Crohn's Disease

1. Overview

Crohn's disease is a chronic, relapsing-remitting inflammatory bowel disease characterised by transmural granulomatous inflammation that can affect any part of the gastrointestinal tract from mouth to anus. Unlike ulcerative colitis, Crohn's disease exhibits discontinuous "skip lesions" and has a predilection for the terminal ileum and proximal colon. The transmural nature of inflammation leads to characteristic complications including strictures, fistulae, and abscesses that distinguish it from other inflammatory bowel conditions. [1]

The disease follows an unpredictable course with periods of active inflammation alternating with remission. Approximately 50% of patients require surgical intervention within 10 years of diagnosis, and despite advances in medical therapy, the disease remains incurable. [2] The burden of Crohn's disease extends beyond gastrointestinal symptoms, with significant extraintestinal manifestations affecting the joints, skin, eyes, and hepatobiliary system, as well as profound impacts on quality of life, particularly in young adults during peak productive years. [3]

Management has evolved significantly over the past two decades with the introduction of biological therapies targeting specific inflammatory pathways. The current therapeutic paradigm involves early aggressive therapy in high-risk patients (top-down approach) versus conventional step-up therapy, with ongoing debate regarding optimal sequencing of treatments. Understanding disease phenotype, location, and behaviour according to the Montreal classification is essential for predicting prognosis and guiding treatment decisions. [4]

2. Epidemiology

Global Distribution

Crohn's disease shows marked geographical variation, with highest incidence rates in North America and Northern Europe (10-20 per 100,000 person-years) compared to lower rates in Asia, Africa, and South America (0.5-3 per 100,000 person-years). [5] However, incidence is rising rapidly in newly industrialised countries, suggesting environmental factors play a significant role in disease pathogenesis. The global prevalence is estimated at 3.2 million people, with prevalence rates of 100-300 per 100,000 in Western countries. [6]

Demographics

The disease exhibits a bimodal age distribution with a major peak between 15-30 years and a smaller peak between 50-70 years. [7] Unlike ulcerative colitis, Crohn's disease shows an equal or slightly higher incidence in females (female:male ratio approximately 1.1-1.3:1). [8] There are striking ethnic differences, with Ashkenazi Jewish populations having 2-4 times higher risk compared to non-Jewish Caucasians, while African-American populations show intermediate risk. [9]

Risk Factors

Genetic susceptibility: First-degree relatives have 10-15 times increased risk, with concordance rates in monozygotic twins of 50-60% compared to 10% in dizygotic twins, indicating strong genetic contribution. [10] Over 200 susceptibility loci have been identified through genome-wide association studies, with NOD2/CARD15, ATG16L1, and IRGM being among the most significant. [11]

Environmental factors: [12]

• Cigarette smoking increases risk 2-4 fold and is associated with more severe disease, earlier need for surgery, and post-operative recurrence
• Appendicectomy before age 20 may be protective (controversial)
• NSAID use may trigger flares in susceptible individuals
• Antibiotic exposure in childhood associated with increased risk
• Dietary factors including high intake of animal protein and omega-6 fatty acids
• Urbanisation and Western lifestyle strongly associated

Microbiome alterations: Patients demonstrate reduced bacterial diversity with decreased Firmicutes (particularly Faecalibacterium prausnitzii) and increased Proteobacteria (particularly adherent-invasive E. coli). [13]

Temporal Trends

Incidence has stabilised or slightly decreased in traditional high-incidence regions (North America, Northern Europe) since the 1990s, but continues to rise dramatically in newly industrialised countries in Asia, South America, and the Middle East. [14] The prevalence continues to increase globally as patients survive longer with improved therapies, creating a growing healthcare burden. Mortality is marginally increased compared to the general population (standardised mortality ratio 1.2-1.5), primarily due to complications, malignancy, and treatment-related adverse effects. [15]

3. Aetiology and Pathophysiology

Genetic Factors

Crohn's disease results from complex interactions between genetic susceptibility, environmental triggers, intestinal microbiota, and immune dysregulation. Over 200 genetic loci have been identified, collectively explaining approximately 20-30% of disease heritability. [16]

NOD2/CARD15 (Chromosome 16q12): The first and most significant susceptibility gene, encoding an intracellular pattern recognition receptor that detects bacterial peptidoglycans. Loss-of-function mutations impair bacterial sensing and clearance, particularly affecting Paneth cells in the ileum. Homozygous carriers have 20-40 times increased risk, though most carriers remain unaffected, indicating incomplete penetrance. The strong association of NOD2 variants with ileal disease explains the anatomical predilection. [17]

Autophagy genes (ATG16L1, IRGM, ULK1): These genes regulate autophagy, the cellular process of degrading and recycling cytoplasmic contents including intracellular bacteria. Dysfunction impairs bacterial clearance and antigen presentation, perpetuating inflammation. ATG16L1 T300A variant is present in 50% of European populations and confers 1.5-2 fold increased risk. [18]

IL23R pathway genes: Multiple variants in IL23R, JAK2, STAT3, and related genes affect Th17 cell differentiation and function, crucial in intestinal immunity. Protective IL23R variants reduce disease risk by 30-40%, representing potential therapeutic targets. [19]

Other pathways: Genes involved in epithelial barrier function (ECM1, CDH1), innate immune responses (TLR4, CARD9), and adaptive immunity (IL12B, IL10, PTPN2) collectively contribute to disease susceptibility.

Immunological Mechanisms

Innate immunity dysfunction: In Crohn's disease, impaired barrier function allows increased bacterial translocation. Defective Paneth cell function results in reduced antimicrobial peptide secretion (α-defensins). Pattern recognition receptors (NOD2, TLR4) show altered signalling, leading to inappropriate inflammatory responses to commensal bacteria.

Th1/Th17-mediated inflammation: Unlike Th2-predominant ulcerative colitis, Crohn's disease is characterised by Th1 and Th17 responses. [20]

• Th1 pathway: Activated by IL-12 and IL-18, producing IFN-γ, which promotes macrophage activation and tissue destruction. Predominates in established disease.
• Th17 pathway: Driven by IL-23 (from dendritic cells and macrophages), IL-6, and TGF-β. Th17 cells produce IL-17A, IL-17F, and IL-22, recruiting neutrophils and promoting transmural inflammation. Critical in disease initiation and maintenance.
• TNF-α amplification: Central pro-inflammatory cytokine produced by macrophages and T cells, driving inflammation through multiple pathways including NF-κB activation, promoting further cytokine production, endothelial activation, and tissue destruction.

Regulatory T cell dysfunction: Reduced numbers or impaired function of CD4+CD25+FoxP3+ Tregs fails to suppress excessive inflammatory responses. IL-10 and TGF-β production is insufficient to maintain immune tolerance to gut microbiota.

Neutrophil infiltration: Massive neutrophil recruitment leads to crypt abscesses, ulceration, and tissue damage. Neutrophil extracellular traps (NETs) perpetuate inflammation and may contribute to thrombotic complications.

Microbiome Dysbiosis

The intestinal microbiome in Crohn's disease shows characteristic alterations: [21]

• Reduced diversity (Shannon index decreased by 30-50%)
• Decreased beneficial bacteria: Faecalibacterium prausnitzii (anti-inflammatory, butyrate-producing), Roseburia, Clostridium clusters IV and XIVa
• Increased pathobionts: Adherent-invasive E. coli (AIEC) strains, Proteobacteria, Fusobacterium
• Reduced butyrate production affecting colonocyte energy metabolism
• Increased sulfate-reducing bacteria producing toxic H₂S

Whether dysbiosis is cause or consequence remains debated, though evidence suggests bidirectional relationships with persistent inflammation perpetuating microbial alterations.

Environmental Triggers

Smoking: Most significant modifiable risk factor, increasing risk 2-4 fold through multiple mechanisms including altered mucus production, increased intestinal permeability, microvascular changes, and enhanced Th1/Th17 responses. Smoking cessation improves outcomes equivalently to immunosuppressive therapy in some studies. [22]

Dietary factors: Western diet high in processed foods, animal proteins, and omega-6 fatty acids while low in fiber promotes dysbiosis and inflammation. Specific additives (emulsifiers, carrageenan) may disrupt mucus layer and increase permeability in susceptible individuals.

Infections: Certain enteric infections may trigger disease in genetically susceptible individuals through molecular mimicry or persistent alterations to microbiome and immune system.

Pathological Features

Macroscopic features:

• Skip lesions: Discontinuous areas of inflammation with normal intervening mucosa
• Deep linear/serpiginous ulcers creating "cobblestone" appearance
• Aphthous ulcers overlying lymphoid aggregates in early disease
• Transmural thickening with bowel wall rigidity
• Mesenteric fat wrapping ("creeping fat") around inflamed bowel
• Strictures from chronic inflammation and fibrosis
• Fistulae connecting bowel loops, bladder, vagina, or skin

Microscopic features:

• Transmural inflammation extending through all bowel wall layers
• Non-caseating epithelioid granulomas (present in only 30-50% of biopsies)
• Lymphoid aggregates and follicles
• Crypt architectural distortion and branching
• Goblet cell depletion
• Pyloric gland metaplasia in gastric involvement
• Neural hyperplasia and fibrosis in chronic disease

4. Clinical Presentation

Symptoms

The clinical presentation varies considerably depending on disease location, extent, behaviour, and presence of complications. The onset is typically insidious over weeks to months, though some patients present acutely.

Gastrointestinal symptoms: [23]

• Diarrhoea (80-90%): Usually non-bloody in isolated small bowel disease; may be bloody with colonic involvement. Nocturnal diarrhoea suggests organic disease. Frequency typically 3-6 times daily in moderate disease.
• Abdominal pain (70-80%): Cramping, colicky pain typically in right lower quadrant (ileal disease) or lower abdomen (colonic disease). Pain after eating suggests partial obstruction or active inflammation.
• Weight loss (60-70%): Results from reduced oral intake (fear of pain), malabsorption, protein-losing enteropathy, and increased metabolic demands. Loss of > 10% body weight indicates severe disease.
• Rectal bleeding (40-50%): More common with colonic involvement; isolated ileal disease rarely causes significant bleeding.
• Perianal symptoms (30-40%): Pain, discharge, skin tags, fissures, fistulae, or abscesses. May precede intestinal symptoms by months to years.

Constitutional symptoms: [24]

• Fatigue (60-80%): Multifactorial from anaemia, inflammation, malnutrition, and disease burden
• Fever (20-40%): Low-grade in active inflammation; high fever suggests complications (abscess, sepsis)
• Night sweats (10-20%): Indicates active inflammation

Malabsorption and deficiency: [25]

• Iron deficiency from chronic blood loss and inflammation-induced hepcidin elevation
• Vitamin B12 deficiency in ileal disease or post-ileal resection (> 60cm resection causes deficiency)
• Fat-soluble vitamin deficiencies (A, D, E, K) in extensive small bowel disease or cholestasis
• Protein-calorie malnutrition in severe, extensive disease
• Zinc, selenium, and micronutrient deficiencies

Signs

General inspection:

• Cachexia or weight loss
• Pallor from anaemia
• Clubbing (in chronic, active disease)
• Signs of malnutrition (muscle wasting, hair loss)
• Growth retardation in paediatric patients
• Peripheral oedema (hypoalbuminaemia, protein-losing enteropathy)

Abdominal examination: [26]

• Tenderness typically in right iliac fossa (terminal ileal disease)
• Palpable inflammatory mass (phlegmon) or abscess
• Distension (obstruction or toxic megacolon)
• Surgical scars from previous resections
• Abdominal wall fistulae (rare)
• High-pitched bowel sounds (partial obstruction) or absent sounds (ileus, perforation)

Perianal examination: (Essential in all patients)

• Skin tags (firm, oedematous, not typical haemorrhoidal tags)
• Anal fissures (often lateral rather than posterior)
• External fistula openings
• Perianal abscesses
• Anal stenosis from chronic inflammation

Disease Phenotype: Montreal Classification

The Montreal classification categorises Crohn's disease by age at diagnosis, location, and behaviour, with significant prognostic and therapeutic implications. [27]

Age at diagnosis (A):

• A1: less than 16 years (typically more extensive and aggressive)
• A2: 17-40 years (commonest presentation)
• A3: > 40 years (may have milder course)

Location (L):

• L1: Terminal ileum ± limited caecal disease (30-40%) - "classical" Crohn's
• L2: Colonic only (20-30%) - can mimic UC, termed "Crohn's colitis"
• L3: Ileocolonic (40-50%) - commonest pattern overall
• L4: Upper GI (modifier) - isolated upper GI disease rare (less than 5%); add modifier to L1-L3 if present

Behaviour (B):

• B1: Non-stricturing, non-penetrating (inflammatory) (60-70% at diagnosis)
• B2: Stricturing (fibrostenotic) (15-20% at diagnosis; increases to 30-40% over time)
• B3: Penetrating (fistulising) (10-15% at diagnosis; increases to 20-30% over time)
• p: Perianal disease modifier (add to any B category if present)

Natural history: Disease behaviour progresses over time, with only ~40% remaining B1 at 10 years. Transition from B1→B2 or B1→B3 occurs in 50-60% of patients over 10-20 years, representing structural damage accumulation (bowel damage progression). [28]

Phenotype-Specific Presentations

Inflammatory (B1): Responds well to medical therapy. Symptoms include diarrhoea, abdominal pain, and weight loss without obstructive symptoms or fistulae. May develop fevers and constitutional symptoms during flares. Treatment focuses on inducing and maintaining remission.

Stricturing (B2): Develops from chronic inflammation and fibrosis. Presents with:

• Intermittent obstructive symptoms (post-prandial cramping pain, bloating, nausea)
• "Food fear" leading to dietary restriction and weight loss
• Possible acute small bowel obstruction requiring emergency intervention
• May have proximal bowel dilatation on imaging
• Less responsive to anti-inflammatory therapy; often requires endoscopic balloon dilatation or surgical stricturoplasty/resection

Penetrating (B3): Results from transmural inflammation creating fistulous tracts. Presentations include:

• Entero-enteric fistulae (often asymptomatic or causing malabsorption)
• Entero-cutaneous fistulae (skin drainage, often post-operative)
• Entero-vesical fistulae (pneumaturia, fecaluria, recurrent UTIs)
• Entero-vaginal fistulae (passage of gas/faeces per vagina)
• Intra-abdominal abscesses (fever, localised pain, tender mass)
• Perianal fistulae and abscesses (pain, discharge, recurrent infections) Treatment requires combination of antibiotics, immunosuppression/biologics, and often surgical drainage or resection.

Perianal disease: Occurs in 30-40% of patients, more common with rectal involvement. [29]

• Simple fistulae: Low intersphincteric or trans-sphincteric
• Complex fistulae: High trans-sphincteric, suprasphincteric, extrasphincteric, or multiple tracts
• Classification by Parks system modified for Crohn's
• MRI pelvis essential for mapping anatomy before treatment
• Management: Antibiotics + biologics (anti-TNF) ± surgical intervention (seton drainage, advancement flap, ligation of intersphincteric fistula tract)

Extraintestinal Manifestations

Occur in 25-40% of patients and may precede, coincide with, or follow intestinal symptoms. [30]

Musculoskeletal (15-20%):

• Type 1 peripheral arthropathy (pauciarticular, large joints): Parallels intestinal disease activity
• Type 2 peripheral arthropathy (polyarticular, small joints): Independent of bowel activity
• Axial arthropathy/ankylosing spondylitis (3-5%): Independent; HLA-B27 associated
• Sacroiliitis (10-15%): Often asymptomatic

Dermatological (10-15%):

• Erythema nodosum (tender, raised, red nodules on shins): Parallels disease activity
• Pyoderma gangrenosum (painful ulcerating lesions): Independent; may worsen despite bowel remission
• Oral aphthous ulcers (20-30%): Often parallel disease activity
• Metastatic Crohn's disease (rare): Cutaneous granulomas at sites distant from GI tract

Ocular (3-10%):

• Episcleritis (painless, red eye): Parallels disease activity
• Uveitis (painful, photophobia, blurred vision): Independent; requires urgent ophthalmology referral
• Scleritis (rare but severe)

Hepatobiliary (3-5%):

• Primary sclerosing cholangitis (PSC): More common in UC but occurs in Crohn's colitis
• Cholelithiasis: Due to ileal disease/resection causing bile salt malabsorption
• Fatty liver: From malnutrition or medications

Renal (5-10%):

• Nephrolithiasis (calcium oxalate stones from fat malabsorption increasing oxalate absorption; uric acid stones from chronic diarrhoea)
• Ureteric obstruction from adjacent inflammation
• Amyloidosis (rare, in chronic untreated disease)

Thromboembolic (1-8%):

• Deep vein thrombosis/pulmonary embolism: Risk increased 3-4 fold, particularly during active disease
• Mechanisms: Inflammation-induced hypercoagulability, thrombocytosis, immobility, central line use

5. Differential Diagnosis

Distinguishing Crohn's disease from other causes of chronic diarrhoea and abdominal pain requires systematic evaluation. The differential varies by predominant disease location and presentation pattern.

Inflammatory Bowel Disease

Ulcerative Colitis: [31]

Indeterminate colitis: 10-15% of IBD cases cannot be definitively classified at presentation, particularly on limited mucosal biopsies. Serial evaluation, cross-sectional imaging, and clinical course usually allow classification.

Infectious Enterocolitis

Intestinal Tuberculosis: [32] Critical differential in endemic areas and immunosuppressed patients. Features favouring TB:

• Ileocaecal involvement with caecal nodularity and distortion
• Positive interferon-gamma release assay (IGRA) or tuberculin skin test
• Chest X-ray evidence of TB (40-50% have concurrent pulmonary TB)
• Short duration of symptoms (less than 12 months)
• Night sweats, weight loss out of proportion to diarrhoea
• Transverse ulcers (Crohn's has longitudinal ulcers)
• Fewer than 4 ulcers on colonoscopy
• Caseating granulomas on histology (though may be non-caseating)
• Positive culture or PCR for Mycobacterium tuberculosis

Trial of anti-TB therapy may be necessary if diagnosis uncertain; lack of response after 2-3 months suggests Crohn's disease.

Yersinia enterocolitica: Causes acute terminal ileitis with right iliac fossa pain mimicking appendicitis or Crohn's. Serology or stool culture diagnostic. Usually self-limiting over 1-3 weeks.

Campylobacter, Salmonella, Shigella: Cause acute self-limiting colitis. Stool culture diagnostic.

Cytomegalovirus (CMV) colitis: In immunosuppressed patients or severe UC/Crohn's flares. Colonoscopy with biopsies showing CMV inclusion bodies; CMV PCR in tissue. Requires ganciclovir therapy.

Clostridium difficile: Always exclude in flares, particularly in hospitalised patients or those on antibiotics. Stool toxin assay diagnostic.

Ischaemic Colitis

Typically in elderly patients with vascular risk factors. [33]

• Sudden onset bloody diarrhoea with abdominal pain
• "Watershed" areas affected (splenic flexure, sigmoid)
• Thumbprinting on CT (submucosal oedema/haemorrhage)
• Usually resolves with supportive care over 1-2 weeks
• Chronic stricture may develop

Malignancy

Colorectal carcinoma: Presents with change in bowel habit, bleeding, weight loss. Older age group typically (> 50 years). Colonoscopy with biopsy diagnostic.

Lymphoma: Small bowel lymphoma (particularly enteropathy-associated T-cell lymphoma in coeliac disease) can mimic Crohn's. CT shows focal bowel wall thickening with lymphadenopathy.

Carcinoid tumour: May cause diarrhoea, flushing, abdominal pain. 24-hour urinary 5-HIAA elevated.

Other Conditions

Coeliac disease: Diarrhoea, weight loss, malabsorption. Serology (tissue transglutaminase antibodies) and duodenal biopsy diagnostic.

Irritable bowel syndrome (IBS): Functional disorder with altered bowel habit and abdominal pain but no objective inflammation. Normal investigations including faecal calprotectin. Diagnosis of exclusion.

Small intestinal bacterial overgrowth (SIBO): Can occur secondary to strictures in Crohn's or be primary. Glucose/lactulose breath testing diagnostic.

Radiation enteritis: History of pelvic radiotherapy. Chronic diarrhoea, bleeding, strictures. Endoscopy shows characteristic telangiectasia.

Medication-induced enteropathy: NSAIDs cause small bowel ulceration and strictures mimicking Crohn's. Detailed drug history essential.

Behçet's disease: Multisystem vasculitis with oral/genital ulcers, ocular inflammation, and intestinal ulceration (particularly ileocaecal region). More common in Mediterranean and Asian populations.

Diverticulitis: Left-sided abdominal pain, fever, altered bowel habit. CT shows sigmoid wall thickening with pericolic fat stranding. Usually in older patients.

6. Investigations

Initial Assessment

Blood tests:

• Full blood count: [34]
  • Anaemia (normocytic from chronic disease, microcytic from iron deficiency, macrocytic from B12/folate deficiency)
  • Leucocytosis (active inflammation or abscess)
  • Thrombocytosis (correlates with disease activity)
• Inflammatory markers:
  • CRP > 5 mg/L in active disease (correlates with endoscopic inflammation)
  • ESR elevated but less specific
  • Normal CRP doesn't exclude active disease (20-30% have normal CRP despite inflammation)
• Liver function tests: Hypoalbuminaemia indicates active disease, malnutrition, or protein-losing enteropathy
• Renal function and electrolytes: Dehydration, pre-renal impairment
• Nutritional markers: Iron studies, B12, folate, vitamin D, zinc

Stool studies: [35]

• Faecal calprotectin: Neutrophil protein correlating with intestinal inflammation
  • less than 50 μg/g: Excludes IBD (NPV 90-95%)
  • 50-200 μg/g: Indeterminate (repeat or further investigation)

  • 200 μg/g: Suggests IBD (PPV 70-80%)

  • Useful for distinguishing IBD from IBS
  • "Monitoring: Levels correlate with disease activity and endoscopic healing"
• Faecal lactoferrin: Alternative inflammatory marker, similar performance
• Microscopy, culture, and sensitivity (MC&S): Exclude bacterial pathogens
• Clostridium difficile toxin: Particularly in flares or recent antibiotic exposure
• Ova, cysts, and parasites: In travellers or endemic areas
• Tuberculosis PCR: In high-risk populations

Endoscopic Evaluation

Ileocolonoscopy with biopsies: [36] Gold standard investigation providing direct visualisation and tissue diagnosis.

Endoscopic findings:

• Aphthous ulcers (early disease): Small (2-3mm) ulcers over lymphoid follicles
• Deep linear or serpiginous ulcers creating "cobblestone" appearance
• Skip lesions with normal intervening mucosa
• Rectal sparing (50% of cases)
• Terminal ileal involvement (80% of cases with ileocolonic disease)
• Strictures (may be difficult/impossible to traverse)

Histological findings:

• Focal chronic inflammation (patchy distribution)
• Crypt architectural distortion
• Transmural inflammation (not seen on mucosal biopsies but inferred from fissuring ulceration)
• Non-caseating epithelioid granulomas (30-50% of biopsies): Highly specific when present
• Increased lymphocytes and plasma cells in lamina propria
• Goblet cell depletion

Biopsy protocol: Multiple biopsies (≥2 per segment) from terminal ileum, caecum, ascending colon, transverse colon, descending colon, sigmoid, and rectum, including normal-appearing mucosa to document skip lesions.

Endoscopic scoring: [37]

• Simple Endoscopic Score for Crohn's Disease (SES-CD): Assesses ulcer size, ulcerated and affected surface, presence of narrowing in 5 bowel segments (ileum, right, transverse, left, rectum). Score 0-3 per parameter per segment. Total score 0-60.
  • "Remission: less than 3"
  • "Mild: 3-6"
  • "Moderate: 7-15"
  • "Severe: > 15"
• Crohn's Disease Endoscopic Index of Severity (CDEIS): More complex, research use

Upper GI endoscopy: Indicated if upper GI symptoms present or in young patients (less than 16 years) where upper GI involvement is more common (30-40%). Biopsies even from macroscopically normal mucosa may show focal gastritis or granulomas.

Capsule endoscopy: [38]

• Indications: Suspected small bowel Crohn's with negative ileocolonoscopy, particularly in patients with symptoms, raised inflammatory markers, or positive faecal calprotectin
• Contraindications: Known or suspected stricture (risk of capsule retention 5-15% in established Crohn's)
• Patency capsule should precede capsule endoscopy in suspected Crohn's to assess for strictures
• Findings: Ulceration, erosions, erythema, strictures, polyps
• Lewis score for quantifying inflammation severity
• Diagnostic yield 40-70% in suspected Crohn's

Cross-Sectional Imaging

MR Enterography (MRE): [39] Preferred modality for small bowel assessment; avoids radiation, excellent soft tissue contrast.

Protocol: Enteric contrast (polyethylene glycol or mannitol solution) to distend small bowel, IV contrast enhancement, multiple sequences.

Findings suggesting active Crohn's:

• Bowel wall thickening (> 3mm; active disease typically > 4-5mm)
• Mural stratification (layered appearance from submucosal oedema)
• Mural hyperenhancement on T1 post-contrast sequences
• Increased T2 signal in bowel wall (oedema)
• Mesenteric fat stranding and hypervascularity ("comb sign")
• Enlarged mesenteric lymph nodes (> 10mm short axis)
• Strictures with proximal dilatation

Complications detected:

• Fistulae (entero-enteric, entero-cutaneous, entero-vesical, entero-vaginal)
• Abscesses (T2 hyperintense fluid collections with rim enhancement)
• Fibrotic strictures (smooth narrowing without marked enhancement or oedema)
• Penetration/perforation

Advantages over CT enterography: No radiation (critical in young patients requiring serial imaging), better soft tissue contrast for fistula/abscess detection, functional cine sequences to assess stricture significance.

MRI Pelvis: Essential for perianal disease mapping before surgical intervention. Shows fistula tracks, abscesses, relation to sphincter complex (Parks classification). [40]

CT Enterography: Alternative when MRI contraindicated or unavailable. Radiation dose 8-15 mSv per study; cumulative radiation in Crohn's patients averages 20-30 mSv over lifetime. Preferentially used in acute presentations where speed is essential.

Ultrasound: Operator-dependent but non-invasive, no radiation. Can assess bowel wall thickness, vascularity (Doppler), complications. Used for monitoring in experienced centres.

Serological Markers

ASCA (Anti-Saccharomyces cerevisiae antibodies): [41]

• Positive in 50-60% of Crohn's disease vs 10-15% of UC and 5% controls
• Specificity 85-95% for Crohn's vs UC
• Associated with fibrostenotic disease, small bowel involvement, need for surgery
• Limited sensitivity precludes use as diagnostic test

pANCA (Perinuclear anti-neutrophil cytoplasmic antibodies):

• Positive in 60-70% of UC vs 10-20% of Crohn's
• ASCA+/pANCA- pattern supports Crohn's; ASCA-/pANCA+ supports UC

Limited clinical utility: Serological markers are not routinely used for diagnosis but may help differentiate indeterminate colitis.

Monitoring Investigations

Faecal calprotectin: Serial measurements correlate with mucosal healing and predict relapse. Levels > 250 μg/g predict relapse within 12 months with sensitivity 70-80%. [42]

Therapeutic drug monitoring: For patients on biologics (infliximab, adalimumab):

• Trough drug levels and anti-drug antibodies guide dose optimization
• Infliximab target trough > 5 μg/mL for maintenance; higher levels (> 10 μg/mL) for mucosal healing
• Anti-drug antibodies predict loss of response and infusion reactions

Repeat endoscopy: Assess mucosal healing (treatment target), evaluate strictures, screen for dysplasia/malignancy in long-standing colonic disease.

Repeat MRE: Monitor response to therapy, particularly in fibrostenotic disease where symptoms may not reflect inflammation.

7. Classification and Staging

Montreal Classification

As described in Section 4, the Montreal classification stratifies by:

• Age at diagnosis (A1/A2/A3)
• Location (L1/L2/L3/L4)
• Behaviour (B1/B2/B3, with perianal modifier 'p')

Disease Activity Indices

Harvey-Bradshaw Index (HBI): [43] Simplified clinical activity index for Crohn's disease based on 5 parameters:

1. General well-being (0-4)
2. Abdominal pain (0-3)
3. Number of liquid stools per day
4. Abdominal mass (0-3)
5. Complications (1 point each): arthralgia, uveitis, erythema nodosum, aphthous ulcers, pyoderma gangrenosum, anal fissure, new fistula, abscess

Interpretation:

• Remission: less than 5
• Mild disease: 5-7
• Moderate disease: 8-16
• Severe disease: > 16

Crohn's Disease Activity Index (CDAI): More complex, includes 8 variables over 7 days. Research use primarily.

• Remission: less than 150
• Mild-moderate: 150-220
• Moderate-severe: 220-450
• Severe: > 450

Endoscopic Activity

SES-CD (Simple Endoscopic Score): Described in Section 6. Mucosal healing (SES-CD 0-2) is therapeutic target associated with improved long-term outcomes including reduced hospitalisation, surgery, and disability.

Severity Classification

Mild-moderate disease:

• Ambulatory, able to tolerate oral intake
• No dehydration, fever, abdominal tenderness, mass, obstruction
• Weight loss less than 10%
• HBI 5-16 or CDAI 150-450

Moderate-severe disease:

• Failed mild-moderate treatment
• Prominent symptoms: fever, weight loss > 10%, abdominal pain/tenderness
• Intermittent nausea/vomiting
• Anaemia
• HBI > 16 or CDAI > 450

Severe-fulminant disease:

• Persisting symptoms despite optimal medical therapy
• High fever, persistent vomiting, evidence of obstruction, peritonism
• Cachexia
• Abscess requiring drainage
• May require hospitalization and IV therapy/surgical intervention

8. Management

The management of Crohn's disease is individualised based on disease location, extent, behaviour, severity, prior treatment response, and patient factors. The overarching goal is to achieve and maintain deep remission (clinical remission + endoscopic healing + normalisation of biomarkers) while minimising treatment toxicity. [44]

Induction of Remission

Mild-Moderate Disease (Ileocaecal)

Budesonide: [45]

• First-line for mild-moderate ileocaecal disease (L1, L3)
• Dose: 9 mg once daily for 8 weeks, then taper (6 mg for 2 weeks, 3 mg for 2 weeks)
• Controlled ileal release with 90% first-pass hepatic metabolism, minimising systemic effects
• Remission induction: 50-60% vs 20% placebo
• Fewer systemic side effects than prednisolone (reduced HPA suppression, less bone loss)
• Not effective for extensive colonic disease

5-Aminosalicylates (5-ASA): [46]

• Limited efficacy in Crohn's disease (unlike UC)
• Meta-analyses show marginal benefit: remission rates 43% vs 38% placebo (NNT 14)
• May be used for mild colonic disease but biologics/immunomodulators preferred
• Dose: Mesalazine 2.4-4.8 g/day in divided doses
• Generally safe but less effective than other options

Moderate-Severe Disease

Systemic corticosteroids: [47]

• Prednisolone 40 mg once daily (or 0.75-1 mg/kg to max 60 mg) orally
• IV hydrocortisone 100 mg QDS or methylprednisolone 40-60 mg daily if unable to tolerate oral
• Duration: 4-8 weeks, then taper by 5 mg/week
• Remission rates: 70-80% at 8 weeks
• NOT suitable for maintenance (tachyphylaxis, toxicity)
• Steroid dependency (inability to reduce below prednisolone 10 mg or budesonide 3 mg within 3 months of starting, or relapse within 3 months of stopping) indicates need for escalation to immunomodulators or biologics

Nutritional therapy (Exclusive Enteral Nutrition, EEN): [48]

• First-line in paediatric Crohn's disease
• Polymeric or elemental formula as sole nutrition for 6-8 weeks
• Efficacy comparable to corticosteroids in children (remission 60-80%)
• Advantages: Promotes growth, mucosal healing, avoids steroid toxicity
• Less effective and poorly tolerated in adults
• Mechanism: Alters microbiome, reduces antigenic load, provides nutrition

Biologic and Advanced Therapies

Increasingly used as first-line therapy in moderate-severe disease, particularly in patients with poor prognostic factors (young age, extensive disease, deep ulceration, perianal disease, early need for steroids). [49]

Anti-TNF agents:

Infliximab (chimeric mouse-human IgG1 monoclonal antibody): [50]

• Mechanism: Binds and neutralises soluble and membrane-bound TNF-α, induces apoptosis of activated T cells
• Dosing: IV infusion 5 mg/kg at weeks 0, 2, 6, then every 8 weeks maintenance
• Induction remission: 58% vs 17% placebo (ACCENT I trial)
• Mucosal healing: 44% vs 18% at week 54
• Perianal fistula closure: 69% vs 13% (ACCENT II trial)
• Steroid-free remission at 1 year: 44% with scheduled maintenance vs 21% episodic
• Loss of response: Occurs in 30-50% over time due to immunogenicity (anti-drug antibodies)
• Combination with azathioprine/methotrexate reduces immunogenicity and improves outcomes

Adalimumab (fully human IgG1 monoclonal antibody): [51]

• Mechanism: Similar to infliximab
• Dosing: SC injection 160 mg week 0, 80 mg week 2, then 40 mg every 2 weeks
• Remission rates: 36-58% at week 26 vs 13% placebo (CLASSIC I/II trials)
• Perianal fistula healing: 30% complete closure vs 13% placebo
• Advantages: Subcutaneous, self-administered, fully human (lower immunogenicity)
• Biosimilars available (reduced cost)

Certolizumab pegol (PEGylated Fc-free anti-TNF): [52]

• Humanised Fab fragment conjugated to polyethylene glycol
• Dosing: SC 400 mg weeks 0, 2, 4, then 400 mg every 4 weeks (or 200 mg every 2 weeks)
• Remission: 37-48% vs 27% placebo
• No placental transfer (lacks Fc portion): May be preferred in pregnancy
• Similar efficacy to other anti-TNFs

Golimumab: [53]

• Fully human anti-TNF
• Dosing: SC 200 mg week 0, 100 mg week 2, then 100 mg every 4 weeks (dose may be increased to 200 mg every 4 weeks if inadequate response)
• Approved for moderate-severe UC; some evidence in Crohn's disease

Anti-TNF summary:

• Primary non-response: 20-40% (lack of response to induction therapy)
• Secondary loss of response: 30-50% over 12 months
• Predictors of response: Higher drug levels, combination with immunomodulator, non-smoker, younger age, shorter disease duration
• Therapeutic drug monitoring guides optimization

Vedolizumab (anti-α4β7 integrin): [54]

• Mechanism: Gut-selective lymphocyte trafficking inhibition; blocks α4β7 integrin on T cells from binding MAdCAM-1 on intestinal endothelium
• Dosing: IV 300 mg at weeks 0, 2, 6, then every 8 weeks
• Remission: 39% vs 22% placebo at week 52 (GEMINI 2 trial)
• Slower onset of action compared to anti-TNFs (may take 12-14 weeks)
• Excellent safety profile: Gut-selective, no increased infection risk, no PML (unlike natalizumab)
• Preferred in patients with infection concerns, history of malignancy, or older age
• SC formulation now available

Ustekinumab (anti-IL12/23 p40 subunit): [55]

• Mechanism: Blocks IL-12 and IL-23, inhibiting Th1 and Th17 differentiation
• Dosing: IV weight-based induction (260 mg if less than 55 kg, 390 mg if 55-85 kg, 520 mg if > 85 kg), then SC 90 mg every 8 weeks (can intensify to every 4 weeks)
• Remission: 53% vs 36% placebo at week 44 (UNITI trials)
• Effective in anti-TNF experienced patients
• Favourable safety profile
• Useful alternative when anti-TNFs fail or contraindicated

JAK inhibitors:

Upadacitinib (selective JAK1 inhibitor): [56]

• Oral small molecule; dose 45 mg once daily for induction (12 weeks), then 15-30 mg once daily maintenance
• Remission: 49% vs 29% placebo at week 52
• Advantages: Oral administration, rapid onset
• Monitoring: Increased infection risk (particularly herpes zoster - consider vaccination), lipid abnormalities, thrombosis risk
• Not first-line in most guidelines; reserved for refractory disease

Maintenance of Remission

Thiopurines: [57]

• Azathioprine: 2-2.5 mg/kg/day (typically 100-200 mg daily)
• 6-Mercaptopurine: 1-1.5 mg/kg/day (active metabolite of azathioprine)
• Mechanism: Purine analogue; inhibits T cell proliferation
• Onset: 8-16 weeks to achieve effect
• Efficacy: Maintains remission in 60-70% at 1 year
• Pre-treatment: Check TPMT (thiopurine methyltransferase) activity
  • "Normal TPMT: Standard dose"
  • "Intermediate TPMT (heterozygous, 10% population): Reduce dose by 50%"
  • "Absent TPMT (homozygous, 0.3%): Absolute contraindication (life-threatening myelosuppression)"
• Monitoring: FBC and LFTs every 2 weeks for 2 months, then monthly for 3 months, then 3-monthly
• Side effects: Bone marrow suppression (5-10%), hepatotoxicity (5%), pancreatitis (3-5%, idiosyncratic, necessitates discontinuation), increased infection risk, lymphoma risk (4-fold increase but absolute risk low ~1 in 1000)
• Use as monotherapy for steroid-sparing or in combination with anti-TNF for improved outcomes

Methotrexate: [58]

• Dose: 15-25 mg once weekly SC or IM (oral poorly absorbed)
• Remission maintenance: 65% at 40 weeks vs 39% placebo
• Alternative to thiopurines if intolerant
• Requires folate supplementation (5 mg weekly, not on same day as methotrexate)
• Monitoring: FBC and LFTs every 2-4 weeks initially, then 2-3 monthly
• Contraindications: Pregnancy (teratogenic), significant liver disease, alcohol excess
• Side effects: Nausea, hepatotoxicity, bone marrow suppression, pneumonitis (rare but serious)

Biologic maintenance:

• Continue induction biologic at standard maintenance intervals
• Combination therapy (biologic + immunomodulator) superior to monotherapy for anti-TNF agents: Reduced immunogenicity, higher drug levels, better outcomes
• SONIC trial: Infliximab + azathioprine vs infliximab monotherapy: Steroid-free remission 57% vs 44%, mucosal healing 44% vs 30% [59]
• Vedolizumab and ustekinumab less benefit from combination therapy

Treatment Strategy: Step-Up vs Top-Down

Conventional step-up: [60]

• Sequential escalation: 5-ASA/budesonide → steroids → immunomodulators → biologics
• Advantages: Exposes fewer patients to potentially toxic therapies, cost-effective
• Disadvantages: Delayed disease control, cumulative bowel damage, higher surgery rates

Accelerated step-up:

• Early introduction of immunomodulators
• Prompter escalation to biologics if inadequate response

Top-down: [61]

• Early use of biologics ± immunomodulators in newly diagnosed patients with poor prognostic features
• REACT trial: Early combined immunosuppression reduced complications (hospitalisation, surgery) vs conventional care: 30.9% vs 41.5% (HR 0.73)
• Rationale: "Window of opportunity"
• early effective treatment prevents irreversible structural damage
• Poor prognostic factors indicating top-down approach:
  • Young age at diagnosis (less than 40 years, particularly less than 25)
  • Extensive small bowel disease
  • Deep ulceration on endoscopy
  • Perianal disease
  • Stricturing or penetrating behaviour at diagnosis
  • Early need for corticosteroids
  • Severe endoscopic lesions (SES-CD > 15)

Current paradigm: Individualised treatment based on risk stratification. High-risk patients benefit from early aggressive therapy; low-risk patients may be managed with conventional step-up approach.

Specific Situations

Perianal Disease

Complex perianal Crohn's requires combined medical and surgical management: [62]

Medical:

• Antibiotics: Metronidazole 400 mg TDS and/or ciprofloxacin 500 mg BD for 6-12 weeks
• Anti-TNF therapy: Most effective medical treatment; induces fistula closure in 30-50%
• Thiopurines: Adjunctive role
• Tacrolimus: Topical or oral in refractory cases

Surgical:

• Examination under anaesthesia (EUA): Assess anatomy, drain abscesses
• Seton drainage: Non-cutting loose setons maintain drainage, prevent abscess recurrence
• Advancement flaps: For simple fistulae with healed rectal disease
• LIFT procedure (Ligation of Intersphincteric Fistula Tract): Success rates 60-70%
• Proctectomy: Last resort for severe uncontrolled perianal disease with rectal involvement

MRI pelvis before surgical intervention to map fistula anatomy and identify abscesses.

Stricturing Disease

Inflammatory strictures: May respond to anti-inflammatory therapy (biologics). Trial of medical therapy for 3-6 months.

Fibrotic strictures: Require intervention:

• Endoscopic balloon dilatation: [63]
  • Suitable for short (less than 4 cm), anastomotic strictures
  • "Success: 75-85% technical success, symptom improvement in 70%"
  • "Complication: Perforation 2-5%"
  • May require repeat dilatations
• Surgical resection or stricturoplasty:
  • "Stricturoplasty: Preserves bowel length, suitable for short strictures"
  • "Resection: For long, complex, or malignant strictures"
  • "Indications: Failed medical/endoscopic therapy, complications, high-grade obstruction"

Penetrating Disease (Fistulae, Abscesses)

Abscesses: [64]

• Require drainage (percutaneous or surgical) before optimizing medical therapy
• Antibiotics alone insufficient; source control mandatory
• Anti-TNF therapy should be withheld/delayed until abscess drained to avoid septic complications

Entero-cutaneous fistulae:

• Often post-operative
• Optimize nutrition (may require TPN if high output)
• Treat underlying disease with biologics ± immunomodulators
• Surgical resection if medically refractory

Entero-vesical fistulae:

• Pneumaturia, fecaluria, recurrent UTIs
• Cystoscopy may show oedema/inflammation at fistula site
• CT or MRI to identify fistula and inflamed bowel segment
• Surgical resection usually required

Entero-vaginal fistulae:

• Passage of gas or stool per vagina
• Examination under anaesthesia, MRI pelvis
• Medical therapy (anti-TNF) + surgery if refractory

Nutritional Support

Indications: [65]

• Malnutrition (BMI less than 18.5, weight loss > 10%, albumin less than 30 g/L)
• Extensive small bowel disease or resection
• Stricturing disease limiting oral intake
• High fistula output
• Pre-operative optimization

Enteral nutrition: Preferred over TPN if gut functional; polymeric or peptide-based formulas

Total parenteral nutrition (TPN):

• Severe malnutrition with non-functioning gut
• High-output fistulae (> 500 mL/day)
• Short bowel syndrome
• Allows bowel rest and fistula closure in selected cases

Micronutrient replacement:

• Iron (IV if oral intolerant or inadequate response): Target ferritin > 100 μg/L
• Vitamin B12 (IM 1 mg every 3 months) in ileal disease/resection > 60 cm
• Vitamin D (loading 300,000 IU then maintenance): Target > 75 nmol/L
• Folate, calcium, zinc as indicated

Surgery

Surgery does not cure Crohn's disease but treats complications and relieves symptoms. 50-70% of patients require surgery within 10 years of diagnosis. [66]

Indications: [67]

• Failed medical therapy with severe symptoms
• Complications:
  • Strictures causing obstruction
  • Abscesses not amenable to percutaneous drainage
  • Perforation
  • Fistulae (entero-cutaneous, entero-vesical, entero-vaginal)
  • Severe haemorrhage (rare)
  • Toxic megacolon (rare in Crohn's)
  • Dysplasia or malignancy
• Growth retardation in children despite optimal medical therapy

Surgical principles:

• Conservative resection: Minimise bowel length removed (resect macroscopically diseased bowel with minimal margins)
• Stricturoplasty for multiple strictures to preserve bowel length
• Avoid diverting stomas if possible (poor outcomes in Crohn's)
• Address perianal disease before restorative procedures

Common procedures:

• Ileocaecal resection: Most common operation for terminal ileal disease; primary anastomosis
• Segmental small bowel resection: For localised disease
• Stricturoplasty: Heineke-Mikulicz (short strictures less than 10 cm) or Finney/Jaboulay (longer strictures); preserves bowel length
• Subtotal colectomy with ileorectal anastomosis: Extensive colonic Crohn's with rectal sparing
• Proctocolectomy with permanent ileostomy: Severe colonic and rectal disease; last resort
• Perianal procedures: Seton insertion, fistulotomy (rarely appropriate in Crohn's), advancement flaps, LIFT

Post-operative recurrence: [68]

• Endoscopic recurrence: 70-80% at 1 year post-resection (Rutgeerts score)
• Clinical recurrence: 20-30% at 5 years, 50% at 10 years
• Risk factors: Smoking, penetrating disease, perforating presentation, multiple resections, extensive disease

Prevention of recurrence:

• Smoking cessation (most important modifiable factor)
• Prophylactic therapy:
  • "Anti-TNF therapy: Most effective (particularly high-risk patients)"
  • "Thiopurines: Moderate efficacy"
  • "Metronidazole: Short-term benefit (3-12 months)"
  • 5-ASA: Limited efficacy, not recommended
• Endoscopic surveillance at 6-12 months post-resection to guide therapy escalation

Monitoring and Treatment Targets

Treat-to-target approach: [69]

• Short-term targets: Clinical remission (HBI less than 5), biomarker normalisation (CRP less than 5 mg/L, faecal calprotectin less than 250 μg/g)
• Long-term target: Mucosal healing (endoscopic remission)
• Transmural healing (MRE showing resolution of inflammation) increasingly recognised as optimal target

Monitoring:

• Clinical assessment: Symptoms, weight, abdominal examination every 3-6 months
• Biomarkers: CRP, faecal calprotectin every 3-6 months
• Therapeutic drug monitoring: For patients on biologics, particularly if loss of response
• Endoscopy: 6-12 months after treatment initiation, then as clinically indicated
• MRE: Small bowel disease monitoring, particularly if endoscopy incomplete
• Bone density (DEXA): Baseline and every 2 years in high-risk patients (prolonged steroid use, post-menopausal women, hypogonadal men)

9. Complications

Intestinal Complications

Strictures: [70]

• Occur in 30-40% of patients over disease course
• Inflammatory (potentially reversible with medical therapy) vs fibrotic (require intervention)
• Presentation: Intermittent cramping abdominal pain, bloating, nausea, food aversion
• Diagnosis: Cross-sectional imaging (MRE/CT), endoscopy
• Management: Medical therapy trial, endoscopic balloon dilatation, stricturoplasty, or resection

Fistulae: [71]

• Occur in 20-40% over lifetime
• Types:
  • "Entero-enteric (bowel to bowel): Often asymptomatic; may cause malabsorption"
  • "Perianal (30-40% of all patients): Fissures, fistulae, abscesses"
  • "Entero-cutaneous: Post-operative or spontaneous; high output may cause malnutrition"
  • "Entero-vesical (bowel to bladder): Pneumaturia, fecaluria, recurrent UTIs"
  • "Entero-vaginal: Passage of gas/stool per vagina"
• Management: Combination medical (antibiotics, anti-TNF) and surgical therapy

Abscesses: [72]

• Intra-abdominal: 10-30% prevalence
• Presentation: Fever, abdominal pain, tender mass, leucocytosis
• Diagnosis: CT or MRI showing fluid collection with rim enhancement
• Management: Percutaneous or surgical drainage + antibiotics; delay biologics until drained
• May require subsequent surgical resection of diseased segment

Perforation: [73]

• Free perforation: Rare (1-3%); surgical emergency
• Covered perforation: More common; forms phlegmon or abscess
• Risk factors: Acute severe disease, corticosteroid use, bowel obstruction

Haemorrhage: [74]

• Massive bleeding rare in Crohn's (less than 1% presentations)
• More common in colonic disease
• Management: Resuscitation, endoscopic therapy, angiographic embolisation, or surgical resection

Toxic megacolon: [75]

• Very rare in Crohn's (more common in UC)
• Transverse colon dilatation > 6 cm with systemic toxicity
• High mortality (15-30%)
• Management: IV steroids, antibiotics, surgical consultation; colectomy if no improvement in 24-48 hours

Extraintestinal Complications

Nutritional deficiencies: [76]

• Iron deficiency anaemia (most common): Chronic blood loss + inflammation-induced hepcidin elevation
• Vitamin B12 deficiency: Ileal disease or resection > 60 cm
• Vitamin D deficiency: Malabsorption, chronic inflammation, reduced sunlight exposure
• Fat-soluble vitamin deficiencies (A, D, E, K): Extensive small bowel disease, bile salt malabsorption
• Protein-calorie malnutrition: Severe, extensive disease; reduced oral intake
• Zinc, selenium deficiencies: Diarrhoea losses

Metabolic bone disease: [77]

• Osteopenia/osteoporosis in 40-50% of IBD patients
• Mechanisms: Corticosteroid use, vitamin D deficiency, calcium malabsorption, chronic inflammation (IL-6, TNF-α promote osteoclast activity)
• Screening: DEXA scan at diagnosis if risk factors (prolonged steroid use, post-menopausal, hypogonadal, low BMI)
• Prevention: Calcium 1200-1500 mg/day, vitamin D > 800 IU/day, weight-bearing exercise, bisphosphonates if T-score -1.5 or less with risk factors

Cholelithiasis: [78]

• 2-3 times increased risk vs general population
• Mechanism: Ileal disease/resection causes bile salt malabsorption, reducing bile salt pool and increasing cholesterol saturation of bile
• Risk increases with extent of ileal resection

Nephrolithiasis: [79]

• 10-25% prevalence (2-3 times general population)
• Calcium oxalate stones (most common): Fat malabsorption leads to saponification of calcium with fatty acids, leaving free oxalate for absorption and urinary excretion
• Uric acid stones: Chronic diarrhoea causes acidic, concentrated urine
• Prevention: Adequate hydration, low-oxalate diet, calcium supplementation (binds oxalate in gut)

Thromboembolic disease: [80]

• 3-4 times increased risk of venous thromboembolism (DVT/PE)
• Mechanisms: Inflammation-induced hypercoagulability (increased fibrinogen, factor VIII, platelets; decreased antithrombin), immobility during flares, central venous catheters, surgery
• Prophylaxis: Thromboprophylaxis during hospitalization, maintain hydration, early mobilisation

Hepatobiliary disease: [81]

• Primary sclerosing cholangitis (PSC): less than 5% of Crohn's (more common in UC)
• Fatty liver: 20-40%; from malnutrition or medications
• Autoimmune hepatitis: Rare association
• Drug-induced liver injury: Azathioprine, methotrexate, biologics

Malignancy

Colorectal cancer: [82]

• Increased risk: RR 2.5 (95% CI 2.2-2.8) vs general population
• Risk factors: Long disease duration (> 8-10 years), extensive colitis, primary sclerosing cholangitis, family history, ongoing inflammation, pseudopolyps
• Lower risk than UC for equivalent extent and duration
• Surveillance: Colonoscopy with chromoendoscopy every 1-2 years starting 8-10 years after diagnosis in patients with colonic involvement > 1 segment

Small bowel adenocarcinoma: [83]

• 60-fold increased risk vs general population (but absolute risk remains low less than 1%)
• Usually in areas of chronic inflammation or excluded bowel loops
• Often presents late; poor prognosis
• No established surveillance strategy

Lymphoma: [84]

• 2-3 fold increased risk vs general population
• Risk increased by thiopurine therapy: 4-5 fold increase; absolute risk ~4 per 10,000 patient-years
• Hepatosplenic T-cell lymphoma: Rare but fatal; associated with combination thiopurine + anti-TNF, particularly in young males
• EBV-associated post-transplant-like lymphoproliferative disorder: Rare, usually in young males on combination immunosuppression

Anal cancer: [85]

• Increased risk with longstanding perianal disease
• HPV may play role; consider HPV vaccination in young patients

Treatment-related malignancies:

• Non-melanoma skin cancer: Increased with thiopurines, anti-TNF therapy
• Advice: Sun protection, annual dermatology review
• Cervical cancer: Increased risk with immunosuppression; ensure up-to-date cervical screening

10. Prognosis

Natural history: [86]

• Chronic relapsing-remitting course in 80-90%
• 10-20% have prolonged remission after initial episode
• less than 5% have continuously active disease despite therapy

Disease progression:

• Behaviour evolution: 40-50% remain inflammatory (B1) at 10 years; 30-40% progress to stricturing (B2), 20-30% to penetrating (B3)
• Once stricturing/penetrating behaviour develops, rarely reverts to inflammatory
• Concept of "bowel damage progression"
• cumulative structural damage (strictures, fistulae, resections) over time

Surgical outcomes: [87]

• 50-70% require surgery within 10 years
• Post-resection endoscopic recurrence: 70-80% at 1 year
• Clinical recurrence: 20-30% at 5 years, 50% at 10 years
• Multiple resections in 30-40% over lifetime
• Short bowel syndrome: Rare (less than 5%) with conservative resection practices

Quality of life: [88]

• Significantly impaired during active disease
• Depression and anxiety in 30-40%
• Work disability in 20-30% over disease course
• Sexual dysfunction common, particularly with perianal disease
• Reduced fertility in women (surgery, medication concerns, disease activity)
• Pregnancy outcomes generally good if disease controlled

Mortality: [89]

• Standardised mortality ratio 1.2-1.5 vs general population
• Causes: Complications (perforation, sepsis), malignancy, thromboembolic disease, treatment-related (infection, malignancy)
• Mortality decreased in recent decades with improved medical and surgical management

Prognostic factors: [90]

Poor prognosis (higher risk of complications, surgery, disability):

• Young age at diagnosis (less than 25 years)
• Extensive small bowel disease
• Perianal disease at diagnosis
• Penetrating or stricturing behaviour at diagnosis
• Deep ulceration on initial endoscopy
• Need for corticosteroids at diagnosis
• Cigarette smoking
• NOD2 mutations (associated with fibrostenotic disease and earlier surgery)

Better prognosis:

• Isolated colonic disease
• Older age at diagnosis
• Non-smoker
• Inflammatory (B1) phenotype

Impact of therapy:

• Mucosal healing associated with reduced hospitalisation, surgery, and disability
• Anti-TNF therapy reduces surgery rates by 30-50% in randomised trials
• Early aggressive therapy in high-risk patients may alter disease course (reduce cumulative bowel damage)

11. Prevention and Screening

Primary Prevention

No proven primary prevention strategies exist. Smoking avoidance and breastfeeding in infancy may reduce risk.

Secondary Prevention (Disease Modification)

• Smoking cessation: Single most important intervention; improves outcomes equivalently to immunosuppressive therapy
• Early aggressive therapy in high-risk patients may prevent disease progression
• Mucosal healing as treatment target reduces long-term complications

Tertiary Prevention (Complication Screening)

Colorectal cancer surveillance: [91]

• Start 8-10 years after diagnosis in patients with colonic involvement > 1 segment
• Colonoscopy with chromoendoscopy every 1-2 years
• More frequent (annually) if PSC, extensive colitis, family history of CRC, or previous dysplasia

Bone health:

• Baseline DEXA if risk factors
• Repeat every 2 years in high-risk (prolonged steroids, post-menopausal)
• Calcium and vitamin D supplementation

Cervical and skin cancer screening:

• Annual skin checks in patients on long-term immunosuppression
• Ensure up-to-date cervical screening
• Consider HPV vaccination in young patients

Infection screening before immunosuppression:

• Hepatitis B surface antigen, core antibody
• HIV (if risk factors)
• Tuberculosis: Chest X-ray, IGRA (interferon-gamma release assay) or tuberculin skin test
• Varicella zoster antibodies (if no clear history of chickenpox)
• Update vaccinations: Influenza (annual), pneumococcal, varicella (if non-immune and not yet immunosuppressed)

Vaccinations in immunosuppressed patients: [92]

• Avoid live vaccines (MMR, varicella, yellow fever) if on biologics or significant immunosuppression
• Inactivated vaccines safe: Influenza, pneumococcal, hepatitis B, HPV, tetanus
• Give vaccines before starting immunosuppression if possible (better response)

12. Key Guidelines

ECCO Guidelines (European Crohn's and Colitis Organisation)

ECCO Consensus on Crohn's Disease Management (2020): [93]

• Evidence-based recommendations on diagnosis, medical therapy, surgical management, and surveillance
• Support treat-to-target approach with mucosal healing
• Recommend anti-TNF therapy or vedolizumab/ustekinumab for moderate-severe disease
• Endoscopic assessment post-operatively to guide therapy

BSG Guidelines (British Society of Gastroenterology)

BSG Consensus on IBD Management (2019): [94]

• UK-specific guidance aligned with NICE
• Recommendations on service delivery, multidisciplinary care
• Surgery and perianal disease management protocols

NICE Guidelines

NICE NG129: Crohn's Disease Management (2019): [95]

• Inducing remission: Conventional glucocorticoids (prednisolone, IV methylprednisolone, or IV hydrocortisone) for acute exacerbations; budesonide for first presentation or single exacerbation in 12 months in ileocaecal disease
• Add-on treatment: Consider azathioprine or mercaptopurine to induce remission if 2 or more exacerbations in 12 months or steroid dose cannot be tapered
• Maintaining remission: Azathioprine or mercaptopurine as monotherapy
• Biologics: Infliximab, adalimumab for induction and maintenance if conventional therapy (immunomodulators) inadequate
• Vedolizumab for moderate-severe disease after failure of anti-TNF or if anti-TNF unsuitable
• Ustekinumab for moderate-severe after failure of anti-TNF and vedolizumab or if unsuitable

ACG Guidelines (American College of Gastroenterology)

ACG Clinical Guideline: Crohn's Disease (2018): [96]

• Similar recommendations to European guidelines
• Emphasise role of therapeutic drug monitoring
• Detailed surgical management algorithms

13. Examination Content

Common Examination Questions

Q1: "How would you investigate a 25-year-old presenting with 3 months of diarrhoea, abdominal pain, and weight loss?"

Model answer: "I would take a systematic approach to investigating chronic diarrhoea in a young patient. First, I'd take a detailed history including stool frequency and character, presence of blood, nocturnal symptoms, abdominal pain pattern, weight loss, extraintestinal symptoms, family history of IBD, and travel/infection history.

Initial blood tests would include FBC looking for anaemia or inflammatory changes, CRP/ESR for inflammation, liver function, renal function, thyroid function, and coeliac serology (tissue transglutaminase antibodies). Stool tests would include MC&S to exclude infection, C. difficile toxin, and faecal calprotectin which, if elevated above 200 μg/g, would suggest inflammatory bowel disease.

If faecal calprotectin is raised and infection excluded, the gold standard investigation is ileocolonoscopy with multiple biopsies from the terminal ileum and all colonic segments. This allows direct visualisation of mucosal inflammation and histological confirmation. I would look for skip lesions, deep ulceration, and cobblestoning suggestive of Crohn's disease.

Cross-sectional imaging with MR enterography would assess small bowel disease extent, detect complications like strictures or abscesses, and help classify disease location according to the Montreal classification. If upper GI symptoms present or the patient is under 16, I'd perform upper GI endoscopy with biopsies.

This approach would allow me to diagnose Crohn's disease, differentiate from ulcerative colitis, assess disease extent and behaviour, and guide treatment decisions." [97]

Q2: "A patient with known Crohn's disease on azathioprine for 2 years presents with worsening symptoms despite compliance. What is your approach?"

Model answer: "This represents loss of disease control despite maintenance therapy. I would first assess disease activity clinically using the Harvey-Bradshaw Index and check objective markers including CRP and faecal calprotectin. I'd exclude precipitating factors such as NSAID use, intercurrent infection including C. difficile, and medication non-compliance.

If disease activity is confirmed, I would perform ileocolonoscopy to assess endoscopic activity and extent, exclude complications like strictures or fistulae, and rule out alternative diagnoses. Cross-sectional imaging with MRE would evaluate small bowel disease and detect transmural complications not visible endoscopically.

For treatment escalation, I would consider several options based on disease severity and phenotype. In moderate-severe active inflammation, I would initiate biologic therapy with anti-TNF agents (infliximab or adalimumab), vedolizumab, or ustekinumab. Anti-TNF therapy can be used as monotherapy but combination with continuing azathioprine improves outcomes by reducing immunogenicity.

If stricturing disease is present, I'd assess whether inflammatory or fibrotic. Inflammatory strictures may respond to medical therapy escalation, while fibrotic strictures require endoscopic balloon dilatation or surgical intervention. For penetrating disease with fistulae or abscesses, drainage must precede or accompany medical therapy escalation.

I would adopt a treat-to-target approach, aiming for clinical remission, biomarker normalisation, and ultimately mucosal healing, reassessing at 12-14 weeks with clinical parameters, biomarkers, and endoscopy at 6-12 months." [98]

Q3: "Describe the Montreal classification for Crohn's disease and its clinical significance."

Model answer: "The Montreal classification categorises Crohn's disease by three key parameters: age at diagnosis, disease location, and disease behaviour, providing prognostic information and guiding therapy.

Age at diagnosis is classified as A1 (less than 16 years), A2 (17-40 years), or A3 (> 40 years). Paediatric-onset disease (A1) tends to be more extensive and aggressive, often requiring earlier biological therapy.

Location is classified as L1 (terminal ileum only), L2 (colonic only), L3 (ileocolonic), with L4 as a modifier for upper GI involvement. Terminal ileal involvement (L1, commonest single location) typically responds well to budesonide. Isolated colonic disease can mimic ulcerative colitis. The L4 modifier is added if any upper GI involvement exists alongside L1-L3 disease.

Behaviour is classified as B1 (inflammatory/non-stricturing, non-penetrating), B2 (stricturing), or B3 (penetrating/fistulising), with 'p' as a modifier for perianal disease. At diagnosis, 60-70% have B1 disease, but this progresses over time with only 40% remaining B1 at 10 years. B2 stricturing disease often requires endoscopic or surgical intervention, while B3 penetrating disease requires combination medical and surgical management. Perianal disease modifier identifies patients requiring specific management strategies including anti-TNF therapy and surgical assessment.

The classification guides treatment selection - for example, early biologics in extensive disease (L3+L4) or complicated behaviour (B2/B3), and influences surgical planning." [99]

Q4: "What are the indications for surgery in Crohn's disease and what are the principles of surgical management?"

Model answer: "Surgery in Crohn's disease does not cure but treats complications and provides symptom relief when medical therapy fails. Approximately 50-70% of patients require surgery within 10 years of diagnosis.

Indications include failed medical therapy with severe symptoms impacting quality of life, and complications including strictures causing obstruction unresponsive to medical therapy or endoscopic dilatation, abscesses not amenable to percutaneous drainage, perforation, fistulae (entero-cutaneous, entero-vesical, entero-vaginal), severe haemorrhage, toxic megacolon, and dysplasia or malignancy. In paediatric patients, growth retardation despite optimal medical therapy is an indication.

The principles of surgical management are conservative resection with minimal margins, removing only macroscopically diseased bowel rather than wide margins, as this doesn't reduce recurrence rates but preserves bowel length. Stricturoplasty is used for multiple short strictures to avoid extensive resection and short bowel syndrome. The most common operation is ileocaecal resection for terminal ileal disease with primary anastomosis.

Post-operative recurrence is common, with endoscopic recurrence in 70-80% at one year and clinical recurrence in 50% at 10 years. Prevention strategies include smoking cessation (most important), and prophylactic medication particularly anti-TNF therapy in high-risk patients. Endoscopic surveillance at 6-12 months post-resection using the Rutgeerts score guides treatment escalation." [100]

Q5: "Discuss the step-up versus top-down treatment approaches in Crohn's disease."

Model answer: "The step-up approach involves sequential escalation from less to more potent therapies: starting with 5-ASA or budesonide, escalating to corticosteroids, then immunomodulators (azathioprine/methotrexate), and finally biologics if each step fails. This approach exposes fewer patients to potentially toxic therapies and is cost-effective but has disadvantages including delayed disease control, cumulative bowel damage during prolonged inflammation, and higher long-term surgery rates.

The top-down approach uses early biologics with or without immunomodulators in newly diagnosed patients, particularly those with poor prognostic features. The REACT trial demonstrated that early combined immunosuppression reduced major adverse outcomes including hospitalisation and surgery compared to conventional management (30.9% vs 41.5%, hazard ratio 0.73). The rationale is a 'window of opportunity' where early effective treatment prevents irreversible structural bowel damage.

Poor prognostic factors favouring top-down therapy include young age at diagnosis (particularly less than 25 years), extensive small bowel disease, deep ulceration on endoscopy, perianal disease, stricturing or penetrating behaviour at diagnosis, and early need for corticosteroids.

Current best practice involves individualised risk-stratified treatment. High-risk patients benefit from early aggressive therapy, potentially altering disease course and reducing cumulative bowel damage. Low-risk patients (older age, limited disease, inflammatory phenotype) may be appropriately managed with conventional step-up, avoiding unnecessary exposure to biologics. The paradigm is shifting toward earlier biologics as safety data accumulate and costs decrease with biosimilars." [101]

Viva Points

Opening statement: "Crohn's disease is a chronic inflammatory bowel disease characterised by transmural granulomatous inflammation affecting any part of the GI tract from mouth to anus, most commonly the terminal ileum, distinguished by discontinuous skip lesions and complications including strictures, fistulae, and abscesses."

Key facts to mention:

• Incidence 10-20 per 100,000 in Western populations; prevalence increasing globally
• Bimodal age distribution, peak 15-30 years
• Genetic (NOD2, ATG16L1) and environmental (smoking most significant) factors
• Montreal classification: Age, Location (L1-L4), Behaviour (B1-B3), perianal modifier
• Th1/Th17-mediated inflammation with TNF-α as central cytokine
• Diagnosis: Ileocolonoscopy with biopsies (gold standard) + MR enterography
• Management: Budesonide for mild ileocaecal; systemic steroids for moderate-severe; anti-TNF/vedolizumab/ustekinumab for moderate-severe or steroid-dependent
• Maintenance: Thiopurines or biologics; treat-to-target with mucosal healing
• Surgery in 50-70% within 10 years; conservative resection principles
• Endoscopic recurrence 70-80% at 1 year post-surgery; prophylaxis with anti-TNF therapy
• Complications: Strictures, fistulae, malnutrition, colorectal cancer risk 2.5-fold increased

Common Mistakes to Avoid

❌ Failing to distinguish Crohn's from UC: Remember key differentiating features - skip lesions, transmural inflammation, fistulae, granulomas, perianal disease favour Crohn's. Rectal sparing in 50% of Crohn's vs always involved in UC.

❌ Using steroids for maintenance: Steroids are for induction only. Prolonged use causes toxicity and tachyphylaxis. Steroid-dependency mandates escalation to immunomodulators or biologics.

❌ Missing intestinal TB in differential: Critical in endemic areas and immunosuppressed patients. Features favouring TB include positive IGRA, concurrent pulmonary TB, transverse ulcers, and caseating granulomas. Trial of anti-TB therapy may be necessary.

❌ Starting anti-TNF with undrained abscess: Risk of septic complications. Always drain abscesses (percutaneous or surgical) before or concurrent with anti-TNF initiation.

❌ Inadequate assessment before surgery: MRI pelvis is essential before perianal surgery to map anatomy. Cross-sectional imaging required to assess small bowel extent before resection planning.

❌ Not offering smoking cessation: Smoking increases risk 2-4 fold, worsens disease severity, increases post-operative recurrence. Cessation improves outcomes equivalently to immunosuppressive therapy.

❌ Failing to monitor for complications: Colorectal cancer surveillance (starting 8-10 years after diagnosis), bone density monitoring (steroids, malabsorption), and treatment-related complications (infections, malignancy) must be addressed.

❌ Not considering nutritional deficiencies: Iron, B12, vitamin D, fat-soluble vitamins commonly deficient. Ileal resection > 60 cm causes B12 deficiency requiring lifelong replacement.

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