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Overview and Recommendations
Background
- •Crohn disease (CD) is a chronic, progressive, transmural inflammatory bowel disease that can affect any segment of the gastrointestinal tract from mouth to anus, characterized by skip lesions, granulomatous inflammation, and a relapsing-remitting course. It carries a substantial morbidity burden and increases the risk of colorectal cancer in patients with colonic involvement, necessitating regular endoscopic surveillance.
- •Incidence varies from 1-2 per 100,000 in Asia to 20-30 per 100,000 in North America and Europe, with prevalence reaching 0.5% in Canada by 2030. Peak onset occurs in the second to fourth decades, with a second smaller peak after age 60; sex distribution is nearly equal.
- •The central pathophysiologic axis involves a dysregulated mucosal immune response to commensal gut microbiota in a genetically susceptible host. Loss-of-function mutations in NOD2 impair bacterial sensing, ATG16L1 variants disrupt autophagy, and ZIP8 variants cause aberrant N-glycosylation, all converging on a breakdown of intestinal homeostasis that drives chronic transmural inflammation.
- •Experimental, clinical, and epidemiologic evidence supports a causal role for specific gut microbes (e.g., Faecalibacterium prausnitzii depletion, adherent-invasive Escherichia coli expansion) and inflammatory proteins (IL-6, TNF-α) in driving disease activity, as confirmed by Mendelian randomization analyses.
- •The Montreal classification stratifies patients by age at diagnosis (A1-A3), disease location (L1-L4), and disease behavior (B1 inflammatory, B2 stricturing, B3 penetrating), with a perianal modifier (p). This framework directly informs prognosis and therapeutic decisions; perianal disease and very-early-onset IBD (VEOIBD, age <6 years) represent distinct phenotypes requiring dedicated management approaches.
- •Risk factors include family history (10- to 20-fold increased risk in first-degree relatives), central obesity (HR 1.45 per 1-SD increase in waist-to-hip ratio), and vitamin D deficiency (<50 nmol/L; HR 1.61). Maternal diet quality and processed meat intake during pregnancy also modulate offspring risk, but interventional data for primary prevention are lacking.
Evaluation
- •Suspect Crohn disease in any patient with chronic (>4 weeks) abdominal pain, diarrhea, and unintentional weight loss, especially when accompanied by perianal disease, a tender right-lower-quadrant mass, or oral aphthous ulcers. The pain is typically crampy and postprandial, and diarrhea is often non-bloody unless there is colonic involvement.
- •Ask about nocturnal symptoms, extraintestinal manifestations (erythema nodosum, anterior uveitis, arthralgias, clubbing), and family history of IBD. Also screen for red-flag symptoms: inability to tolerate oral intake for >24 hours, high-volume diarrhea (>10 stools/day), fever >38.5°C, involuntary guarding, or unexplained tachycardia/hypotension, these suggest severe or complicated disease requiring urgent evaluation.
- •Examine for right-lower-quadrant tenderness (sensitivity ~60-70%), abdominal distension with high-pitched bowel sounds (suggesting stricture), perianal fissures/fistulas/abscesses (present in 30-40% of patients), digital clubbing (10-20%), and oral cobblestoning or aphthous ulcers (5-10%). A tender fixed mass in the right lower quadrant suggests an inflammatory phlegmon or abscess.
- •Order ileocolonoscopy with multiple biopsies from the terminal ileum and each colonic segment, this is the gold-standard diagnostic test (sensitivity ~90%). Key endoscopic features include aphthous ulcers, deep serpiginous ulcers, cobblestoning, and skip lesions. Biopsies should be taken from both ulcerated and normal-appearing mucosa to detect transmural inflammation and non-caseating granulomas (present in 30-50% of biopsies).
- •Obtain esophagogastroduodenoscopy (EGD) with biopsies in children, young adults, and patients with upper GI symptoms, as upper tract involvement occurs in up to 48.7% of patients and may be asymptomatic yet histologically active.
- •Perform magnetic resonance enterography (MRE) to evaluate small bowel disease beyond the reach of the colonoscope, assess transmural inflammation, and detect complications such as abscesses, fistulae, and strictures. MRE has a sensitivity of 85-90% and specificity of 90-95% for active small bowel inflammation. CT enterography is reserved for acute settings where speed is critical.
- •Consider capsule endoscopy when ileocolonoscopy and MRE are nondiagnostic but clinical suspicion remains high. A patency capsule should be administered first to confirm luminal patency, as capsule retention occurs in 1-5% of patients with known strictures.
- •Check fecal calprotectin (best noninvasive screening tool; level >150 μg/g has 90% sensitivity and 80% specificity for active CD) and C-reactive protein (elevated in 70-80% of active cases, but may be normal in isolated ileal disease). Fecal calprotectin is also used to monitor response to therapy and predict relapse.
- •Assess disease severity at diagnosis using the Montreal classification. The Harvey-Bradshaw Index (HBI) is preferred in outpatient clinics for rapid triage, while the Crohn's Disease Activity Index (CDAI) remains the gold standard for clinical trials.
- •Screen for latent tuberculosis (IGRA), hepatitis B (HBsAg, anti-HBc), and HIV before initiating any biologic therapy. Check baseline vitamin D (25-OH) level and consider DXA scanning for bone density after 3 months of cumulative corticosteroid exposure.
Management
- •For mild-to-moderate active disease, exclusive enteral nutrition (EEN) or the Crohn's disease exclusion diet (CDED) with 50% partial enteral nutrition induces rapid clinical remission within 3-6 weeks; this is first-line in pediatric patients to avoid corticosteroids and preserve growth.
- •For moderate-to-severe active disease, initiate systemic corticosteroids: prednisone 40-60 mg orally once daily or intravenous methylprednisolone 40-60 mg daily, followed by a taper over 8-12 weeks. Corticosteroids are not recommended for maintenance therapy due to toxicity and lack of efficacy.
- •In patients with endoscopically active ileal CD colonized with adherent-invasive Escherichia coli, a 12-week course of oral ciprofloxacin 500 mg twice daily plus rifaximin 800 mg twice daily significantly improves endoscopic response (TEOREM trial). Do not use antibiotics empirically without evidence of AIEC colonization.
- •For steroid-refractory or steroid-dependent disease, initiate infliximab induction: 5 mg/kg intravenously at weeks 0, 2, and 6. Target a week-2 trough concentration ≥3.5 μg/mL, as this predicts higher rates of clinical remission and mucosal healing at week 30. Proactive therapeutic drug monitoring (TDM) during maintenance reduces the risk of disease worsening.
- •For maintenance therapy, continue infliximab 5 mg/kg intravenously every 8 weeks or adalimumab 40 mg subcutaneously every other week (after 160/80 mg induction). Higher adalimumab trough concentrations are associated with increased rates of clinical remission at week 56 (OR 1.34 per 1 μg/mL increase).
- •In patients with prior anti-TNF failure or contraindications, use vedolizumab 300 mg intravenously every 8 weeks after standard induction. Baseline drug clearance predicts deep biochemical remission at week 30; therapeutic drug monitoring can guide dose optimization.
- •Natalizumab 300 mg intravenously every 4 weeks is effective for anti-TNF-refractory Crohn disease but is limited by the risk of progressive multifocal leukoencephalopathy (PML). Reserve for patients who have failed all other biologics and are JC virus antibody-negative.
- •Do not use 5-aminosalicylates (5-ASA) for maintenance in Crohn disease, a meta-analysis found no increased risk of relapse with discontinuation (RR 1.02). Do not use antibiotics for long-term maintenance; the TEOREM trial showed benefit only for 12-week induction in AIEC-colonized patients.
- •Do not use fecal microbiota transplantation for induction or maintenance of remission, a Cochrane review found insufficient evidence of benefit. Do not use tesnatilimab (anti-NKG2D), a phase 2 trial demonstrated no dose-response and only modest clinical benefit.
- •When loss of response occurs during maintenance therapy: confirm active disease, check drug trough levels and anti-drug antibodies. If subtherapeutic levels without antibodies, escalate dose (e.g., infliximab 10 mg/kg or shorten to every 6 weeks; adalimumab 40 mg weekly). If therapeutic levels with active disease, switch to a different mechanism of action. If high-titer antibodies, switch to another agent within the same class or to a different class.
- •Refer to a gastroenterologist and colorectal surgeon for severe or complicated disease (abscess, obstruction, perforation, toxic megacolon). Emergency colectomy is indicated for perforation, uncontrolled hemorrhage, or failure of medical therapy in fulminant colitis.
- •For hospitalized patients, initiate VTE prophylaxis with enoxaparin 40 mg subcutaneously once daily (CrCl ≥30 mL/min) unless contraindicated by active bleeding. Consider extending prophylaxis for 4 weeks post-discharge in high-risk patients.
- •Target nutritional intake of 25-30 kcal/kg/day and 1.2-1.5 g protein/kg/day. For patients with prolonged ileus or malnutrition, enteral nutrition via nasogastric or nasojejunal tube is superior to parenteral nutrition, reducing infectious complications by 40%.
- •For fibrostenotic strictures ≤5 cm without deep ulceration, consider endoscopic balloon dilation (EBD), technical success >85%, but long-term surgery-free survival is ~50% at 3 years. Endoscopic stricturotomy may offer higher single-session success for multi-segmental disease.
- •For perianal fistulas, manage with drainage of abscesses, seton placement, and anti-TNF therapy (infliximab 5 mg/kg at 0, 2, and 6 weeks). Complex fistulas are associated with a 5-year colectomy rate of 25-30%.
- •In pediatric patients, EEN or CDED is first-line for induction; infliximab is dosed at 5 mg/kg IV at weeks 0, 2, and 6, then every 8 weeks, with dose escalation to 10 mg/kg if trough levels are subtherapeutic. Vedolizumab pharmacokinetic studies support weight-based dosing to match adult exposure.
- •In pregnancy, continue biologic therapy (anti-TNF agents are low risk; consider discontinuation around week 30-32 for infliximab). Methotrexate and thalidomide are contraindicated. Most biologics are compatible with breastfeeding.
- •In elderly patients (age ≥60), prioritize vedolizumab over anti-TNF agents to minimize systemic infection risk. Screen for and correct vitamin D deficiency to maintain levels ≥75 nmol/L. Minimize corticosteroid exposure.
- •Before starting biologic therapy, ensure latent TB screening, hepatitis B serologies, and age-appropriate vaccinations (including recombinant zoster vaccine) are complete. Patients on combination therapy with thiopurines require annual skin cancer screening.
Board Review — High Yield
- •Montreal classification, Standard system for subtyping Crohn disease by age (A1-A3), location (L1-L4), and behavior (B1 inflammatory, B2 stricturing, B3 penetrating); perianal modifier (p) added to any B category.
- •NOD2 mutation, Loss-of-function mutations (R702W, G908R, 1007fs) impair bacterial sensing, reduce defensin production, and predispose to ileal and stricturing disease.
- •Non-caseating granuloma, Pathognomonic histologic finding in Crohn disease, present in 30-50% of biopsies; composed of epithelioid histiocytes and multinucleated giant cells.
- •Fecal calprotectin, Best noninvasive marker for distinguishing inflammatory from functional bowel disease; level >150 μg/g has 90% sensitivity and 80% specificity for active Crohn disease.
- •Infliximab trough at week 2, Target ≥3.5 μg/mL; associated with higher rates of clinical remission and mucosal healing at week 30. Proactive TDM reduces risk of disease worsening.
- •Vedolizumab, Gut-selective α4β7 integrin antagonist; preferred in elderly patients due to lower systemic infection risk; baseline drug clearance predicts deep biochemical remission at week 30.
- •TEOREM trial, Ciprofloxacin + rifaximin for 12 weeks improved endoscopic response in AIEC-colonized ileal Crohn disease (45% vs 22%; NNT = 4.3).
- •Exclusive enteral nutrition (EEN), First-line therapy for pediatric Crohn disease; induces remission in 80-85% of children with improved growth and mucosal healing compared to corticosteroids.
- •Prognosis, 50% of patients develop stricturing or penetrating complication within 10 years; 70% require at least one intestinal resection over lifetime. Active smoking doubles risk of postoperative relapse.
- •Pregnancy and biologics, Anti-TNF agents should be continued through pregnancy; risk of adverse outcomes is driven by disease activity, not drug exposure. Methotrexate and thalidomide are contraindicated.
Deep Dive — Evidence Details
Definition, Classification & Nomenclature
- ▸Montreal classification (age, location, behavior) guides prognosis and therapy.
- ▸VEOIBD (<6 years) often has monogenic basis and may require different management.
Crohn disease (CD) is a chronic, progressive, transmural IBD affecting any GI segment, with skip lesions and non-caseating granulomas. The Montreal classification stratifies by age (A1<16, A2 17-40, A3>40), location (L1 terminal ileum, L2 colon, L3 ileocolon, L4 upper GI modifier), and behavior (B1 inflammatory, B2 stricturing, B3 penetrating, p perianal modifier). The Paris classification refines pediatric CD with L4a/L4b and B2B3 categories. Very early onset IBD (VEOIBD, age<6) often has monogenic defects and may present with Crohn's-like enteritis in primary immunodeficiencies [5]C4. Perianal disease is a distinct phenotype requiring dedicated management [10]B3b.
Pearl: The Montreal and Paris classification systems provide the essential framework for subtyping Crohn disease by age, location, and behavior, which directly informs prognosis and treatment strategy; perianal disease and VEOIBD represent special phenotypes that require dedicated approaches [10]B3b[5]C4.
| Axis | Category | Description |
|---|---|---|
| Age (A) | A1: <16 years | Pediatric onset |
| A2: 17-40 years | Adult onset | |
| A3: >40 years | Late onset | |
| Location (L) | L1: Terminal ileum | Ileal disease |
| L2: Colon | Colonic disease | |
| L3: Ileocolon | Both ileal and colonic | |
| L4: Upper GI modifier | Proximal to terminal ileum (added to L1-L3) | |
| Behavior (B) | B1: Non-stricturing, non-penetrating | Inflammatory phenotype |
| B2: Stricturing | Fibrostenotic disease | |
| B3: Penetrating | Fistulizing or abscess-forming | |
| p: Perianal modifier | Added to any B category if perianal fistulas, abscesses, or fissures present |
Pathophysiology & Mechanism
- ▸NOD2 and ATG16L1 variants are key genetic risk factors.
- ▸TNF-α is central; anti-TNF therapy is mainstay but immunogenicity can cause loss of response.
Dysregulated mucosal immune response to gut microbiota in genetically susceptible host drives transmural inflammation. Key genetic variants: NOD2 loss-of-function impairs bacterial sensing, predisposing to ileal disease; ATG16L1 T300A disrupts autophagy, increasing IL-1β and perianal CD risk [13]A1a; ZIP8 A391T causes aberrant N-glycosylation and barrier dysfunction [23]C4. Immune dysregulation features expanded Th17 cells and TNF-α-driven inflammation. Leukocyte trafficking via α4 integrin/MAdCAM-1 is targeted by natalizumab [15]A1a[16]A1a. Gut dysbiosis includes reduced Faecalibacterium prausnitzii and expansion of adherent-invasive E. coli (AIEC). Fungal dysbiosis via CARD9 pathway also contributes [22]C4. Epithelial barrier disruption and TRP channel upregulation lead to visceral hypersensitivity [12]D5.
Pearl: The interplay of genetic susceptibility (NOD2, ATG16L1, ZIP8), Th17/Treg imbalance, and gut dysbiosis creates a self-perpetuating cycle of inflammation that explains the chronic relapsing course of Crohn disease and provides targets for biologic therapy.
| Gene | Variant | Functional Consequence | Clinical Association |
|---|---|---|---|
| NOD2 | R702W, G908R, 1007fs | Impaired bacterial sensing, reduced defensins | Ileal disease, stricturing phenotype |
| ATG16L1 | T300A (rs2241880) | Defective autophagy, increased IL-1β | Perianal Crohn disease [13]A1a |
| ZIP8 | A391T | Aberrant N-glycosylation, barrier dysfunction | Increased susceptibility [23]C4 |
| CARD9 | Multiple SNPs | Impaired antifungal immunity | Fungal dysbiosis, severe colitis [22]C4 |
Epidemiology, Etiology & Risk Factors
- ▸Family history is strongest risk factor (OR 10-20).
- ▸Central obesity and vitamin D deficiency are modifiable risk factors.
Incidence varies from 1-2/100,000 in Asia to 20-30/100,000 in North America/Europe; prevalence up to 0.5% in Canada [25]B2c. Peak age 20-40 years; slight female predominance. Family history confers 10-20 fold increased risk. Modifiable risk factors: central obesity (HR 1.45 per 1-SD waist-to-hip ratio) [30]B2b; vitamin D deficiency (<50 nmol/L) increases risk (HR 1.61) [32]B2b; maternal diet quality during pregnancy lowers offspring risk (HR 0.74 per 1-SD) [36]B2b; high processed meat intake increases risk (HR 1.42) [36]B2b. Pediatric constipation may precede diagnosis (19.7% prevalence) [34]C4. Upper GI involvement is common in Asian populations (48.7% histologic) [29]B2b.
Pearl: Central obesity and vitamin D deficiency are independently associated with incident Crohn disease, but causality remains unproven; family history remains the strongest identifiable risk factor, with a 10- to 20-fold increase in first-degree relatives [25]B2c[30]B2b[32]B2b.
| Risk Factor | Odds Ratio / Hazard Ratio | Evidence Level |
|---|---|---|
| Family history (first-degree relative) | OR 10-20 | 2a (multiple cohorts) |
| Central obesity (per 1-SD WHR) | HR 1.45 (95% CI 1.18-1.78) [30]B2b | 2b (prospective cohort) |
| Vitamin D deficiency (<50 nmol/L) | HR 1.61 (95% CI 1.12-2.31) [32]B2b | 2b (prospective cohort) |
| Maternal diet quality (per 1-SD) | HR 0.74 (95% CI 0.56-0.98) [36]B2b | 2b (prospective cohort) |
| Maternal processed meat intake | HR 1.42 (95% CI 1.02-1.98) [36]B2b | 2b (prospective cohort) |
| Pediatric constipation | Prevalence 19.7% [34]C4 | 4 (cross-sectional) |
Clinical Presentation
- ▸Classic triad: RLQ pain, chronic diarrhea, weight loss.
- ▸Perianal disease and oral ulcers are highly suggestive of CD.
Insidious onset of right lower quadrant or periumbilical pain, chronic non-bloody diarrhea, and weight loss over weeks to months [37]D5. Physical exam: tender RLQ mass (20-30% sensitivity, ~95% specificity for complicated disease) [37]D5; perianal inspection reveals skin tags, fissures, fistulas in 30-40%; clubbing in 10-20%; oral aphthous ulcers in 5-10%. Montreal phenotypes: Inflammatory (B1) ~70% at diagnosis; Stricturing (B2) ~15-20% with obstructive symptoms; Penetrating (B3) ~10-15% with fistulas/abscesses; Perianal (p) ~20-30% [13]A1a[37]D5. Red flags: inability to tolerate oral intake >24h, >10 stools/day, fever >38.5°C, peritonitis signs, tachycardia, hypotension. Atypical presentations: isolated perianal disease, gastroduodenal CD mimicking PUD, systemic onset with arthralgias/erythema nodosum, growth failure in children, and Niemann-Pick type C mimicking CD [38]C4[41]D5[42]C4.
Pearl: When a patient presents with right lower quadrant pain and chronic diarrhea, the presence of perianal disease, a tender abdominal mass, or oral ulcerations increases the pre-test probability of Crohn disease over ulcerative colitis to >90% in appropriate epidemiological contexts [37]D5[13]A1a.
| Sign / Maneuver | Technique | Expected Finding in Active Crohn Disease | Performance (Sensitivity / Specificity) |
|---|---|---|---|
| Abdominal mass | Deep palpation of the right lower quadrant | Tender, fixed mass representing an inflammatory phlegmon or abscess | Low sensitivity (~20-30%), high specificity (~95%) for complicated disease [37]D5 |
| Right lower quadrant tenderness | Gradual deep palpation with rebound assessment | Localized tenderness with or without guarding | Sensitivity ~60-70%, specificity ~80% for ileal involvement |
| Perianal inspection | Visual inspection of perianal skin, digital rectal exam | Skin tags, fissures, fistulas (30-40% of patients), abscesses | Highest yield for perianal CD variant; sensitivity ~85% for active perianal fistulas |
| Abdominal distension | Inspection and percussion | Tympanitic distension with high-pitched bowel sounds in stricturing phenotype | Non-specific but demands urgent flat-plate imaging if present |
| Clubbing | Inspection of nail beds | Digital clubbing (10-20% of patients) correlates with chronic inflammation | Low sensitivity but high specificity relative to irritable bowel syndrome |
| Oral examination | Inspection of buccal mucosa, lips | Aphthous ulcers, cobblestoning (5-10%) | ~10% sensitivity, pathognomonic when present |
| Variant (Montreal) | Key Features | Frequency at Diagnosis |
|---|---|---|
| Inflammatory (B1) | Abdominal pain, diarrhea, weight loss without stricture or fistula | ~70% at diagnosis [37]D5 |
| Stricturing (B2) | Obstructive symptoms: postprandial pain, nausea, vomiting, abdominal distension | ~15-20% [38]C4 |
| Penetrating (B3) | Internal fistulas (enteroenteric, enterovesical, enterocutaneous), abscesses | ~10-15% |
| Perianal (p) | Anal fissures, fistulas, perirectal abscesses | ~20-30% of all CD patients; may co-exist with B1-B3 [13]A1a |
| Isolated duodenal (L4) | Epigastric pain, early satiety, vomiting due to proximal stricture | ~1-2% of paediatric cases [38]C4 |
Diagnosis & Workup
- ▸Ileocolonoscopy with biopsies is gold standard (sens ~90%).
- ▸Fecal calprotectin >150 μg/g is best noninvasive screening test.
Gold standard: ileocolonoscopy with multiple biopsies from terminal ileum and each colonic segment, even if mucosa appears normal [43]C4. Sensitivity ~90% for active disease. Key endoscopic features: aphthous ulcers, deep serpiginous ulcers, cobblestoning, skip lesions. Histology: non-caseating granulomas (30-50%), transmural inflammation, fissuring ulcers. Cross-sectional imaging: MR enterography (MRE) preferred (sens 85-90%, spec 90-95%) for small bowel assessment and detecting complications [45]A1a. CTE reserved for acute settings. Capsule endoscopy if MRE negative but high suspicion (retention risk 1-5%; use patency capsule first). Laboratory: fecal calprotectin >150 μg/g (sens 90%, spec 80%) best noninvasive marker [44]A1b; CRP elevated (70-80% sens); vitamin D often low [32]B2b. Diagnostic algorithm: clinical suspicion → fecal calprotectin + CRP → ileocolonoscopy with biopsies → MRE → histologic confirmation → staging (Montreal classification).
Pearl: Ileocolonoscopy with biopsies remains the gold standard for diagnosis, but MRE is essential for evaluating small bowel disease and detecting complications that alter ; fecal calprotectin is the most sensitive noninvasive screening tool and should be used to guide the decision to proceed to endoscopy [44]A1b[45]A1a.
Severity, Staging & Risk Stratification
- ▸CDAI and SES-CD are standard for clinical trials and endoscopic assessment.
- ▸CAR >0.102 identifies high-risk patients for postoperative complications.
Severity assessed by clinical indices (CDAI, HBI), endoscopic scores (SES-CD, Rutgeerts), and biomarkers (CRP, fecal calprotectin). CDAI <150 remission, 150-220 mild, 221-450 moderate, >450 severe. SES-CD ≥7 indicates moderate-severe endoscopic activity; mucosal healing (SES-CD ≤2) is therapeutic target. Rutgeerts score for postoperative recurrence (i0-i4). Biomarker-based: CRP-to-albumin ratio (CAR) >0.102 predicts 30-day complications after surgery [54]C4. Emerging tools: CTE-based radiomics models predict mucosal healing (AUC 0.85) [50]B3b; machine learning models predict flares and need for surgery with >80% accuracy [14]B2a. Postoperative risk: nomogram for intestinal fistula (C-index 0.78) incorporating CRP, albumin, disease duration, penetrating phenotype [53]B3b. Limitations: CDAI cumbersome, HBI subjective, SES-CD requires endoscopy. Composite scores integrating clinical, endoscopic, and molecular data are needed.
Pearl: Severity stratification in Crohn disease requires integration of clinical indices (CDAI, HBI), endoscopic scores (SES-CD), and biomarkers (CRP, fecal calprotectin, CAR); emerging radiomics and ML models promise to refine risk prediction, but no single tool suffices [50]B3b[54]C4.
Acute Management
- ▸Corticosteroids first-line for moderate-severe flares; taper over 8-12 weeks.
- ▸Infliximab induction with target trough ≥3.5 μg/mL at week 2 improves outcomes.
Step 1: Severity classification using HBI or CDAI. Mild (HBI<8, CDAI<220), moderate (HBI 8-16, CDAI 220-450), severe (HBI>16, CDAI>450). Severe features (fever, tachycardia, hypotension, peritonitis) warrant hospitalization. Step 2: First-line - Mild-to-moderate pediatric: exclusive enteral nutrition (EEN) or CDED with 50% partial enteral nutrition (78% remission at week 6) [58]A1b. Moderate-to-severe: systemic corticosteroids (prednisone 40-60 mg PO daily or methylprednisolone 40-60 mg IV daily) with taper over 8-12 weeks [61]A1b[63]C4. For AIEC-colonized ileal disease: ciprofloxacin 500 mg BID + rifaximin 800 mg BID for 12 weeks (TEOREM trial) [44]A1b. Step 3: Rescue - Steroid-refractory: infliximab 5 mg/kg IV at weeks 0,2,6; target week-2 trough ≥3.5 μg/mL [64]B2b. Fulminant colitis: IV steroids + surgical consult; rescue with infliximab or cyclosporine. Step 4: Monitoring - Reassess HBI/CDAI at weeks 2,6,12; infliximab trough at week 2 (target ≥3.5 μg/mL) and before 4th infusion (3-7 μg/mL). Step 5: Transition to maintenance - Continue infliximab 5 mg/kg q8w with proactive TDM [2]A1b. For surgery, Kono-S anastomosis reduces endoscopic recurrence (22.2% vs 51.2%; NNT=4) [59]A1b.
Pearl: For acute severe Crohn disease, initiate corticosteroids promptly and assess response within 7 days; early infliximab induction with target trough ≥3.5 μg/mL at week 2 improves long-term outcomes, and dietary therapy is a safe first-line option in children [58]A1b[64]B2b.
| Drug | Indication | Starting dose | Target / max dose | Key monitoring |
|---|---|---|---|---|
| Prednisone | Moderate-severe flare | 40-60 mg PO daily | Taper over 8-12 weeks | Blood glucose, blood pressure, infection |
| Methylprednisolone IV | Severe flare | 40-60 mg IV daily | Same | Same |
| Infliximab | Steroid-refractory / fistulizing | 5 mg/kg IV at weeks 0, 2, 6 | 10 mg/kg if subtherapeutic | Trough levels, anti-drug antibodies |
| Ciprofloxacin | AIEC-colonized ileal CD | 500 mg PO BID | Same for 12 weeks | QT interval, tendon pain |
| Rifaximin | AIEC-colonized ileal CD | 800 mg PO BID | Same for 12 weeks | None specific |
Long-term & Definitive Medical Management
- ▸Infliximab and adalimumab are first-line maintenance biologics.
- ▸Vedolizumab is effective after anti-TNF failure; 5-ASA is not recommended.
Maintenance therapy aims to sustain remission. Anti-TNF agents are first-line: infliximab 5 mg/kg IV q8w or adalimumab 40 mg SC q2w (after induction). Steroid-free remission ~40% at 1 year [1]A1a. Subcutaneous infliximab (120 mg SC q2w) is an alternative [28]C4. Adalimumab trough concentrations correlate with remission (OR 1.34 per 1 μg/mL) [51]B2b. Biosimilar SB5 non-inferior to reference [70]A1b. Vedolizumab 300 mg IV q8w for anti-TNF failures; pediatric clearance predicts deep remission [27]B2b. Natalizumab 300 mg IV q4w for refractory cases, but PML risk limits use [15]A1a[16]A1a. Dietary therapy: EEN or CDED effective for induction, especially in children; 3-week trial predicts success [58]A1b. What NOT to do: 5-ASA ineffective (RR 1.02) [72]A1a; antibiotics not for maintenance; FMT insufficient evidence [24]D5; tesnatilimab no benefit [71]A1b. Treatment failure: confirm active disease, check trough/antibodies, escalate dose or switch class.
Pearl: Anti-TNF agents (infliximab 5 mg/kg IV q8w or adalimumab 40 mg SC q2w) remain first-line maintenance for moderate-to-severe Crohn disease, with vedolizumab as an effective second-line option; 5-ASA and antibiotics have no role in long-term maintenance [1]A1a[72]A1a.
| Drug | Starting dose | Target/max dose | Renal adjustment | Hepatic adjustment | Key monitoring |
|---|---|---|---|---|---|
| Infliximab (IV) | 5 mg/kg at 0, 2, 6 weeks | 5 mg/kg every 8 weeks | None | None | Trough levels, anti-drug antibodies, LFTs |
| Infliximab (SC) | 120 mg SC every 2 weeks after IV loading | 120 mg SC every 2 weeks | None | None | Trough levels, anti-drug antibodies |
| Adalimumab | 160 mg SC week 0, 80 mg week 2 | 40 mg SC every other week | None | None | Trough levels, anti-drug antibodies |
| Vedolizumab | 300 mg IV at 0, 2, 6 weeks | 300 mg IV every 8 weeks | None | None | Trough levels (consider in loss of response) |
| Natalizumab | 300 mg IV every 4 weeks | 300 mg IV every 4 weeks | None | None | JC virus antibody, MRI for PML |
| Option | Indication/Line | Dose | Key Trial | Outcome | Evidence Level |
|---|---|---|---|---|---|
| Infliximab | First-line for moderate-severe luminal CD | 5 mg/kg IV q8w | ACCENT I (not in refs) | Steroid-free remission ~40% at 1 year [1]A1a | 1a |
| Adalimumab | First-line or after infliximab failure | 40 mg SC q2w | SERENE CD [51]B2b | Exposure-response: OR 1.34 per 1 μg/mL for remission at week 56 | 2b |
| Vedolizumab | Anti-TNF failure or contraindication | 300 mg IV q8w | GEMINI 2 (not in refs) | Remission ~39% at 52 weeks [27]B2b | 2b |
| Natalizumab | Anti-TNF failure (limited use) | 300 mg IV q4w | ENCORE (not in refs) | Remission ~26% at 12 weeks [15]A1a[16]A1a | 1a |
| Exclusive Enteral Nutrition | Pediatric first-line or adjunct | 100% formula for 6-8 weeks | Meta-analysis [65]D5 | Remission rate ~80% vs 40% with steroids | 5 |
Endoscopic & Procedural Management
- ▸EBD for strictures ≤5 cm; technical success >85%.
- ▸Chromoendoscopy with targeted biopsies for surveillance in long-standing colitis.
Endoscopic balloon dilation (EBD) is first-line for short fibrotic strictures ≤5 cm without deep ulceration or fistula. Technical success >85%; cumulative surgery-free rate 68% at 1 year, 52% at 3 years [83]B2b. Repeat dilations common (mean 2.3 sessions); perforation risk 2-4%. Endoscopic stricturotomy for multi-segmental strictures: combined surgical-endoscopic approach achieved 100% technical success, 86% surgery-free at 18 months [31]C4. Surveillance colonoscopy for Crohn colitis >1/3 colon for ≥8 years: chromoendoscopy with targeted biopsies preferred; interval 1-3 years [86]D5. Capsule endoscopy for small bowel evaluation when conventional workup negative; identifies lesions in 20-30% [80]B3b; contraindicated if stricture suspected (use patency capsule).
Pearl: Endoscopic balloon dilation is effective for short fibrotic strictures, but long-term surgery-free survival is modest (~50% at 3 years); repeat dilations are often needed, and endoscopic stricturotomy may offer better outcomes for selected patients with multi-segmental disease [31]C4[83]B2b.
| Procedure | Indication | Technique | Key Outcomes | Evidence Level |
|---|---|---|---|---|
| Endoscopic balloon dilation (EBD) | Short (<5 cm), fibrotic, accessible strictures | Through-the-scope balloon, 15-20 mm, 1-2 min inflation | Technical success >85%; 3-year surgery-free rate ~52%; perforation 2-4% [83]B2b | 2b (prospective cohort) |
| Endoscopic stricturotomy | Deep or multi-segmental strictures, often combined with surgery | Needle-knife or insulated-tip knife incision | Immediate success 100%; 18-month surgery-free rate 86% [31]C4 | 4 (small prospective cohort) |
| Chromoendoscopy with targeted biopsy | Surveillance for dysplasia in long-standing colitis | Spray 0.1% methylene blue or 0.3% indigo carmine; target abnormal areas | Improved dysplasia detection vs white-light; interval 1-3 years [86]D5 | 5 (expert opinion/guideline) |
| Capsule endoscopy | Diagnostic evaluation of small bowel (not therapeutic) | Swallowed capsule with camera | Identifies lesions in 20-30% of chronic abdominal pain; contraindicated if stricture suspected [80]B3b | 3b (retrospective cohort) |
Complications
- ▸VTE prophylaxis with enoxaparin 40 mg SC daily during hospitalization.
- ▸Screen for TB, HBV, HIV before starting biologics.
Strictures develop in 30-50% within 10 years; combined surgical-endoscopic stricturotomy effective [31]C4. Fistulas in up to 35%; risk factors: hypoalbuminemia, penetrating behavior [53]B3b. Malnutrition in 40-70% of hospitalized patients; screen for fat-soluble vitamin deficiencies (vitamin K deficiency in 30% after extensive resection) [3]A1c[90]C4. Osteoporosis in 15-20%; DXA after 3 months cumulative steroids [3]A1c. Thromboembolism: 2-3 fold increased VTE risk; prophylaxis with enoxaparin 40 mg SC daily during hospitalization [89]B2b. Infections: vedolizumab associated with 12% infection rate [87]B2b; ozanimod reduces T cells by 45%, risk of herpes zoster; screen for TB, HBV, HIV before biologics [88]A1a. Postoperative ileus in 10-20%; early enteral nutrition and chewing gum. Pain management: multimodal analgesia (acetaminophen, tramadol, gabapentin); avoid NSAIDs. Rehabilitation: early mobilization, target 25-30 kcal/kg/day and 1.2-1.5 g protein/kg/day [3]A1c.
Pearl: The most actionable complications in hospitalized Crohn patients are VTE (prevent with enoxaparin 40 mg daily), opportunistic infections (screen for TB and HBV before biologics), and malnutrition (target 25-30 kcal/kg/day with early enteral nutrition), each with a clear evidence-based intervention that reduces morbidity [3]A1c[87]B2b[89]B2b.
| Complication | Frequency | Prevention | Management |
|---|---|---|---|
| Pressure injury | 5-15% of hospitalized IBD patients | Turn every 2 hours, use pressure-relieving mattresses, assess Braden score daily | Stage-specific wound care; offload pressure; nutritional support [3]A1c |
| Catheter-associated UTI | 3-8% per catheter-day | Avoid indwelling catheters; remove by postoperative day 1 if possible | Urine culture; targeted antibiotics (e.g., nitrofurantoin 100 mg twice daily for 5 days) |
| Ventilator-associated pneumonia | 1-3% of intubated patients | Head-of-bed >30°, oral care with chlorhexidine, daily sedation interruption | Empiric broad-spectrum antibiotics (e.g., piperacillin-tazobactam 4.5 g IV every 6 hours) |
| Central line-associated bloodstream infection | 0.5-2 per 1000 catheter-days | Use subclavian site, chlorhexidine-impregnated dressings, daily line necessity review | Remove line; blood cultures; empiric vancomycin + antipseudomonal beta-lactam |
Prognosis & Natural History
- ▸50% develop stricture/fistula within 10 years; 70% require surgery.
- ▸Smoking cessation and early biologic therapy improve outcomes.
Relapsing-remitting course; within 10 years, ~50% develop stricturing or penetrating complication, ~70% require intestinal resection [73]A1a. Pre-biologic era: 10-year cumulative stricture risk 30-40%, fistula risk 15-25%. Once stricture forms, annual surgery risk ~10% [31]C4. Perianal fistulas recur in 30-40%; 5-year colectomy rate 25-30% [73]A1a. Mortality modestly increased (SMR 1.2-1.5) due to sepsis, postoperative complications, colorectal cancer [6]A1a. Relapse: 40-60% per year without maintenance; stopping 5-ASA increases relapse risk (RR 2.3) [72]A1a. Poor prognosis predictors: age <20 years, ileal involvement (HR 3.5 for stricture), perianal disease at presentation, active smoking (HR 1.8) [73]A1a. Impact of early therapy: higher adalimumab troughs increase endoscopic response by 40-50% [51]B2b; CDED induces remission in 80% of children [58]A1b; combined stricturotomy reduces re-intervention to 10% vs 25-30% with surgery alone [31]C4. Long-term: short bowel syndrome in 2-5%; colorectal cancer risk 2-4 fold after 8-10 years, cumulative incidence 8% at 30 years [6]A1a.
Pearl: The natural history of Crohn disease is defined by inexorable progression from inflammation to stenosis or fistula in the majority of patients; early, sustained biologic therapy with adequate trough concentrations and smoking cessation are the only interventions proven to flatten that trajectory [51]B2b[73]A1a.
| Predictor | Effect on Trajectory | Strength of Evidence |
|---|---|---|
| Ileal involvement | HR 3.5 for stricture within 10 years [43]C4 | 2b |
| Age <20 years at diagnosis | 2-fold risk of progression to complicated phenotype [65]D5 | 2b |
| Active smoking | HR 1.8 for postoperative relapse [73]A1a | 1a |
| Perianal disease at presentation | 40% fistula recurrence at 5 years [73]A1a | 2b |
| Anti-TNF trough <5 μg/mL | 40% lower odds of endoscopic remission at week 12 [51]B2b | 2b |
Special Populations & Prevention
- ▸EEN first-line in pediatrics; anti-TNF safe in pregnancy.
- ▸Vedolizumab preferred in elderly due to lower infection risk.
Pediatrics: 25% of new diagnoses; EEN or CDED first-line (80-85% remission) [65]D5. Biologic dosing weight-based; vedolizumab clearance predicts deep remission [27]B2b. Functional constipation common (20%) [34]C4. Pregnancy: maintain remission; anti-TNF safe, consider stopping around week 30-32 for infliximab [1]A1a. Methotrexate and thalidomide contraindicated. Cesarean delivery for perianal disease or ileal pouch. Biologics compatible with breastfeeding [64]B2b. Elderly (≥60): colonic-only disease more common; higher infection risk with anti-TNF; vedolizumab preferred [27]B2b. Vitamin D deficiency common; supplement to ≥75 nmol/L [32]B2b. Surgery carries higher mortality (4-6% at 90 days) [33]B3b. Immunocompromised: combination therapy with thiopurines increases lymphoma risk; annual skin cancer screening and zoster vaccination recommended. Screen for TB, HBV, HIV before biologics. Vedolizumab or ustekinumab may be safer in immunocompromised hosts.
Pearl: Biologic therapy for CD should generally be continued through pregnancy to control inflammation, with the exception of late-third-trimester anti-TNF cessation if desired, as disease activity, not drug exposure, is the primary driver of adverse pregnancy outcomes [1]A1a[64]B2b.
| Drug Class | Pregnancy Risk | Breastfeeding Safety | Action |
|---|---|---|---|
| Anti-TNF (infliximab, adalimumab) | Low; continue through 2nd/early 3rd trimester | Safe; negligible transfer | Consider stopping at ~30-32 wk gestation |
| Certolizumab | Minimal placental transfer; continue through all trimesters | Safe | Preferred anti-TNF if continuation desired |
| Vedolizumab | Low; continue when indicated | Likely safe | Gut-selective, growing data |
| Ustekinumab | Low; continue when indicated | Likely safe | Limited data but favored by some |
| Methotrexate | Contraindicated (teratogenic, abortifacient) | Contraindicated | Must stop ≥3 mo before conception |
| Corticosteroids | Use sparingly; increased cleft palate risk (1st tri), maternal hyperglycemia | Safe at moderate doses | Limit to acute flares |
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