Crohn Disease

Genetic Factors

• Genome-wide Association Studies (GWAS):
  • Over 71 genetic susceptibility loci have been identified, with significant associations involving the CARD15/NOD2 gene, the IBD5 locus, ATG16L1 (autophagy-related), and IL23R (interleukin-23 receptor).
  • CARD15/NOD2 polymorphisms are particularly associated with ileal disease and earlier-onset CD.
  • Additional loci, including STAT3, JAK2, PTPN22, and ITLN1, have been implicated in immune signaling and intestinal microbial recognition.
• Autophagy Pathway Genes:
  • Variants in ATG16L1 and IRGM suggest defective bacterial clearance mechanisms, emphasising the importance of autophagy in pathogenesis.
• Genetic Contribution:
  • Identified genetic factors explain less than 20% of heritable risk, underscoring the importance of environmental triggers.
    
    

Environmental Factors

• Diet and Lifestyle:
  • Diets low in fruits, vegetables, and fiber but high in refined sugars and ultra-processed foods have been linked to increased CD risk.
  • Smoking is strongly associated with disease onset and progression, doubling the risk of developing CD.
• Medications and Exposures:
  • Use of oral contraceptives, NSAIDs, and antibiotics has been implicated in disease initiation or exacerbation.
• Other Factors:
  • Lack of breastfeeding during infancy and a sedentary lifestyle may contribute to susceptibility.
  • Deficiencies in vitamin D and zinc are often observed but their causative roles are uncertain.
    
    

Microbial and Infectious Influences

• Pathogenic Microorganisms:
  • Species like Mycobacterium avium paratuberculosis, Campylobacter, and Pseudomonas have been linked to disease onset or exacerbation.
  • Whether these microbes play a causative role or are secondary to existing inflammation remains debated.
• Dysbiosis:
  • An imbalance in gut microbiota composition is frequently observed, potentially driving inappropriate immune activation.
    
    

Immunologic and Cytokine Pathways

• Immune Dysregulation:
  • CD is marked by an exaggerated Th1 and Th17 immune response, with elevated levels of IL-12, IL-23, and TNF-α promoting chronic inflammation.
• TNF-α Role:
  • TNF-α is a key proinflammatory mediator, with its overexpression linked to mucosal damage and systemic inflammation.
    
    

Psychosocial and Miscellaneous Factors

• Stress and Psychosocial Stressors:
  • Though not directly causal, stress is a recognised exacerbating factor in disease flares.
• Surgical History:
  • Unlike in ulcerative colitis, appendectomy does not provide a protective effect in CD.
    
    

Cellular and Molecular Mechanisms

• Immune Dysregulation:
  • Dysregulated Th1 and Th17 immune responses drive chronic inflammation, mediated by cytokines such as IL-12, IL-23, and TNF-α.
  • Deficiencies in epithelial barrier integrity and innate immune recognition exacerbate mucosal inflammation and tissue injury.
• Inflammatory Cascade:
  • Pro-inflammatory mediators released by immune cells include:
    • Arachidonic acid metabolites.
    • Platelet-activating factors.
    • Proteases and free radicals, leading to epithelial damage and tissue destruction.
      
      

Histological Features

• Initial Lesion:
  • Focal inflammatory infiltrates around intestinal crypts progress to superficial ulcerations and non-caseating granulomas.
  • Granulomas involve all layers of the intestinal wall but may not always be present.
• Chronic Changes:
  • Neutrophilic infiltration forms crypt abscesses and destroys crypts, causing mucosal atrophy and villous blunting.
  • Alternating areas of inflamed and normal mucosa result in characteristic "skip lesions."
    
    

Macroscopic and Endoscopic Findings

• Early Changes:
  • Hyperemia and edema of mucosa, visible on endoscopy.
• Advanced Findings:
  • Deep, serpiginous ulcers and a cobblestone appearance due to intervening healthy mucosa.
  • Thickened bowel walls with luminal narrowing, leading to obstruction and strictures.
• Complications:
  • Penetrating disease manifests as fistulae (enteroenteral, enterovesical, enterocutaneous).
  • Chronic transmural inflammation predisposes to abscess formation and adhesions.
    
    

Nutritional and Systemic Implications

• Nutritional Impact:
  • Terminal ileum involvement disrupts bile acid reabsorption, leading to:
    • Steatorrhea and malabsorption.
    • Fat-soluble vitamin deficiencies (A, D, E, K).
    • Gallstone and oxalate kidney stone formation.
• Extraintestinal Manifestations:
  • Skin: Erythema nodosum, pyoderma gangrenosum.
  • Joints: Peripheral arthritis, ankylosing spondylitis.
  • Eyes: Uveitis, episcleritis.
  • Liver: Primary sclerosing cholangitis, gallstones.
    
    

Disease Progression

• Acute inflammation causes reversible symptoms like edema and spasm.
• Chronic disease leads to fibrosis, strictures, fistulae, and adhesions.
• "Creeping fat" (mesenteric fat wrapping around inflamed bowel) contributes to local inflammation.
  
  

Vienna Classification of Crohn Disease

1. Age at Diagnosis:
   • A1: ≤40 years.
   • A2: >40 years.
2. Disease Location:
   • L1: Terminal ileum (± cecum involvement).
   • L2: Colon (excluding small bowel involvement).
   • L3: Ileocolon (both small and large bowel involvement).
   • L4: Upper gastrointestinal (proximal to terminal ileum, excluding mouth).
3. Disease Behavior:
   • B1: Non-stricturing, non-penetrating.
   • B2: Stricturing (luminal narrowing with pre-stenotic dilation).
   • B3: Penetrating (fistulae, abscesses, or other perforating complications).

Montreal Classification of Crohn’s Disease

1. Age at Diagnosis:

• A1: ≤16 years.
• A2: 17–40 years.
• A3: >40 years.

•  L1: Terminal ileum (± cecum involvement).
• L2: Colon (excluding small bowel involvement).
• L3: Ileocolon (both small and large bowel involvement).
• L4: Upper gastrointestinal (proximal to terminal ileum, excluding mouth).
  • L4a: Oesophagus, stomach, duodenum.
  • L4b: Jejunum and proximal ileum

• B1: Non-stricturing, non-penetrating.
• B2: Stricturing (luminal narrowing with pre-stenotic dilation).
• B3: Penetrating (fistulae, abscesses, or other perforating complications).
  • p: Perianal disease modifier (applies to any B classification if perianal disease is present)

Global and Regional Prevalence and Incidence

• North America and Europe:
  • Incidence rates:
    • 20.2 per 100,000 person-years in North America.
    • 12.7 per 100,000 person-years in Europe.
  • Prevalence rates:
    • 319 per 100,000 in Canada.
    • 322 per 100,000 in Germany.
• Asia and Developing Regions:
  • Incidence rates in Asia range from 0.5 to 4.2 per 100,000 persons, with Japan reporting a prevalence of 27 per 100,000 individuals.
  • Newly industrialising regions in Asia, South America, and Africa are experiencing rising incidence.
    
    

Urban vs. Rural Distribution

• Higher prevalence in urban areas than in rural regions, possibly due to environmental exposures and healthcare access disparities.
  
  

Age and Gender Distribution

• Bimodal Age Distribution:
  • First peak: Ages 15–30 years (young adulthood).
  • Second peak: Ages 50–70 years (more pronounced in women).
• Gender Differences:
  • Slight female predominance in adults, with rates 1.1–1.8 times higher in women.
  • Pediatric Crohn disease has a higher incidence in males (male-to-female ratio ~1.6:1).
    
    

Ethnic and Genetic Factors

• Ethnic Variability:
  • Higher prevalence in white populations and individuals of Ashkenazi Jewish descent, with the latter group exhibiting a 2- to 4-fold increased risk.
  • Lower prevalence in Asians, Africans, and South Americans.
• Familial and Genetic Risk:
  • 10–25% of patients report a first-degree relative with Crohn's disease.
    
    

Time Trends

• Epidemiologic studies show statistically significant increases in incidence globally, particularly in newly industrialised countries. Time-trend analyses reveal stabilisation or slight declines in incidence in highly industrialised regions.
  
  

Environmental Influences

• Urbanisation and adoption of Western diets have been linked to increased disease prevalence. Smoking is a known risk factor, doubling the likelihood of disease development.
  
  

Key Historical Factors

Risk Factors:

1. Ethnicity and Genetics:
   • White ethnicity and Ashkenazi Jewish ancestry are associated with higher prevalence.
   • Family history is significant, with 10–25% of patients reporting an affected first-degree relative.
2. Age of Onset:
   • Bimodal distribution, peaking between 15–40 years and 50–60 years.
3. Environmental Exposures:
   • Smoking increases the risk and severity of Crohn's disease (CD).
   • Diets high in refined sugars, low in fiber, or rich in ultra-processed foods may be contributory.

Symptoms

1. Abdominal Pain:
   • Frequently localised to the right lower quadrant or periumbilical region.
   • Often crampy and relieved by defecation.
   • May mimic acute appendicitis or present as diffuse pain in colitis.
2. Diarrhoea:
   • Intermittent, chronic, and non-bloody, although bloody diarrhea may occur, especially in colonic disease.
   • Diarrhea may worsen at night and often fluctuates over long periods.
3. Weight Loss:
   • Commonly results from reduced oral intake due to pain or fear of eating.
   • Malabsorption and nutrient deficiencies contribute to progressive weight loss.
4. Fatigue:
   • A prominent feature caused by systemic inflammation, malnutrition, and chronic disease burden.
5. Fever:
   • Low-grade fever is typical; higher-grade fever may indicate abscess formation or perforation.
6. Bowel Obstruction:
   • Recurrent postprandial bloating, cramping, and loud bowel sounds.
   • Chronic inflammation and fibrosis can lead to progressive strictures, presenting as obstipation or vomiting.
7. Perianal Disease:
   • History of perianal pain, drainage, or discomfort.
   • May present with recurrent infections, fistulae, or abscesses.
8. Systemic and Extraintestinal Symptoms:
   • Malabsorption:
     • Symptoms of nutrient deficiencies, including fatigue, weakness, and steatorrhea, may arise from bile salt malabsorption or intestinal damage.
   • Extraintestinal Manifestations:
     • Symptoms of arthritis, eye irritation (uveitis, episcleritis), or skin changes (erythema nodosum, pyoderma gangrenosum).
9. Duration and Intermittency:
   • Symptoms may precede diagnosis by years, with periods of remission and recurrence.
     
     

Importance of Historical Details

• Growth Failure in Children:
  • Growth delays or failure to thrive may be the earliest sign in pediatric populations.
• Triggers and Aggravating Factors:
  • Emotional or physical stress often correlates with symptom flares.
  • Prior surgical history, especially involving the gastrointestinal tract, may indicate previous disease progression or complications.
    
    

General Observations

• Malnutrition and Vital Signs:
  • Signs of malnutrition, including pallor, low body mass index, and muscle wasting.
  • Fever, tachycardia, or hypotension may indicate active inflammation, dehydration, or complications like sepsis.
    
    

Abdominal Examination

1. Inspection:
   • Visible abdominal scars from prior surgeries or enterocutaneous fistulae in advanced cases.
   • Abdominal distension may suggest bowel obstruction or significant inflammatory changes.
2. Auscultation:
   • Hyperactive bowel sounds may indicate obstruction or active inflammation.
   • Absent or reduced bowel sounds could signify ileus or severe inflammation.
3. Palpation:
   • Localised Tenderness:
     • Commonly in the right lower quadrant, correlating with terminal ileal involvement.
   • Mass Formation:
     • A palpable inflammatory mass may represent thickened bowel loops or abscess formation.
   • Guarding and Rebound Tenderness:
     • May indicate peritonitis due to perforation or intra-abdominal abscess.
4. Percussion:
   • Tympany may indicate dilated bowel loops or obstruction.
     
     

Perianal and Rectal Examination

• Perianal Findings:
  • Present in ~25–30% of patients.
  • Findings include skin tags, fissures, fistulae, abscesses, or scarring.
• Rectal Examination:
  • May reveal gross or occult blood, reduced sphincter tone, or rectal masses.
  • Perianal pain and purulent discharge are common with active fistulae or abscesses.
    
    

Extraintestinal Manifestations

1. Skin:
   • Erythema Nodosum:
     • Painful, red nodules typically found on the anterior lower legs.
   • Pyoderma Gangrenosum:
     • Deep, necrotic ulcers with violaceous borders, often on the extremities.
2. Eyes:
   • Signs of episcleritis (redness and irritation) or uveitis (pain, photophobia, blurred vision).
   • A slit-lamp examination may be necessary to confirm uveitis.
3. Oral Cavity:
   • Aphthous ulcers, mucosal inflammation, and discomfort are common findings.
4. Joints:
   • Peripheral arthritis (large joints such as knees, ankles).
   • Axial involvement, such as sacroiliitis or ankylosing spondylitis.
5. Liver and Biliary System:
   • Right upper quadrant tenderness may indicate primary sclerosing cholangitis or gallstones.
6. Renal and Pelvic Exam:
   • Flank tenderness could suggest nephrolithiasis.
   • Examination of the genital area may reveal fistulae or associated skin changes.
     
     

Paediatric-Specific Examination

• Growth Parameters:
  • Monitoring height, weight, and growth velocity is critical to detect growth delays.
  • Decreased growth velocity is often the earliest sign of Crohn's disease in children.
• Pubertal Development:
  • Delayed puberty may be evident in adolescents, requiring Tanner staging.
    
    

Laboratory Investigations

1. Blood Tests:
   • Complete Blood Count (CBC):
     • Anaemia (chronic inflammation, iron deficiency, B12/folate malabsorption).
     • Leukocytosis (inflammation, infection, steroid use).
     • Thrombocytosis (marker of active inflammation).
   • Inflammatory Markers:
     • C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) correlate with disease activity.
   • Nutritional Markers:
     • Serum albumin, iron studies, vitamin D, vitamin B12, and folate levels to evaluate malnutrition or malabsorption.
   • Electrolytes:
     • May reveal hypokalemia, hypocalcemia, or hypoalbuminemia in cases of chronic diarrhea.
2. Stool Tests:
   • Pathogen Screening:
     • Stool cultures, ova and parasite tests, and Clostridioides difficile toxin assays to exclude infectious causes.
   • Fecal Calprotectin or Lactoferrin:
     • Non-invasive markers of intestinal inflammation, useful in distinguishing inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS).
       
       

Endoscopic Evaluation

1. Ileocolonoscopy:
   • Gold standard for diagnosis:
     • Endoscopic findings include:
       • Skip lesions: Segmental inflammation interspersed with normal mucosa.
       • Cobblestone appearance: Ulcers and nodularity.
       • Pseudopolyps: Hypertrophied mucosa.
       • Rectal sparing.
   • Biopsies are essential for histologic confirmation:
     • Granulomas (present in 30–50% of cases) strongly support CD diagnosis but are not mandatory.
2. Upper Endoscopy (Oesophagogastroduodenoscopy):
   • Indicated in cases with upper gastrointestinal symptoms (e.g., nausea, dyspepsia, or early satiety).
   • Findings may include gastric/duodenal ulcerations or inflammation.
3. Video Capsule Endoscopy (VCE):
   • Visualises small bowel lesions not accessible by conventional endoscopy.
   • Contraindicated in suspected strictures due to capsule retention risks.
     
     

Imaging Studies

1. Small Bowel Imaging:
   • CT Enterography (CTE) and MRI Enterography (MRE):
     • Identify small bowel involvement, strictures, and penetrating complications (e.g., fistulae or abscesses).
     • Preferred for assessing disease distribution and transmural involvement:
       • Segmental wall thickening (>2 mm).
       • "Comb sign" (engorged mesenteric vessels).
       • Creeping fat and bowel strictures with upstream dilation.
   • MRE is favored for younger patients or those requiring repeated imaging due to its lack of radiation exposure.
2. Pelvic MRI:
   • Evaluates perianal disease, defining fistulae and abscess tracts.
3. Ultrasound:
   • Useful for detecting bowel wall thickening, abscesses, and hyperemia.
   • Highly operator-dependent and limited in obese patients.
4. Plain Radiography:
   • May reveal complications such as bowel obstruction, perforation, or toxic megacolon.
     
     

Advanced Diagnostics

1. Histology:
   • Biopsies from endoscopic evaluations reveal:
     • Non-caseating granulomas.
     • Cryptitis or crypt abscesses.
     • Transmural lymphoid aggregates.
2. Serologic Testing:
   • Anti-Saccharomyces cerevisiae antibodies (ASCA):
     • More prevalent in CD than ulcerative colitis.
   • p-ANCA (perinuclear antineutrophil cytoplasmic antibody):
     • More common in ulcerative colitis but may be positive in some CD cases.
       
       

Emerging and Specialised Tools

1. Fecal Biomarkers:
   • Serial measurements of fecal calprotectin are increasingly used to monitor disease activity and predict relapses.
2. Cross-sectional Imaging with PET/CT:
   • Experimental use in assessing inflammation and complications such as abscesses or fistulae.
     
     

Inflammatory Bowel Diseases

1. Ulcerative Colitis (UC):
   • Distinguishing Features:
     • Continuous colonic involvement starting at the rectum.
     • No small bowel or perianal disease.
   • Investigations:
     • Colonoscopy: Rectal involvement, no skip lesions.
     • Biopsy: Diffuse mucosal inflammation without granulomas.
     • Laboratory: Anti-glycan antibodies more common in CD.
2. Indeterminate Colitis:
   • Used when features of both CD and UC are present, making differentiation impossible.
   • Evolution into definitive CD or UC may occur with time.
     
     

Infectious Causes

1. Infectious Colitis:
   • Pathogens: Shigella, Salmonella, Campylobacter, Escherichia coli O157:H7, Yersinia, Clostridioides difficile, parasites (Entamoeba histolytica).
   • Features:
     • Acute diarrhea, abdominal pain, and fever.
     • History of travel or foodborne illness.
   • Investigations:
     • Stool culture, ova and parasite examination, and pathogen-specific tests.
2. Cytomegalovirus (CMV) Colitis:
   • Mimics CD in immunocompromised patients.
   • Investigations:
     • Biopsy with histological findings of cytomegalic cells and inclusion bodies.
3. Intestinal Tuberculosis:
   • Features:
     • Terminal ileitis, weight loss, and fever.
     • Endemic regions or immunosuppression increase suspicion.
   • Investigations:
     • Biopsy: Caseating granulomas, acid-fast bacilli staining, TB PCR or culture.
4. Amoebiasis:
   • Mimics CD with diarrhea and ileocecal inflammation.
   • Investigations:
     • Stool testing for Entamoeba histolytica.
       
       

Malabsorption Syndromes

1. Coeliac Disease:
   • Features:
     • Diarrhea, weight loss, and abdominal pain, resembling CD.
   • Investigations:
     • Serology: Tissue transglutaminase-IgA antibody.
     • Biopsy: Villous atrophy and crypt hyperplasia.
2. Lactose Intolerance:
   • Features:
     • Diarrhoea, bloating, and flatulence after dairy ingestion.
   • Investigations:
     • Hydrogen breath test.
       
       

Functional Disorders

1. Irritable Bowel Syndrome (IBS):
   • Features:
     • Abdominal pain, diarrhea, and bloating without systemic symptoms or inflammation.
   • Investigations:
     • Normal fecal calprotectin, CRP, and ileocolonoscopy findings.
       
       

Ischemic and Structural Conditions

1. Ischemic Colitis:
   • Features:
     • Left-sided abdominal pain with bloody diarrhea.
     • Risk factors: Atherosclerosis, hypoperfusion states.
   • Investigations:
     • Colonoscopy: Mucosal friability, segmental ischemia.
2. Diverticular Colitis:
   • Inflammation restricted to interdiverticular mucosa.
   • Investigations:
     • Colonoscopy: Inflammation sparing diverticular orifices.
3. Appendicitis:
   • Mimics CD with right lower quadrant pain and fever.
   • Investigations:
     • Imaging: CT or ultrasound confirms inflammation limited to the appendix.

Neoplasms and Other Rare Conditions

1. Colorectal Cancer:
   • Mimics CD with weight loss, obstruction, or altered bowel habits.
   • Investigations:
     • Colonoscopy with biopsy.
     • Imaging: CT or MRI for staging.
2. Common Variable Immunodeficiency (CVID):
   • Features:
     • Chronic diarrhoea, abdominal pain, and weight loss.
   • Investigations:
     • Serum immunoglobulin levels.
3. Endometriosis:
   • Features:
     • Cyclical abdominal pain in women of reproductive age.
   • Investigations:
     • Laparoscopy.
4. Radiation Colitis:
   • History of pelvic radiation.
   • Investigations:
     • Colonoscopy: Ulcerations and mucosal friability.
       
       

Providing Information and Support

• Tailored Information: Provide age-appropriate, culturally sensitive, and literacy-level-suitable advice. Resources should address:
  • Nature and prognosis of CD.
  • Impact on growth and puberty in children.
  • Implications for fertility and sexual health.
  • Importance of smoking cessation to reduce disease activity.
• Comprehensive Support:
  • Explain treatment options, monitoring requirements, and potential side effects.
  • Discuss body image concerns, especially for patients undergoing surgery or living with chronic disease.
  • Address concerns about school or workplace accommodations, transitions between pediatric and adult services, and social interactions.
• Multidisciplinary Input:
  • Engage the patient, family members, and multidisciplinary teams (gastroenterologists, dietitians, surgeons) in care planning.
    
    

Inducing Remission

1. Monotherapy

• Conventional Glucocorticosteroids:
  • First-line therapy for initial presentations or single exacerbations.
  • Effective for controlling inflammation and achieving remission.
• Budesonide:
  • Considered for mild ileal or right-sided colonic disease.
  • Provides lower systemic side effects compared to conventional steroids but is less effective.
• Aminosalicylates:
  • May be used for mild disease if glucocorticosteroids are contraindicated. Less effective than steroids but with fewer adverse effects.
• Enteral Nutrition:
  • Especially beneficial for children and adolescents to promote growth and reduce systemic side effects. Exclusive enteral nutrition is an option for remission induction

• Azathioprine/Mercaptopurine:
  • Add to glucocorticosteroids for patients experiencing frequent exacerbations (>2/year) or those unable to taper steroid doses.
  • TPMT activity testing is essential to reduce the risk of myelosuppression.
• Methotrexate:
  • Alternative for patients intolerant to thiopurines or with TPMT deficiency.
  • Effective for steroid-sparing and remission induction but requires careful monitoring due to hepatotoxicity and teratogenicity.

• Infliximab and Adalimumab:
  • Indicated for severe, refractory disease or fistulising CD.
  • Patients must be monitored for infection risks, including tuberculosis and hepatitis reactivation.
• Combination Therapy:
  • Combining biologics with immunosuppressants (e.g., infliximab + azathioprine) is more effective for inducing remission but increases the risk of immunosuppression-related complications.
    
    

Maintaining Remission

• Thiopurines:
  • Effective for corticosteroid-dependent remission maintenance.
  • Azathioprine or mercaptopurine is preferred for maintaining remission achieved with steroids.
• Methotrexate:
  • Reserved for patients intolerant to thiopurines or those requiring corticosteroid-sparing agents.
  • Administer intramuscularly or subcutaneously, with careful monitoring of liver and bone marrow function.
• Biologics:
  • Continue the same agent used for induction if effective.
  • Alternatives like ustekinumab or vedolizumab are considered for patients unresponsive to TNF-alpha inhibitors.
• Surgical Remission Maintenance:
  • Postoperative maintenance with azathioprine ± metronidazole is effective for preventing recurrence in ileocolonic CD.
    
    

Post-Surgical Maintenance

• Medication:
  • Azathioprine alone or in combination with metronidazole for 3 months postoperatively to maintain remission.
  • Biologics are not routinely recommended unless started preoperatively.
• Monitoring:
  • Regular endoscopic evaluation to detect early recurrence.
  • Nutritional optimization and surveillance for complications like short bowel syndrome are critical.
    
    

Surgical Interventions

• Indications for Surgery:
  • Early surgery is an option for patients with refractory ileal disease or growth failure.
  • Address complications like strictures, fistulas, or obstruction.
• Stricture Management:
  • Balloon dilation for short, simple strictures accessible via colonoscopy.
  • Surgical resection for more complex or refractory strictures.
    
    

Monitoring and Risk Assessment

• Bone Health:
  • Monitor bone density in children with risk factors such as low BMI or chronic steroid use.
• Infection Screening:
  • Screen for tuberculosis, hepatitis B/C, and opportunistic infections in patients starting immunosuppressive or biological therapy.
• Side Effect Monitoring:
  • Regular laboratory tests for neutropenia, hepatotoxicity, and thiopurine metabolite levels to ensure safety.
    
    

Special Populations

• Emphasise growth monitoring, nutritional support, and age-appropriate interventions.
• Address pubertal delays and psychosocial concerns.
• Pregnancy:
  • Optimise disease control before conception.
  • Discuss the safety of biologics and thiopurines during pregnancy and lactation.
• Elderly:
  • Carefully evaluate the risks of immunosuppression and comorbidities in older adults.

Emerging Treatments and Research

• Future Directions:
  • Investigate novel agents like JAK inhibitors and S1P modulators for refractory CD.
  • Explore the role of microbiome-based therapies, including fecal microbiota transplantation and probiotics.
  • Evaluate cost-effectiveness and long-term safety of biosimilars in real-world settings.
    
    

Natural History

• Relapse and Remission:
  • Most patients experience periodic exacerbations interspersed with remission.
  • Approximately 10–20% of individuals achieve prolonged remission following their initial presentation.
  • The relapse rate within the first year after diagnosis is approximately 50%, with about 10% developing a chronic relapsing course.
• Surgical Intervention:
  • Surgical management is common, particularly for complications like strictures, fistulas, or abscesses.
  • Up to 90% of patients with ileocolonic disease may require surgery within 10 years of diagnosis, though 50% may not need additional surgical interventions.
  • Gastroduodenal CD often necessitates gastrojejunostomy bypass in about one-third of cases with obstruction.
• Complications and Disease Progression:
  • Early indicators of severe disease include young age at diagnosis (<40 years), perianal disease, and initial corticosteroid requirement.
  • Proximal small bowel involvement correlates with higher mortality rates compared to ileal or ileocecal disease.
    
    

Mortality

• General Observations:
  • CD is associated with a slight decrease in life expectancy, particularly with disease duration, socioeconomic factors, and post-surgical complications.
  • Population studies indicate a 1.4 to 1.5-fold increased mortality compared to the general population.
• Causes of Death:
  • Gastrointestinal malignancies, including colorectal cancer, are leading causes of disease-related mortality.
  • Other causes include non-Hodgkin's lymphoma, sepsis, pulmonary embolism, and complications of gastrointestinal disease.
• Impact of Surgery:
  • The risk of mortality increases in the immediate postoperative period, especially within 30 days of gastrointestinal surgery.
  • Post-surgical recurrence is common, with an endoscopic recurrence rate of approximately 90% at the anastomosis site.
• Corticosteroid Impact:
  • Current corticosteroid use is associated with higher mortality, highlighting the importance of tapering and minimising long-term dependence.
    
    

Prognostic Factors

• High-Risk Characteristics:
  • Age <30 years at diagnosis.
  • Active or recent tobacco use.
  • Elevated inflammatory markers (CRP or fecal calprotectin).
  • Extensive bowel involvement or long-segment disease.
  • Deep colonic ulcers visualised on colonoscopy.
  • Presence of perianal disease or extraintestinal manifestations (e.g., arthritis, uveitis).
  • History of bowel resections or short intervals between surgeries.
• Genetic Markers:
  • Variants in the CARD15 gene have been linked to specific disease patterns, including ileal disease, stricture formation, and early-onset CD.
  • Ongoing research may enhance prognostication and targeted treatment approaches.
    
    

Surveillance and Long-Term Management

• Endoscopic Monitoring:
  • Surveillance endoscopy is recommended within 6–12 months post-surgery and every 1–3 years subsequently if no endoscopic recurrence is observed.
• Post-Surgical Recurrence:
  • Risk factors for early recurrence include smoking, short duration from diagnosis to surgery, penetrating disease, and multiple resections.
  • Preventive strategies, including smoking cessation and biologic therapy, may mitigate recurrence risk.
• Emerging Trends:
  • Improved therapies have reduced the risk of gastrointestinal cancer in CD, with ongoing advancements offering better disease control and outcomes.

Intestinal Complications

• Aetiology: Repeated inflammation leads to bowel wall thickening and fibrosis, causing luminal narrowing.
• Clinical Features: Symptoms include abdominal pain, nausea, vomiting, and bowel obstruction.
• Management:
  • Acute cases: Bowel rest, nasogastric suction, corticosteroids.
  • Chronic strictures:
    • Endoscopic balloon dilation for strictures ≤4 cm.
    • Surgical options include strictureplasty (for segments <10 cm) or resection for longer or complex strictures.
  • Colonic strictures often require segmental resections or subtotal colectomy.
• Cancer Risk: Strictureplasty sites may harbor carcinoma.
  
  

• Fistulas: Abnormal tracts connecting bowel loops or other organs. Types include enteroenteric, enterovesical, and enterocutaneous.
• Abscesses: Localized collections presenting with fever, pain, and abdominal tenderness.
• Management:
  • Antibiotics and drainage for abscesses.
  • Surgical intervention for complex fistulas or recurrent infections.
    
    

• Definition: Non-obstructive colonic dilation with systemic toxicity due to severe colitis.
• Management:
  • Intensive medical therapy: Corticosteroids, antibiotics, or immunosuppressants.
  • Surgical colectomy in refractory cases.
    
    

• Increased Risk: Patients with longstanding colonic CD have a heightened risk of colorectal cancer, anal squamous cell carcinoma, and small bowel adenocarcinoma.
• Surveillance: Regular endoscopic monitoring for dysplasia.
  
  

• Aetiology: Extensive surgical resections leave insufficient bowel for nutrient absorption.
• Management: Parenteral nutrition, hydration, and electrolyte supplementation.
  
  

Extraintestinal Complications

• Osteoporosis and Fractures:
  • Causes: Corticosteroid use, malabsorption, inflammation.
  • Prevention: Calcium and vitamin D supplementation, bisphosphonates, smoking cessation.
• Arthropathy:
  • Types: Peripheral arthritis, axial arthritis (e.g., ankylosing spondylitis).
  • Treatment: Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or biologics (e.g., infliximab).
    
    

• Cholelithiasis:
  • Causes: Bile salt malabsorption and fat malabsorption.
  • Incidence: Affects up to one-third of patients with ileitis or ileal resections.
• Primary Sclerosing Cholangitis (PSC):
  • Rare but severe liver involvement.
  • Ursodeoxycholic acid is occasionally used.
• Fatty Liver and Liver Abscess:
  • Caused by malnutrition, corticosteroids, or portal pyaemia.
    
    

• Nephrolithiasis:
  • Pathophysiology: Hyperoxaluria due to fat malabsorption, acidosis, and dehydration.
  • Types: Calcium oxalate and uric acid stones.
  • Prevention: Adequate hydration and dietary modifications.
    
    

• Erythema Nodosum: Tender red nodules, often linked to disease flares.
• Pyoderma Gangrenosum: Ulcerative lesions requiring corticosteroids or biologics.
  
  

• Manifestations: Episcleritis, uveitis, iritis.
• Management: Topical or systemic corticosteroids and ophthalmologic referral.
  
  

• Anaemia:
  • Causes: Chronic inflammation, iron deficiency, vitamin B12 or folate deficiency.
  • Management: Treat underlying cause, nutritional supplementation.
• Thrombosis:
  • CD is associated with a hypercoagulable state.
  • Preventive measures include anticoagulation in high-risk patients.
    
    

Treatment-Related Complications

• Adverse Effects:
  • Azathioprine: Risk of sepsis and lymphoma.
  • Methotrexate: Myelosuppression, hepatotoxicity, pulmonary fibrosis.
• Monitoring:
  • Regular blood counts and liver function tests.
  • Avoid live vaccinations and assess prior exposure to infections (e.g., varicella, hepatitis B).
    
    

• Tumor Necrosis Factor (TNF)-alpha Inhibitors:
  • Risks: Tuberculosis reactivation, opportunistic infections.
  • Pre-treatment: Screening for latent tuberculosis, hepatitis B, and C.
  • Long-term: Slightly increased risk of malignancies (e.g., lymphoma).
    
    

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