• Anemia: from chronic disease, blood loss, or deficiencies of iron, folate, or B12 (ileal disease)
• Leukocytosis: mild = active disease; marked = abscess or suppurative complication
• ESR and CRP: nonspecific inflammatory markers used to monitor activity; CRP correlates well with clinical and endoscopic activity in CD
• Fecal calprotectin: pooled sensitivity 88%, specificity 73% vs. endoscopically active IBD; UC specificity (79%) > CD (67%); useful for distinguishing IBD from IBS and monitoring treatment response
• Fecal lactoferrin: also a sensitive marker of intestinal inflammation
• Hypoalbuminemia: marker of malnutrition and active disease
• Vitamin B12: reduced if >100 cm of terminal ileum is diseased or resected

Serologic Markers

• ASCA (Anti-Saccharomyces cerevisiae antibodies): positive in 40-70% of CD, <15% of UC
• pANCA (perinuclear antineutrophil cytoplasmic antibody): positive in 55% of UC, 20% of CD (mainly colonic)
• ASCA+/pANCA- combination: sensitivity 55%, specificity 93% for CD
• Additional antibodies (anti-I2, anti-Cbir1, anti-OmpC) are associated with CD

Radiology

• CT enterography / MR enterography: have replaced barium studies as standard imaging; excellent for extent of disease, strictures, fistulas, abscesses, and perianal disease
• MRI enterography is preferred in younger patients and for monitoring (no radiation)
• The "comb sign" on MRI (engorged peri-enteric vasculature around the inflamed bowel) is characteristic of active CD

Activity Scoring

• Crohn Disease Activity Index (CDAI): remission = CDAI <150; response = reduction ≥100 points. Components include stool frequency, abdominal pain, well-being, complications, use of antidiarrheal drugs, abdominal mass, hematocrit, and body weight.
• Symptoms alone do not always correlate with objective mucosal inflammation; mucosal healing (endoscopic + biomarker-based) has emerged as a primary therapeutic target.
• Goldman-Cecil Medicine, p. 1599-1606; Sleisenger & Fordtran, p. 2318

8. Treatment

Drug Classes

1. Aminosalicylates (5-ASA)

• Sulfasalazine and mesalamine are the backbone of mild-moderate UC treatment
• Oral mesalamine (4 g/day) + topical mesalamine enemas for distal-to-extensive UC
• Response rates ~45-55% for mild-moderate UC
• Not clearly effective for small bowel Crohn disease alone; sulfasalazine helps ileocolonic/colonic CD

2. Corticosteroids

• Oral prednisone (40-60 mg/day) for moderate-severe flares - not for maintenance
• Budesonide (9 mg/day enteric-coated): ~70% response for distal ileal/right colonic CD with fewer systemic effects
• IV corticosteroids (methylprednisolone/hydrocortisone) for hospitalized severe disease
• Patients not responding within 3-5 days of IV steroids should be considered for rescue therapy (infliximab or cyclosporine in UC; infliximab or surgery in CD)

3. Immunomodulators (Antimetabolites)

• Azathioprine (2.5 mg/kg/day) and 6-mercaptopurine: used for maintenance; not for rapid induction (takes 3-6 months to work)
• Methotrexate: effective for maintaining remission in CD; preferred over azathioprine/6-MP in males under 35 due to lymphoma risk with thiopurines
• Risk of lymphoma with thiopurines - especially in young men

4. Anti-TNF-alpha Biologics

• Infliximab (chimeric mouse-human IgG1, IV): approved for moderate-severe CD and UC, fistulizing CD, and CD/UC with high-risk prognostic indicators. Dosing: 5 mg/kg at weeks 0, 2, 6, then every 8 weeks.
• Adalimumab (fully human IgG1, SC): approved for moderate-severe CD and UC
• Golimumab (fully human IgG1, SC): approved for UC
• Certolizumab pegol (pegylated Fab fragment IgG4, SC): approved for CD
• Combination of infliximab + azathioprine is more effective than either alone for CD induction and maintenance
• Early "top-down" anti-TNF therapy based on biomarkers (fecal calprotectin ≥250 μg/g, CRP ≥5 mg/L) yields better clinical and endoscopic outcomes than purely symptom-driven decisions

5. Anti-Integrin Biologics

• Vedolizumab (anti-α4β7 integrin): gut-selective, used for moderate-severe CD and UC refractory to other therapies
• Natalizumab (anti-α4 integrin): reserved for refractory CD due to risk of progressive multifocal leukoencephalopathy (PML) from JC virus; requires strict TOUCH prescribing program

6. Anti-IL-12/23 Biologics

• Ustekinumab (anti-p40 subunit of IL-12 and IL-23, IV induction then SC maintenance): effective for moderate-severe CD and UC
• Risankizumab (anti-IL-23 p19): approved for CD and UC

7. JAK Inhibitors (Small Molecules - Oral)

• Upadacitinib (selective JAK inhibitor): approved for moderate-severe UC; induction 45 mg once daily x 8 weeks, then maintenance 15-30 mg once daily
• Tofacitinib: approved for UC; rapid onset; carries cardiovascular and VTE risk warnings

Treatment Algorithms

• Mesalamine (oral + topical) → corticosteroids for flares → immunomodulators or biologics for steroid-dependent/refractory disease

• Sulfasalazine or budesonide → escalate to immunomodulators or anti-TNF

• Anti-TNF ± antimetabolite (combination superior to monotherapy) OR ustekinumab OR vedolizumab
• Meta-analysis: adalimumab, infliximab + azathioprine, or ustekinumab are the three most effective therapies for induction and maintenance of CD remission

• NPO + IV fluids + parenteral corticosteroids
• If no response in 3-5 days: infliximab or surgery

• IV corticosteroids (methylprednisolone 60 mg/day or hydrocortisone 400 mg/day)
• If no response in 3-5 days: rescue therapy with infliximab or cyclosporine (IV), or colectomy
• Goldman-Cecil Medicine, p. 1700-1760

9. Surgical Management

Ulcerative Colitis

• Surgery (total proctocolectomy) is curative for UC - unlike CD
• Indications: acute severe UC refractory to medical therapy, toxic megacolon, perforation, dysplasia/cancer, medically refractory disease
• The preferred procedure is total proctocolectomy with ileal pouch-anal anastomosis (IPAA/J-pouch)
• Pouchitis (inflammation of the J-pouch) occurs in ~50% of patients long-term; treated with antibiotics (metronidazole, ciprofloxacin)

Crohn Disease

• Surgery is not curative (disease recurs at the anastomosis in >50% within 10 years)
• Indications: obstruction, abscess, fistula refractory to treatment, medically refractory disease, perforation, cancer
• Conservative resection with strictureplasty preferred over wide resections to preserve bowel length and prevent short bowel syndrome

10. Colorectal Cancer Risk

• UC: risk begins after ~7 years of disease; rises ~10% per decade; up to 34% at 30 years (tertiary center data); recent population studies suggest CRC risk may be declining
• Risk correlates with disease duration and extent (pancolitis > left-sided > proctitis)
• CD ileocolitis: CRC risk 4-20x the general population; mucinous carcinomas are common; often arise in bypassed or strictured segments

• Sleisenger & Fordtran, p. 2617

11. Recent Evidence (2024-2026)

Summary Table: CD vs. UC at a Glance