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Concepts in Inflammatory Bowel Disease Management

Overview

  • Inflammatory Bowel Diseases (IBDs): Chronic, idiopathic inflammatory disorders of the intestinal tract, primarily including Ulcerative Colitis (UC) and Crohn Disease (CD).
  • Characteristics:
    • Chronic, relapsing course.
    • Profound effects on patients' lives.
    • Significant challenges for healthcare systems.
  • Current State:
    • No curative medical therapy available.
    • Advances in understanding have improved health outcomes.

Genetics of IBD

Familial Aggregation and Genetic Susceptibility

  • Familial Aggregation: Strongest risk factor; first-degree relatives have ~15-fold higher risk.
  • Ethnic Differences: Variations in incidence and prevalence suggest genetic factors.
  • Associated Genetic Disorders:
    • Ankylosing spondylitis.
    • Psoriasis.
    • Glycogen storage disease type 1b.
    • Hermansky-Pudlak syndrome.

Twin Concordance Studies

  • Monozygotic Twins:
    • CD Concordance: 35%–58%.
    • UC Concordance: 16%–19%.
  • Dizygotic Twins:
    • CD Concordance: 0%–4%.
    • UC Concordance: 0%–5%.
  • Conclusions:
    • Both genetic and environmental factors contribute.
    • Stronger genetic influence in CD compared to UC.

Identification of Susceptibility Genes

Linkage Studies

  • Chromosome 16 (IBD1 locus): First CD susceptibility gene mapped.
  • NOD2 Gene:
    • Located on chromosome 16.
    • Encodes an intracellular receptor binding muramyl dipeptide (MDP).
    • Variants:
      • Three low-frequency risk variants identified.
      • Odds Ratios (ORs):
        • Heterozygotes: OR 2–4.
        • Homozygotes: OR 20–40.
      • Present in 30%–40% of CD cases (European descent).

Genome-Wide Association Studies (GWAS)

  • Technological Advances: Mapping using selected single nucleotide polymorphisms (SNPs).
  • Key Discoveries:
    • TNFSF15: Associated with CD in Japanese population.
    • IL23R: Susceptibility gene for both UC and CD; implicates the IL-23/Th17 axis.
    • Autophagy Genes: ATG16L1 and IRGM.
    • Innate Immunity Genes: TLR4, CARD9, STAT3.
    • Adaptive Immunity Genes: HLA, IRF5, PTPN22.

Meta-Analyses of GWAS

  • Large-Scale Studies:
    • Over 75,000 cases and controls.
    • Identified 163 IBD loci.
  • Shared Loci:
    • 110 loci confer risk to both UC and CD.
  • Disease-Specific Loci:
    • CD-specific: 30 loci.
    • UC-specific: 23 loci.
  • Notable Genes and Pathways:
    • NOD2: Highest risk for CD in Europeans (OR ~1.5).
    • HLA: Major risk factor for UC (OR ~1.15).
    • Cytokine Signaling: IFN-γ, IL12, TNF-α, IL10.
    • Th17 Signaling Pathway: IL23R, IL12B, JAK2, TYK2, STAT3.

Multiethnic Association Studies

  • Expanded Cohorts:
    • Included individuals of East-Asian, Indian, and Iranian descent.
    • Added 38 new IBD loci.
  • Findings:
    • Direction and magnitude of effects consistent across populations.
    • Genetic heterogeneity observed at some loci due to differences in allele frequencies and effect sizes.

Key Points Summary (Table 161.1)

  • Polygenic Nature:
    • Both UC and CD are polygenic.
    • CD has a stronger genetic influence.
  • Confirmed IBD Loci: Over 200 loci identified.
    • CD-specific: 37 loci.
    • UC-specific: 27 loci.
    • Common to Both: 137 loci.
  • Genetic Variation Across Ethnicities:
    • Genetic architecture varies among different populations.
  • Shared Susceptibility:
    • IBD shares genes with other immune-mediated disorders.
  • Major Risk Factors:
    • NOD2: Highest risk for CD in Caucasians.
    • HLA: Major risk factor for UC in all populations.
  • Homeostatic Pathways Involved:
    • Innate Immunity.
    • Autophagy (notably in CD).
    • Antimicrobial Defense.
    • IL-17/IL-23 Pathway.
    • Adaptive Immunity.
    • Barrier Function and Epithelial Restitution.

Rare Variants and Whole Exome Sequencing (WES)

  • Limitations of GWAS:
    • Remaining genetic contributions from rare variants.
  • WES Applications:
    • Identifies rare mutations not detected by GWAS.
    • Example: Mutation in XIAP gene in a boy with intractable CD.
  • Very Early Onset IBD (VEOIBD):
    • Occurs in children <6 years old.
    • Often resistant to standard therapies.
    • Associated with single gene mutations (e.g., IL-10, IL-10R, NCF2, LRBA, TTC7).

Epidemiology of Inflammatory Bowel Disease (IBD)

  • Modern Disease: IBD diagnoses increased significantly in the second half of the 20th century.
  • Highest Prevalence and Incidence:
    • Western World: Europe, North America, and Oceania.
      • Prevalence: Up to 0.5%.
      • Incidence: 10–30 per 100,000 per year.
  • Europe:
    • Highest Incidence: Western Europe.
    • Lower Incidence: Countries adjacent to the Mediterranean.
    • Variable Incidence: Eastern Europe (ranges from low to high).
  • Non-Western Countries:
    • Limited data from Japan, China, South Korea, South America, and South Africa.
    • Significantly lower incidence compared to Western countries.
  • Migration Studies:
    • Emigrants from low-prevalence countries to developed nations show an increased incidence of IBD in successive generations.
    • Highlights the importance of environmental factors in disease development.
  • Increasing Incidence in Western countries confirmed by time-trend analyses.
  • Fading North-South Gradient in Europe regarding IBD incidence.
  • Rising Incidence in Urbanized Societies:
    • East Asia: South Korea, Japan, China, Hong Kong.
    • Developing Countries.
  • Disproportionate Increase in Childhood IBD over recent decades.

Environmental Factors

Western Diet

  • Sequential Rise of IBD linked to adoption of a high–animal fat/low-fiber Western diet.
  • Observational Studies:
    • Increased Risk:
      • High consumption of meat and fats.
      • Particularly polyunsaturated fatty acids (PUFAs) and omega-6 (n-6) fatty acids.
    • Protective Factors:
      • Diets rich in fiber, fruits, and vegetables.
  • Key Studies:
    • European Prospective Investigation into Cancer and Nutrition (EPIC):
      • Higher intake of linoleic acid (an n-6 PUFA found in red meat, cooking oils, margarine) linked to a higher incidence of Ulcerative Colitis (UC).
      • Higher consumption of omega-3 (n-3) PUFA docosahexaenoic acid associated with a lower incidence of UC.
    • Nurses’ Health Study:
      • Greater intake of long-chain n-3 PUFAs and a higher n-3:n-6 PUFA ratio were protective against UC.
      • Higher consumption of fiber, especially from fruits, correlated with a lower risk of Crohn Disease (CD) but not UC.

Other Environmental Factors

  • Cigarette Smoking:
    • Crohn Disease (CD):
      • Increased Risk and more aggressive disease progression.
      • Complications include stricturing, fistulizing disease, need for immunosuppressive therapy and surgery, earlier postoperative recurrence, and increased reoperation rates.
      • Smoking Cessation:
        • Leads to decreased CD activity.
        • Lowers risk of postoperative recurrence.
    • Ulcerative Colitis (UC):
      • Protective Effect: Lower risk of disease reactivation and colectomy.
  • Appendectomy:
    • Before age 20 for appendicitis (not nonspecific abdominal pain) associated with a lower incidence of UC.
  • Vitamin D Deficiency:
    • Linked to an increased risk of both UC and CD.
  • Nonsteroidal Anti-inflammatory Drugs (NSAIDs):
    • Associated with an increased risk of developing both UC and CD.

Key Points Summary (Table 161.2)

  • Highest Prevalence and Incidence of IBD are in the Western world.
  • IBD Frequency Increasing in developing countries.
  • Disproportionate Increase in the pediatric population.
  • Over 1 million Americans are affected by IBD.
  • Significant Burden on the U.S. healthcare system.

Etiopathogenesis of Inflammatory Bowel Disease (IBD)

Animal Models of IBD

  • Development Period: 1990s and early 2000s.
  • Types of Models:
    • Aberrant Immunoregulation Models:
      • Genetically Engineered Mice:
        • Underexpressed Immune Molecules: IL2−/−, IL10−/−, TCR−/−.
        • Overexpressed Immune Molecules: TNF1ΔARE, STAT4.
      • Regulatory T-Cell Transfer: CD45RB^high → SCID mice.
    • Epithelial Barrier Defect Models:
      • Defective Barrier Genes: Dominant-negative N-cadherin, mdr1a−/−, Muc2−/−.
    • Toxin-Induced Colitis:
      • TNBS-Induced Colitis.
  • Inflammatory Profiles:
    • Th1 Response:
      • Excessive secretion of IL-12, IFN-γ, TNF-α.
      • Associated with Crohn Disease (CD).
    • Th2 Response:
      • Increased levels of IL-4, IL-5, IL-13.
      • Ulcerative Colitis (UC) is an atypical Th2 disorder:
        • Enhanced production of IL-5 and IL-13.
        • Low levels of IL-4.
  • Discovery of Th17 Cells:
    • Early 2000s: Shift from Th1/Th2 paradigm.
    • Th17 Cells:
      • Stimulated by IL-23.
      • IL-17 production increased in some animal models and in IBD, especially CD.
    • Genetic Link:
      • IL23R identified as an IBD susceptibility gene in 2006 GWAS.

Limitations of Animal Models

  • Genetic Homogeneity:
    • Models have single genetic defects vs. the genetic heterogeneity in human IBD.
  • Incomplete Disease Representation:
    • Most models do not replicate small bowel disease or complications like strictures and fistulas.
  • Key Insight:
    • Germ-Free Conditions:
      • Susceptible animals do not develop IBD without exposure to microbes.
      • Highlights the critical role of commensal intestinal flora in IBD pathogenesis.

Gene Discovery and Autophagy

  • NOD2 Gene:
    • First Gene definitively linked to CD.
    • Encodes an intracellular receptor in intestinal monocytes and Paneth cells.
    • Binds muramyl dipeptide (MDP), a component of bacterial cell walls.
    • Implications:
      • Suggests IBD partly results from an aberrant innate immune response to bacterial motifs.
  • Mechanistic Uncertainties:
    • Loss-of-Function Mutations in NOD2 may lead to:
      • Decreased Antibacterial Activity of Paneth cells.
      • Impaired autophagy—the body's way of cleaning out damaged cells and pathogens.
      • Loss of tolerogenic (anti-inflammatory) functions under chronic MDP stimulation.
  • Other Autophagy Genes:
    • ATG16L1 and IRGM also increase CD risk.
  • Impaired Autophagy Studies:
    • In Vitro Findings:
      • NOD2 and ATG16L1 risk alleles linked to impaired autophagy of pathogens like Salmonella.
    • Monocyte Studies:
      • CD patients with ATG16L1 risk allele have monocytes less effective at killing adherent-invasive Escherichia coli.
    • ATG16L1-Deficient Mice:
      • Show impaired autophagy in the ileum.
      • Paneth Cell Abnormalities:
        • Decreased, aberrant, and disorganized granules.
        • Defective granule exocytosis.
      • Altered expression of genes regulating response to cell injury.
    • Human Correlation:
      • CD patients homozygous for ATG16L1 risk allele exhibit similar Paneth cell defects.

Intestinal Microbiome (Dysbiosis)

  • New Frontier in IBD Research.
  • Gut Microbiota:
    • Trillions of microbial cells in the intestine.
    • Microbial genes vastly outnumber human genes (~10 million microbial genes).
  • Functions of Microbiota:
    • Homeostasis:
      • Maturation and education of the immune system.
      • Protection against pathogens.
      • Detoxification.
  • Dysbiosis:
    • Imbalance in microbial composition.
    • Changes in relative abundance of bacterial taxa.
    • Decreased Diversity of the microbial community.
  • Interactions with Autophagy Genes:
    • ATG16L1 Risk Allele Effects:
      • Inflamed ileal tissue shows increased Fusobacteriaceae.
      • Protective allele associated with different microbial patterns.
    • Noninflamed Tissue: ATG16L1 allele does not affect bacterial composition.
  • Functional Changes:
    • Dysbiosis includes alterations in microbial functions, not just composition.
  • Intestinal Virome:
    • Changes in the virome (viruses within the gut) observed in IBD patients.
  • Causality Considerations:
    • Dysbiosis is not definitively a cause of inflammation.
    • May be a result of inflammation.
    • Possible bidirectional relationship between microbiota and inflammation.

Diet and the Microbiome

  • Diet as a Determinant:
    • Dietary habits significantly influence the intestinal microbiome.
  • Comparative Studies:
    • European vs. African Children:
      • Significant differences in gut microbiota linked to diet.
    • U.S. vs. Malawi and Venezuelan Populations:
      • Pronounced differences in bacterial composition and functional genes.
  • Dietary Components Influencing Microbiome:
    • Animal Protein and Fat.
    • Fiber Intake.
  • Potential Mechanisms Linking Diet to IBD:
    • Alteration of Microbiome: Western diet may promote growth of pro-inflammatory bacteria.
    • Epithelial Barrier Effects: Diet may impact gut lining integrity.
    • Inflammatory Mediators: Dietary components may influence inflammation.
  • Other Influencing Factors:
    • Mode of Birth (e.g., cesarean vs. vaginal delivery).
    • Age.
    • Infections.
    • Antibiotic Use.
    • Gut Inflammation.
    • Genetics.
    • Cigarette Smoking.

Summary and Current Understanding

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  • Advancements in Understanding IBD Pathogenesis:
    • Focus on abnormal immune regulation via the IL-17/IL-23 pathway.
    • Recognition of autophagy defects.
    • Importance of intestinal dysbiosis.
  • Development of Complex Animal Models:
    • Incorporate:
      • Autophagy abnormalities.
      • Interactions with specific commensal bacteria and viruses.
      • Dietary interventions.
  • Current Model of IBD Pathogenesis:
    • Genetic Susceptibility and environmental factors are necessary but not sufficient alone.
    • Intestinal Dysbiosis is suspected to be a major pro-inflammatory factor.
    • The Western diet may promote growth of bacteria that contribute to intestinal inflammation.

Phenotypic Variability of Inflammatory Bowel Disease (IBD)

Overview

  • Phenotypic Variability: IBD exhibits significant variation in disease presentation and progression.
  • Crohn Disease (CD):
    • Initially described as affecting the terminal ileum.
    • Later recognized to involve proximal small bowel and/or colon.
    • Variability in age of onset and risk of stricturing, perforating, and perianal complications.
  • Ulcerative Colitis (UC):
    • Presentation ranges from nonprogressive proctitis to extensive colitis or pancolitis.
    • Some patients experience proximal extension of initially distal disease.
    • Younger age at diagnosis associated with a greater risk of colectomy.

Montreal Classification (2005)

  • Purpose: Standardize IBD phenotypes for consistency in clinical studies.
  • Categories:
    • Crohn Disease (CD):
      • Age of Onset.
      • Disease Location.
      • Disease Behavior:
        • Stricturing or penetrating complications.
        • Perianal disease.
    • Ulcerative Colitis (UC):
      • Disease Extent.
      • Severity of Relapses.
    • IBD Type Unclassified (IBDU):
      • Isolated colitis without clear evidence favoring CD or UC.

  • Limitations:

    • Does not classify UC by age at diagnosis.
    • Lacks classification based on long-term risk.

    Table 161.3: Montreal Classification of Inflammatory Bowel Disease (IBD):

    Crohn's Disease

    • Age at Diagnosis (A):
      • A1: 16 years or younger.
      • A2: 17–40 years.
      • A3: Over 40 years.
    • Location (L):
      • L1: Terminal ileum.
      • L2: Colon.
      • L3: Ileum and colon.
      • L4: Upper GI.
      • Upper Gastrointestinal (GI) modifier (L4):
        • L1 + L4: Terminal ileum and upper GI.
        • L2 + L4: Colon and upper GI.
        • L3 + L4: Ileocolic and upper GI.
    • Behavior (B):
      • B1: Non-stricturing, nonpenetrating.
      • B2: Stricturing.
      • B3: Penetrating.
      • Perianal Disease Modifier (P):
        • B1p: Nonpenetrating and perianal.
        • B2p: Stricturing and perianal.
        • B3p: Penetrating and perianal.

    Ulcerative Colitis

    • Disease Extent (E):
      • E1: Ulcerative proctitis (limited to the rectum).
      • E2: Left-sided UC (limited to colon distal to splenic flexure).
      • E3: Extensive UC (disease proximal to splenic flexure).
    • Disease Severity (S):
      • S0: Clinical remission (no symptoms).
      • S1 (Mild): Four or fewer stools/day, with or without blood, no systemic illness, normal inflammatory markers.
      • S2 (Moderate): More than four stools/day with minimal signs of systemic toxicity.
      • S3 (Severe): Six or more bloody stools/day, pulse rate ≥90 beats/min, temperature ≥37.5°C, hemoglobin <10.5 g/100 mL, ESR ≥30 mm/h.

Genetic and Environmental Correlations with Phenotype

  • Genetic Factors:
    • NOD2 Mutations:
      • Associated with small bowel CD and stricturing complications.
    • HLA-DRB1*0103 Allele:
      • Linked to severe and extensive UC.
    • Large-Scale Study Findings:
      • Three Loci Associated with IBD Phenotype:
        • NOD2, MHC (HLA region), MST1 (3p21).
      • NOD2:
        • Correlated with CD location, behavior, and age at diagnosis.
        • Influence on behavior largely due to its association with location and age.
      • HLA:
        • Linked to age of onset, CD location and behavior, UC extent, and need for surgery.
      • MST1:
        • Associated with age of IBD onset.
      • Genetic Risk Scores:
        • Combined data from 163 IBD genes.
        • Classified IBD into:
          • Ileal CD.
          • Colonic CD.
          • UC.
        • Suggests disease location is partly genetically determined.
  • Environmental Factors:
    • Cigarette Smoking:
      • Increased risk of complicated CD.
      • Decreased risk of severe UC requiring colectomy.
    • Intestinal Microbiome:
      • Early research indicates specific bacteria may influence disease complications.
      • Ruminococcus linked to stricturing in CD.
      • Veillonella linked to penetrating complications.
      • Potential interactions between microbiome and genetics.

Future Directions in Classification

  • Advancements:
    • Integration of genetic, microbiomic, and inflammatory pathway data.
    • Use of computational methods to develop comprehensive classification schemes.
  • Goals:
    • Incorporate systems biology of IBD.
    • Provide risk stratification.
    • Predict therapeutic responses.

Variation in Care and Quality Improvement in Inflammatory Bowel Disease

Variation in Care

  • Impact on Healthcare:
    • Leads to differences in quality, outcomes, and costs.
    • Identified as a target for quality improvement.
  • Areas of Variation:
    • Anemia Management.
    • Vaccination Practices.
    • Venous Thromboembolism (VTE) Prophylaxis.
    • Clostridium difficile Testing.
    • Colectomy Rates for UC:
      • Geographical disparities within the U.S.
  • Variation Among Specialists:
    • Significant differences in treatment approaches, even among IBD experts.
    • Study showed wide ranges in the use of:
      • Immunomodulators.
      • Prednisone.
      • Antibiotics.
      • Aminosalicylates.
      • Infliximab.

Principles of Medical Therapy in Inflammatory Bowel Disease (IBD)

Overview

  • Ulcerative Colitis (UC) and Crohn Disease (CD) are lifelong diseases with a relapsing and remitting course.
  • Main Goals of Therapy:
    • Induction of Clinical Remission: Achieving symptom-free periods.
    • Maintenance of Remission: Preventing disease relapse.
  • Additional Goals:
    • Improve quality of life.
    • Prevent complications:
      • Disease-related: e.g., strictures, fistulas.
      • Treatment-related: e.g., opioid dependence, excessive diagnostic radiation exposure.
    • Restore and maintain nutritional status.
    • Optimize preoperative status.
    • In CD, prevent postoperative recurrence.

Assessment of Disease Severity

  • Traditional Approach: Based on symptoms and laboratory indicators.

  • Disease Activity Classification:

    Ulcerative Colitis (UC)

    • Mild
    • Moderate
    • Severe
    • Based on Truelove-Witts Criteria:
      • Frequency of diarrhea
      • Presence of blood in stool
      • Fever
      • Heart rate
      • Hemoglobin levels
      • Erythrocyte sedimentation rate (ESR)

    Crohn Disease (CD)

    • Remission: Asymptomatic, off steroids.
    • Mild-Moderate Disease: Mild symptoms without severe systemic signs.
    • Moderate-Severe Disease: Prominent symptoms like fever, weight loss, abdominal pain.
    • Severe-Fulminant Disease: Persistent symptoms despite treatment, signs of obstruction or abscess.
    • Limitations:
    • Inadequate for Regulatory Purposes: Lacks objective measures.
    • Development of Disease Activity Indices:
      • Incorporate symptoms, signs, laboratory results, and sometimes endoscopic activity.
      • Example: Crohn's Disease Activity Index (CDAI).
      • CDAI Limitations: Poor correlation with endoscopic activity.

Role of Endoscopy

  • Most Objective Assessment of disease severity, especially in UC.
  • Endoscopic Healing:
    • Definition: Absence of visible inflammation on endoscopy.
    • Associated with improved long-term outcomes in both UC and CD.
    • Goals:
      • Sustained Clinical Remission.
      • Steroid-Free Remission.
      • Reduced hospitalizations and surgeries.
  • Challenges:
    • Achievability: Even potent therapies achieve endoscopic healing in a minority of patients.
    • Disease Duration: Longer-standing CD responds less well to therapy.
  • Consensus: Endoscopic healing should be a treatment goal in clinical practice.

Risk Stratification in Therapy Selection

  • Traditional Approach:
    • Based solely on current symptom severity.
    • Does not account for long-term risks (e.g., strictures, colectomy).
  • Evolving Approach:
    • Incorporates endoscopic severity and predictors of long-term risk.
    • Risk Factors:
      • Young age at diagnosis
      • Extensive disease
      • Need for steroids at diagnosis
      • Perianal disease at diagnosis
    • Guideline Recommendations:
      • Use of immunomodulators and biologics in high-risk patients.
      • Future algorithms will emphasize risk stratification.

Classes of Medical Therapies for IBD

  • Aminosalicylates: First-line for mild to moderate UC.
  • Corticosteroids: Used for induction of remission in both UC and CD.
  • Immunomodulators:
    • Thiopurines: AZA and 6-MP.
    • Methotrexate: Used mainly in CD.
  • Biologic Therapies:
    • Anti-Tumor Necrosis Factor-alpha (Anti-TNF-α) Agents: Infliximab, adalimumab, golimumab, certolizumab pegol.
    • Integrin Receptor Antagonists: Vedolizumab.
    • Interleukin Inhibitors: Ustekinumab (in CD).
  • Calcineurin Inhibitors: Cyclosporine and tacrolimus (mainly in UC).
  • Antibiotics: Limited role, mainly in perianal CD.

Medical Therapies for Ulcerative Colitis (UC)

Aminosalicylates (5-ASA)

  • Mechanism of Action:
    • Inhibit NF-κB activation.
    • Inhibit prostaglandin synthesis.
    • Scavenge free radicals.
  • Formulations:
    • Sulfasalazine (SASP):
      • Combines sulfapyridine and 5-ASA.
      • Sulfapyridine: Carrier molecule; responsible for most side effects.
    • Mesalamine (5-ASA):
      • Sulfa-free formulations.
      • Designed for colon-specific release.
  • Efficacy:
    • Induction of remission in mild to moderate UC.
    • Remission Rates: Approximately 40% with 5-ASA vs. 20% with placebo.
  • Dosing:
    • Induction: 2.0–4.8 g/day.
    • Maintenance: Same as induction; higher doses may be more effective.
  • Rectal Formulations:
    • Suppositories: For distal 10 cm of rectum.
    • Enemas: Reach up to the splenic flexure.
    • Combination Therapy: Oral + rectal 5-ASA is more effective.
  • Use in UC:
    • First-line treatment for mild to moderate UC.
    • Effective for both induction and maintenance of remission.
    • Rectal formulations (suppositories, enemas) are beneficial for distal UC.
  • Side Effects:
    • Generally well-tolerated.
    • May cause diarrhea, headaches, rare pancreatitis, and interstitial nephritis.
  • Common Errors:
    • Not optimizing dose.
    • Neglecting rectal therapies in distal disease.
    • Using formulations with high pill burden, affecting compliance.

Corticosteroids

  • Uses:
    • Induction of Remission:
      • Mild-Moderate Disease: Oral steroids.
      • Severe Disease: Intravenous (IV) steroids.
      • Distal Disease: Topical steroids (foams, enemas).
  • Dosing:
    • Oral Prednisone: 40–60 mg/day until remission, then tapered.
    • IV Methylprednisolone: 20 mg every 8 hours.
    • Budesonide: Extended-release formulations for mild-moderate UC.
  • Efficacy:
    • Effective in reducing inflammation and inducing remission.
  • Use in UC:
    • Induction of Remission:
      • Mild-Moderate UC: Oral or rectal steroids.
      • Severe UC: Intravenous steroids.
    • Not effective for maintenance of remission.
  • Side Effects:
    • Short-Term: Hyperglycemia, fluid retention, mood changes.
    • Long-Term: Osteoporosis, hypertension, infection risk, adrenal suppression.
  • Monitoring:
    • Assess response by day 3 in severe UC.
  • Important Considerations:
    • Systemic steroids indicate a more aggressive disease course.
    • Steroid-Sparing Agents should be initiated to maintain remission.

Cyclosporine

  • Role:
    • Rescue Therapy in severe, steroid-refractory UC.
    • Alternative to colectomy in acute settings.
  • Administration:
    • IV Infusion: 2 mg/kg/day.
    • Adjust dose to achieve target serum concentrations (150–250 ng/mL).
  • Efficacy:
    • Short-term avoidance of colectomy in approximately 80% of patients.
  • Use in UC:
    • Rescue therapy for severe UC failing intravenous steroids.
    • Administered as continuous IV infusion.
  • Limitations:
    • High relapse rates without thiopurine maintenance.
    • Significant toxicity and need for intensive monitoring.
  • Adverse Effects:
    • Nephrotoxicity, hypertension, seizures, infections.
  • Usage Considerations:
    • Reserved for compliant patients under expert care.
    • Prophylaxis against Pneumocystis jiroveci is required.

Thiopurines (Azathioprine and 6-Mercaptopurine)

  • Mechanism of Action:
    • Immunomodulation by inhibiting DNA/RNA synthesis.
    • Induce apoptosis of activated T cells.
  • Metabolism:
    • Metabolized to active 6-thioguanine nucleotides (6-TGN).
    • Thiopurine Methyltransferase (TPMT) enzyme activity affects dosing.
    • TPMT Testing is mandatory before initiation.
  • Efficacy:
    • Effective in maintaining steroid-free remission.
    • Used in steroid-dependent or frequently relapsing UC.
  • Combination Therapy:
    • Enhances efficacy of anti-TNF-α agents by reducing anti-drug antibodies (ADAs).
  • Use in UC:
    • Maintenance of remission in steroid-dependent patients.
    • Combination therapy with anti-TNF-α agents to enhance efficacy and reduce antibody formation.
  • Adverse Effects:
    • Leukopenia, hepatotoxicity, pancreatitis.
    • Increased risk of lymphoma and non-melanoma skin cancer.
  • Monitoring:
    • Regular blood counts and liver function tests.
    • Therapeutic Drug Monitoring guides dosing adjustments.

Anti-Tumor Necrosis Factor-alpha (Anti-TNF-α) Agents

  • Agents:
    • Infliximab (Remicade): IV administration.
    • Adalimumab (Humira): Subcutaneous (SC) administration.
    • Golimumab (Simponi): SC administration.
  • Mechanism of Action:
    • Neutralize soluble and membrane-bound TNF-α.
    • Induce apoptosis of inflammatory cells.
  • Indications:
    • Moderate to Severe UC:
      • As first-line therapy.
      • In steroid-dependent or steroid-refractory patients.
  • Efficacy:
    • Induce and maintain remission.
    • Infliximab shows rapid onset; useful in hospitalized patients.
  • Combination Therapy:
    • Thiopurines can be added to reduce immunogenicity and enhance efficacy.
  • Use in UC:
    • Induction and maintenance of remission in moderate to severe UC.
    • Effective in steroid-refractory or steroid-dependent disease.
    • Infliximab can be used in severe UC failing IV steroids.
  • Adverse Effects:
    • Infusion/injection reactions.
    • Infections: Bacterial, tuberculosis, fungal.
    • Hepatotoxicity, heart failure exacerbation, demyelinating disorders.
  • Monitoring:
    • Screen for latent tuberculosis and hepatitis B before initiation.
    • Therapeutic Drug Monitoring helps manage loss of response.

Vedolizumab (Entyvio)

  • Mechanism of Action:
    • Targets α4β7 integrin on lymphocytes.
    • Blocks lymphocyte trafficking to the gut.
  • Efficacy:
    • Effective in inducing and maintaining remission in UC.
    • More effective in anti-TNF-α naïve patients.
  • Indications:
    • Moderate to Severe UC:
      • As first-line therapy.
      • In patients with inadequate response or intolerance to anti-TNF-α agents.
  • Use in UC:
    • Induction and maintenance of remission in moderate to severe UC.
    • Option for patients who failed anti-TNF-α therapy.
  • Administration:
    • IV Infusion at standard intervals.
    • Some patients may require dose escalation.
  • Safety Profile:
    • Generally well-tolerated.
    • No reported cases of progressive multifocal leukoencephalopathy (PML).

Other Therapies

  • Methotrexate:
    • Not effective in UC at standard doses.
  • Antibiotics:
    • No proven benefit in UC when added to steroids.
  • Fecal Microbiota Transplantation (FMT):
    • Mixed results; not recommended in guidelines.
  • Probiotics:
    • Inconsistent evidence; generally not recommended.
  • Nicotine:
    • May reduce symptoms in active UC but not effective for maintenance.
  • Diet and Nutrition:
    • No specific dietary guidelines.
    • Patients may be advised to avoid aggravating foods.
  • Antidiarrheal Agents:
    • Useful for symptom relief in mild disease.
    • Contraindicated in severe disease due to risk of toxic megacolon.

Approach to Therapy in Ulcerative Colitis

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Mild UC

Ulcerative Proctitis or Proctosigmoiditis

  • Induction Therapy:
    • Rectal 5-ASA = First line for distal UC(suppositories or enemas)
    • Oral 5-ASA
    • Combination therapy is more effective than monotherapy.
    • Rectal steroids may be used instead of rectal 5 -ASA
  • Maintenance Therapy:
    • Continued use of rectal and/or oral 5-ASA.

Left-Sided and Extensive UC

  • Induction Therapy:
    • Oral 5-ASA (higher doses may be needed)
    • Rectal 5-ASA for distal symptoms.
  • Maintenance Therapy:
    • Oral 5-ASA, possibly with rectal 5-ASA.

Moderate UC

  • Induction Therapy Options:
    • Oral Corticosteroids (e.g., prednisone)
    • Budesonide (for less severe cases)
    • Anti-TNF-α Agents
    • Vedolizumab
  • Maintenance Therapy:
    • Thiopurines (after steroid induction)
    • Anti-TNF-α Agents (continue if used for induction)
    • Vedolizumab

Severe UC

  • Induction Therapy:
    • Intravenous Corticosteroids
      • Assess response after 3 days.
    • Infliximab (alternative to steroids or after steroid failure)
    • Cyclosporine (after failure of IV steroids)
  • Maintenance Therapy:
    • Thiopurines
    • Anti-TNF-α Agents
    • Vedolizumab
  • Surgical Consultation:
    • Considered if there is no response to medical therapy.

Summary of Key Points

  • Treatment Phases:
    • Induction of Remission: Achieving symptom control.
    • Maintenance of Remission: Preventing relapse.
  • Therapy Selection:
    • Based on disease severity and risk stratification.
    • Endoscopic healing is an important goal.
  • Medication Highlights:
    • 5-ASA: First-line for mild to moderate UC.
    • Corticosteroids: Effective for induction but not maintenance.
    • Thiopurines: Useful for maintenance and as steroid-sparing agents.
    • Anti-TNF-α Agents: Effective for moderate to severe UC.
    • Vedolizumab: Option for moderate to severe UC, especially after anti-TNF failure.
  • Adverse Effects and Monitoring:
    • Be vigilant for infections, organ toxicities, and malignancies.
    • Regular laboratory monitoring is essential.
  • Importance of Individualized Care:
    • Therapy should be tailored to each patient's disease severity, risk factors, and response to treatment.
    • Patient education on medication adherence and side effect recognition is crucial.

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Medical Therapies for Crohn Disease (CD)

Corticosteroids

  • Uses:
    • Induction of Remission in moderate to severe CD.
    • Oral Steroids: Prednisone.
    • Budesonide: For mild to moderate ileocecal CD.
    • IV Steroids: For severe, hospitalized patients.
  • Limitations:
    • Do not induce mucosal healing.
    • Not effective for perianal fistulizing disease.
  • Important Consideration:
    • Steroid use indicates aggressive disease; initiate steroid-sparing agents.

Antibiotics

  • Limited Role in luminal CD.
  • Perianal Fistulas:
    • Metronidazole and Ciprofloxacin may reduce fistula drainage.
    • Used as adjunctive therapy but do not heal fistulas.
  • Postoperative Prophylaxis:
    • Reduce recurrence but less effective than other agents.
  • Other Uses:
    • Treat small intestinal bacterial overgrowth.
    • Address septic complications.

Thiopurines

  • Uses:
    • Maintenance Therapy in steroid-dependent CD.
    • May provide long-term benefits if initiated early.
  • Combination Therapy:
    • Combined with anti-TNF-α agents to reduce immunogenicity.
  • Efficacy:
    • Less effective than anti-TNF-α agents in preventing postoperative recurrence.
  • Adverse Effects and Monitoring:
    • Similar to UC; TPMT testing and regular monitoring required.

Methotrexate

  • Mechanism of Action:
    • Stimulates release of adenosine, leading to anti-inflammatory effects.
  • Uses:
    • Effective in maintaining remission.
    • Steroid-sparing agent.
  • Administration:
    • Typically 15 mg intramuscularly weekly.
  • Limitations:
    • Not effective for induction of remission.
    • No data supporting use in perianal disease or postoperative prevention.

Anti-TNF-α Agents

  • Agents:
    • Infliximab, Adalimumab, Certolizumab Pegol.
  • Mechanism of Action:
    • Neutralize TNF-α and reduce inflammation.
  • Uses:
    • Induction and Maintenance of remission in moderate to severe CD.
    • Effective for perianal fistulizing disease.
  • Combination Therapy:
    • Best outcomes with thiopurine or methotrexate added.
  • Efficacy:
    • Induce mucosal healing.
    • Decrease hospitalizations and surgeries.
  • Adverse Effects:
    • Similar to UC; infections, infusion reactions, screening required.

Vedolizumab

  • Mechanism of Action:
    • Blocks lymphocyte trafficking to the gut.
  • Uses:
    • Moderate to Severe CD.
    • May be effective in anti-TNF-α experienced patients, but with delayed onset.
  • Efficacy:
    • Induces mucosal healing.
  • Safety Profile:
    • Favorable, with no significant safety concerns identified.

Ustekinumab (Stelara)

  • Mechanism of Action:
    • Targets p40 subunit of IL-12 and IL-23 cytokines.
  • Uses:
    • Moderate to Severe CD, including anti-TNF-α failures.
    • Ideal for patients with psoriasis or anti-TNF-α induced psoriasis.
  • Administration:
    • Initial IV dose based on weight.
    • Maintenance: 90 mg SC every 8 weeks.
  • Safety Profile:
    • Well-tolerated; similar safety in psoriasis patients.

Approach to Therapy in Crohn Disease

  • Key Observations:
    • Symptoms do not correlate well with disease activity.
    • Endoscopic Healing predicts better outcomes.
  • Treatment Goals:
    • Achieve clinical and endoscopic remission.
  • Risk Stratification:
    • Assess current inflammatory burden and long-term risk factors.
    • Low-Risk Patients:
      • Treated with budesonide or prednisone, with or without AZA.
    • High-Risk Patients:
      • Treated with anti-TNF-α monotherapy or combination therapy.
  • Therapy Considerations:
    • Early use of anti-TNF-α agents in high-risk patients.
    • Methotrexate for patients intolerant to thiopurines.

  • Emerging Therapies:

    • Positioning of vedolizumab and ustekinumab in treatment algorithms is evolving.

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Principles of Surgical Management in Inflammatory Bowel Disease (IBD)

Overview

  • Surgical Intervention:
    • Ulcerative Colitis (UC):
      • Approximately 20–30% of patients may require colectomy.
      • Surgery is curative.
    • Crohn Disease (CD):
      • About 50% of patients may need surgical procedures during their lifetime.
      • Surgery addresses complications but is not curative.

Indications for Surgery

Ulcerative Colitis (UC)

  • Medical Refractory Disease: Failure to respond to medical therapy.
  • Dysplasia or Carcinoma: Presence of precancerous or cancerous lesions.
  • Other Indications:
    • Toxic Megacolon.
    • Uncontrolled Hemorrhage.
    • Perforation.
    • Obstruction or Stricture (raising concern for malignancy).
    • Failure to Thrive in pediatric patients.

Crohn Disease (CD)

  • Complications:
    • Obstruction due to strictures.
    • Free Perforation of the bowel.
    • Abscesses: Intraabdominal or pelvic.
    • Symptomatic Fistulas: Enteroenteric, enterocutaneous, perianal.
    • Cancer: Increased risk in longstanding disease.
  • Note: Surgery is less frequently performed for medically refractory disease due to advances in pharmacotherapy.

Optimizing Surgical Outcomes

  • Patient Education and Empowerment:
    • Inform patients about:
      • Indications for surgery.
      • Preoperative Preparations.
      • Surgical Approach.
      • Recovery Process.
      • Expected Outcomes and Potential Complications.
    • Help patients set realistic expectations for postoperative bowel habits and quality of life.

Preoperative Optimization Principles

  1. Early Assessment:
    • Comprehensive history and physical examination.
    • Evaluation by surgeon and anesthesiologist.
  2. Modifiable Risk Factors:
    • Smoking Cessation.
    • Glycemic Control.
    • Correction of Anemia.
    • Nutritional Optimization.
    • Review of Medications.
    • Management of Intraabdominal Infection.

Smoking Cessation

  • Impact on Surgical Outcomes:
    • Smoking is associated with worse postoperative outcomes.
    • Increased risk of respiratory complications, wound healing issues, and cardiovascular events.
  • Recommendations:
    • Abstinence from smoking for at least 4 weeks before surgery reduces complications.
    • Interventions:
      • Behavioral Therapy.
      • Nicotine Replacement.
      • Medications (e.g., varenicline).
    • Counseling and Support are essential.

Glycemic Control

  • Importance:
    • Postoperative hyperglycemia increases risk of infections and complications, even in nondiabetic patients.
  • Management:
    • Optimize blood glucose levels before surgery.
    • Monitor and manage glucose levels postoperatively.
    • Minimize steroid use when possible to reduce hyperglycemia risk.

Anemia

  • Prevalence:
    • Common in IBD patients due to iron deficiency, vitamin B12 deficiency, and chronic inflammation.
  • Management:
    • Identify and treat the underlying cause.
    • Iron supplementation, vitamin B12 injections, or blood transfusions as needed.
    • Transfusion Threshold:
      • Hemoglobin less than 7 g/dL may require transfusion prior to surgery.

Nutritional Status

  • Malnutrition in IBD:
    • Affects a significant proportion of patients, more common in CD than UC.
    • Contributing factors:
      • Malabsorption.
      • Increased energy expenditure.
      • Decreased oral intake.
  • Assessment:
    • Evaluate for macro and micronutrient deficiencies.
  • Management:
    • Nutritional Support:
      • Enteral Nutrition (preferred when possible).
      • Parenteral Nutrition if enteral feeding is not feasible.
    • Goals:
      • Improve nutritional status.
      • Enhance immune function.
      • Reduce postoperative complications.

Preoperative Medications

  • Medication Review:
    • Assess all prescribed and over-the-counter medications, including supplements and herbal remedies.
  • Steroids:
    • Risks:
      • Increased risk of wound complications and infections.
      • Higher incidence of venous thromboembolism (VTE).
    • Recommendations:
      • Reduce dose or discontinue if possible before surgery.
      • Consider a staged surgical approach (e.g., temporary ostomy) in patients on high-dose steroids.
  • Biologic Agents (e.g., Anti-TNF-α):
    • Conflicting evidence on impact on postoperative outcomes.
    • Recommendations:
      • Evaluate the timing of the last dose.
      • Weigh the risks and benefits of continuing vs. holding therapy.
  • Vedolizumab:
    • Limited data; some studies suggest a potential increase in postoperative infections.

Intraabdominal Infection

  • Impact on Surgery:
    • Presence of infection increases risk of postoperative complications.
  • Management:
    • Preoperative antibiotics.
    • Drainage of abscesses (percutaneous or surgical).
    • Stabilization before elective surgery.

Surgical Considerations

Surgical Options in Ulcerative Colitis

  • Restorative Proctocolectomy with Ileal Pouch–Anal Anastomosis (IPAA):
    • One-Stage Procedure:
      • Total proctocolectomy with IPAA without diverting ileostomy.
      • Rarely performed due to high morbidity.
    • Two-Stage Procedure:
      • Proctocolectomy with IPAA and diverting loop ileostomy.
      • Second surgery to reverse ileostomy.
    • Modified Two-Stage Procedure:
      • First Stage: Total abdominal colectomy with end ileostomy.
      • Second Stage: Completion proctectomy with IPAA without ileostomy.
    • Three-Stage Procedure:
      • First Stage: Total abdominal colectomy with end ileostomy.
      • Second Stage: Completion proctectomy with IPAA.
      • Third Stage: Ileostomy reversal.
  • Choice of Procedure:
    • Depends on patient's condition, medication use, and surgeon's assessment.
    • Modified Two-Stage Approach:
      • May reduce risk of anastomotic complications.
      • Offers balance between safety and number of surgeries.

Liver Transplantation and IPAA

  • Context:
    • Patients with UC may have primary sclerosing cholangitis (PSC).
    • Both IPAA and liver transplantation may be needed.
  • Considerations:
    • IPAA can be performed before or after liver transplantation.
    • Studies show no increased morbidity when both procedures are performed.
    • Close monitoring for pouchitis is necessary postoperatively.

Special Considerations in Crohn Disease

Management of Perianal Disease

  • Prevalence:
    • Occurs in approximately 30% of CD patients.
  • Multidisciplinary Approach:
    • Collaboration between gastroenterologists and surgeons.
  • Assessment:
    • Physical examination.
    • Imaging:
      • MRI of the pelvis.
      • Endorectal ultrasound.
    • Exam Under Anesthesia: To assess fistula tracts.
  • Treatment:
    • Seton Placement:
      • Drains fistulas.
      • Prevents abscess formation.
    • Medical Therapy:
      • Anti-TNF-α agents are first-line therapy.
      • Other biologics like vedolizumab have limited data.
  • Surgical Options:
    • Endorectal Advancement Flap: For complex fistulas.
    • Ligation of Intersphincteric Fistula Tract (LIFT) procedure.
    • Stem Cell Therapy: Emerging treatment.
    • Simple Fistulotomy: For superficial fistulas.

Strictureplasty for Bowel Preservation

  • Purpose:
    • Bowel-sparing procedure to avoid short bowel syndrome.
  • Techniques:
    • Heineke-Mikulicz: For strictures up to 5 cm.
    • Finney and Jaboulay: For longer strictures up to 20 cm.
  • Indications:
    • Multiple strictures.
    • Previous extensive resections.
    • Avoiding short bowel syndrome.
  • Outcomes:
    • Similar morbidity and recurrence rates compared to resection.
    • Decision between strictureplasty and resection is individualized.

Prevention of Postoperative Recurrence

  • Recurrence Types:
    • Endoscopic: Detected via colonoscopy.
    • Clinical: Symptom recurrence.
  • Risk Factors for Recurrence:
    • Non-Modifiable:
      • Young age at diagnosis.
      • Penetrating disease.
      • Perianal disease.
      • Genetic factors (e.g., NOD2/CARD15 mutations).
    • Modifiable:
      • Smoking.
      • Surgical technique.
      • Postoperative complications.
      • Medication adherence.
  • Management Strategies:
    • Smoking Cessation.
    • Pharmacologic Prophylaxis:
      • Early initiation of anti-TNF-α agents and/or thiopurines.
    • Monitoring:
      • Endoscopic surveillance 6–12 months post-surgery.
      • Adjust therapy based on findings.

Conclusion

  • Collaborative Care:
    • Optimal management of IBD requires a multidisciplinary team.
    • Close coordination between gastroenterologists and surgeons enhances patient outcomes.
  • Patient-Centered Approach:
    • Education and empowerment are crucial.
    • Tailoring surgical and medical interventions to individual patient needs.
  • Advancements in Therapy:
    • Evolving medical treatments offer new opportunities to improve surgical outcomes.
    • IBD centers provide specialized care to address the complex needs of these patients.