Crohn's Disease

Definition & Overview

Epidemiology

• CD and ulcerative colitis (UC) together constitute the two major forms of inflammatory bowel disease (IBD).
• Highest incidence is in North America, Northern Europe, and other Western countries.
• Bimodal age of onset: peaks in the 2nd–4th decades and a smaller peak in the 6th–7th decades.
• Slightly more common in women.
• Higher rates in Ashkenazi Jewish populations; urban > rural.

Pathogenesis

Genetics

• Over 200 genetic loci are associated with IBD. The most important is NOD2 (also called CARD15) on chromosome 16 — variants are associated with stricturing or fistulizing phenotype and increased surgical risk.
• ASCA (anti-Saccharomyces cerevisiae antibody) correlates with small intestinal disease; anti-OmpC predicts internal perforations; anti-CBir1 (antiflagellin) is associated with penetrating/stricturing disease.

Immunology

• Th1-mediated response dominates (IL-12, TNF-α, IFN-γ). IL-23/Th17 axis also implicated.
• Breakdown of intestinal barrier → microbial translocation → uncontrolled innate and adaptive immune activation → chronic transmural inflammation.
• Proteases and matrix metalloproteinases drive tissue destruction, sinus tracts, and fistula formation.

Environmental Factors

• Smoking increases risk and worsens disease course (opposite of UC).
• Appendectomy, altered gut microbiome, Western diet, and prior enteric infections are implicated.

Pathology

Clinical Features

Typical Presentation by Location

• Insidious onset of crampy RLQ pain, diarrhea (non-bloody or minimally bloody), weight loss
• RLQ mass or fullness on exam (matted bowel loops)
• Can mimic appendicitis

• Diarrhea ± blood (less profuse bleeding than UC)
• Tenesmus less prominent (rectum often spared)
• Abdominal pain more prominent than UC
• May present as fulminant colitis

• Occurs in ~24% before intestinal symptoms (mean lead time 4 years)
• Skin tags ("elephant ear" type 1 — soft, nontender; type 2 — edematous, hard)
• Eccentric anal fissures, ulcers, perianal fistulas, abscesses

• Gastroduodenal CD: "bamboo-joint" gastric folds, H. pylori-negative PUD, epigastric pain
• Esophageal: dysphagia, odynophagia (<2% of patients)
• Proximal jejunal: younger at diagnosis, more extensive resection required

Systemic/Extraintestinal Manifestations

• Musculoskeletal: peripheral arthritis, axial arthropathy (ankylosing spondylitis, sacroiliitis)
• Ocular: episcleritis, uveitis
• Dermatologic: erythema nodosum, pyoderma gangrenosum
• Hepatobiliary: primary sclerosing cholangitis (less common than in UC), fatty liver, cholelithiasis
• Metabolic: vitamin B12/fat-soluble vitamin deficiencies (terminal ileal disease/resection), osteoporosis

Disease Classification

• Age at diagnosis: A1 (≤16 yrs), A2 (17–40 yrs), A3 (>40 yrs)
• Location: L1 ileal, L2 colonic, L3 ileocolonic (± L4 upper tract modifier)
• Behavior: B1 inflammatory, B2 stricturing, B3 penetrating (± p perianal modifier)

• Inflammatory (B1): active inflammation, no fibrosis or fistula
• Stricturing (B2): fibrotic stenosis → obstructive symptoms
• Penetrating/Fistulizing (B3): transmural penetration to adjacent structures

Diagnosis

• Findings: aphthous ulcers → deep longitudinal/serpiginous ulcers → cobblestone mucosa, skip lesions, strictures

• MR enterography (preferred): mural thickening, hyperenhancement, the comb sign (engorged peri-enteric vasculature), fistula/abscess detection — avoids radiation
• CT enterography: similar but radiation exposure
• Capsule endoscopy: evaluates small bowel mucosa (contraindicated if stricture suspected)

• CRP: elevated in active disease; correlates with endoscopic activity
• Fecal calprotectin: pooled sensitivity 88%, specificity 67% for CD vs. endoscopically active disease; useful for monitoring relapse and biologic response
• Fecal lactoferrin: also useful marker of intestinal inflammation

• CDAI (Crohn's Disease Activity Index): remission = CDAI <150; response = CDAI decrease ≥100 points
• Mucosal healing (endoscopic remission) is now the primary therapeutic target, as symptoms alone poorly correlate with objective disease activity

Treatment

Mild-to-Moderate Disease

• Budesonide 9 mg/day (oral, controlled ileal-release): first-line for ileocecal disease — superior to placebo and 5-ASA, ~15% less effective than prednisolone but far fewer systemic side effects (~90% first-pass hepatic metabolism)
• Aminosalicylates (5-ASA): minimal efficacy in CD (unlike UC)
• Antibiotics (metronidazole, ciprofloxacin): for perianal/fistulizing disease and septic complications; not for luminal disease maintenance

Moderate-to-Severe Disease

• Prednisone 40–60 mg/day tapering over 6–12 weeks; ~80% response at 1 month
• NOT effective for maintenance — no benefit at 6, 12, or 24 months in meta-analyses
• 20% are steroid-resistant; 45% relapse or cannot taper within 1 year (steroid-dependence)

• Azathioprine/6-mercaptopurine: effective for steroid-sparing and maintenance; onset 3–4 months; monitor for myelosuppression (check TPMT activity), hepatotoxicity, lymphoma risk
• Methotrexate: 25 mg IM weekly for induction, 15 mg IM for maintenance; alternative for thiopurine-intolerant patients; folate supplementation required

Complications

Fistulas & Abscesses

• Perianal fistulas: 15–35% of patients; simple (low-lying) vs. complex (multiple tracts, involve scrotum/labia/buttocks)
• Enteroenteric, enterovesical, enterocutaneous, rectovaginal fistulas from transmural penetration
• Intra-abdominal abscess: spiking fevers + focal tenderness; masked by steroids → maintain high suspicion; managed with percutaneous drainage + antibiotics, then elective resection

Stricture

• Long-standing transmural inflammation → fibrotic stenosis
• Distinguish from inflammatory stricture (responds to anti-inflammatory therapy) vs. fibrostenotic (requires endoscopic dilation or surgery)
• All strictures require biopsy to exclude malignancy

Malignancy

• Colorectal cancer: increased risk with colonic CD (similar to UC); surveillance colonoscopy recommended after 8–10 years of colonic disease
• Small bowel adenocarcinoma: rare but elevated relative risk

Small Bowel Obstruction (SBO)

• CD is the cause in ~5% of all SBOs
• Must distinguish: active inflammatory flare vs. fibrotic stricture vs. unrelated cause (adhesions, hernia, cancer)
• Up to 75% of CD patients require at least one abdominal surgery in their lifetime

Surgery

• Risk of surgery: 16% at 1 year, 33% at 5 years, 47% at 10 years after diagnosis (population-based data)
• Rates have declined significantly over recent decades with expanded biologic therapy
• Guiding principle: preserve intestinal length — wide margins do NOT reduce recurrence
• Most common operation: ileocecal resection with primary anastomosis (often laparoscopic)
• Strictureplasty: preferred over resection for scattered strictures to spare bowel
• Laparoscopic ileocecal resection vs. infliximab (LIR:C trial): equivalent QOL at 12 months in limited (<40 cm) ileal disease — surgery may be a primary alternative in selected patients
• After resection: recurrence at anastomosis in 20–50%; routine post-operative colonoscopy at 6–12 months + early re-introduction of immunomodulators/biologics reduces recurrence

Recent Evidence

• IL-23p19 antagonists vs. ustekinumab (PMID 40071763, Am J Gastroenterol 2025): meta-analysis of RCTs shows IL-23p19 antagonists (risankizumab, mirikizumab) outperform ustekinumab
• Perianal Crohn's disease (PMID 40315877, Lancet Gastroenterol Hepatol 2025): novel diagnostic criteria and management consensus for isolated perianal CD
• Persistence of advanced therapies (PMID 38651771, Aliment Pharmacol Ther 2024): meta-analysis on long-term drug persistence in IBD