Inflammatory Bowel Disease Overview

Inflammatory Bowel Diseases (IBDs)

• IBDs are chronic systemic inflammatory disorders.
• Typically classified into two subtypes: Crohn's Disease (CD) and Ulcerative Colitis (UC).
• Primarily target the gastrointestinal tract, but can affect many organ systems through extraintestinal manifestations.

IBD Definition

• IBDs are chronic systemic inflammatory disorders.
• Crohn's disease involves the gastrointestinal tract from mouth to anus in a discontinuous fashion.
• Structures, abscesses, or fistulas that penetrate neighboring organs or perianal skin develop.
• Inflammation in UC affects only the colon and rectum in a continuous fashion.
• Both conditions are lifelong diseases characterized by recurrent episodes of diarrhea (often bloody), abdominal pain, malaise, and weight loss.

Inflammatory Bowel Diseases (IBDs) Classifications

• Crohn's Disease (CD)
• Ulcerative Colitis (UC)
• Indeterminate colitis (IC): A mixed presentation of CD and UC features.
• Microscopic Colitis: Rare conditions with inflammation but minimal macroscopic findings.

Crohn's Disease (CD)

• First described in 1932 by B.B. Crohn.
• A chronic inflammatory disease of unknown etiology.
• Characterized by a typically focal and transmural inflammatory process.
• It can affect any part of the gastrointestinal tract from mouth to anus.

Ulcerative Colitis (UC)

• An idiopathic inflammatory disease.
• Characterized by recurring episodes of inflammation.
• Primarily affects the colon and rectum in a continuous fashion.

Global Increase of Inflammatory Bowel Disease

• IBD incidence and prevalence have increased globally.
• Industrial Revolution, Great Acceleration of Populations, Globalization; were contributing factors in the Western World.
• Increased incidence rates in Western World starting 1800's, and in Newly Industrialized Countries from 1950's
• Trend shows continuing increase in developing countries since 2000

Interplay and Determinants of IBD Incidence, Prevalence and Mortality

• Economic factors and environmental factors are key determinants of IBD development.
• Factors like improved hygiene are linked to higher incidences in some populations.

Incidence Ranges for Inflammatory Bowel Disease (IBD)

• Incidence rates for Crohn's disease and ulcerative colitis vary across regions in the Western world.
• CD incidence ranges from 0.4 to 22.8 cases per 100,000 person-years.
• UC incidence rate ranges from 2.4 to 44 per 100,000 person-year.

Global Map of Epidemiological Stages of IBD Evolution (2020)

• Map indicated regions of the world with differing disease stage prevalence.
• Data displayed prevalence and incidence among various countries using population-based data.

Incidence of IBD in Europe (2014)

• Highest incidence rates were observed in Northern European countries, such as the Netherlands.
• Lowest rates in some Southern/Eastern European countries, including Moldova and Romania.

Burden of Inflammatory Bowel Disease in Europe (2020)

• Approximately 2.0 million people affected by IBD in Europe.
• Represents about 0.2-0.3% of the European population.

IBD Pathogenesis

• Genetic susceptibility and environmental factors contribute to the development of IBD.
• Complex immune system and microbiota interactions trigger disturbances.
• Abnormal gut microbiota may play a critical role in IBD diseases.
• Environmental triggers such as infections, medications.

Genetic Susceptibility of IBD

• Heritable risk is significant, higher in first-degree relatives of patients with IBD.
• Multiple genes are involved, not a single 'susceptibility gene'.
• Identification of many risk variants from genome-wide association studies.

IBD Related Genes

• Genes implicated in Crohn's disease and ulcerative colitis (overlapping and distinct).
• Important in IBD pathogenesis in multiple pathways of immune function, inflammation, cellular barriers

Etiologic theories of Inflammatory Bowel Disease

• Defective mucosal barrier function
• Defective microbial clearance
• Persistent specific infection
• Dysbiosis (abnormal ratio of beneficial and detrimental commensal microbial agents)
• Aberrant immunoregulation

The Intestinal Epithelium

• The layer consists of enterocytes, goblet cells, neuroendocrine cells, Paneth cells, M cells, and stem cells.
• These cells regulate intestinal homeostasis.
• Tight junctions between these cells separate intra-luminal pathogens from the subepithelial lamina propria.
• Mucus, defensins, and other antimicrobial peptides defend against pathogens in the gut.

The Mucus Layer

• Comprises components of glycosylated mucin secreted by goblet cells, and antimicrobial peptides secreted by Paneth cells.
• Plays a role in mucosal defense and IBD pathogenesis.
• Goblet cell depletion and/or reduced mucus layer can be significant findings in UC.

Integrity of Intestinal Epithelium

• Tight junctions in epithelial cells are essential for preventing permeability to pathogens, maintain bacterial defense.
• Breakdown of tight junction associated barrier leads to activation of the intestinal immune system.
• Changes in permeability allow bacterial invasion (and resulting immune responses.)

The Intestinal Immune System

• Innate immune components (e.g., macrophages, dendritic cells, neutrophils) in the gut.
• Innate immunity functions in recognizing and controlling pathogens in the gut under normal conditions.
• Adaptive immunity components (e.g., T cells, B cells) play a crucial role in the pathogenesis of IBD.

IBD Pathology: Macroscopic Features

• Crohn's Disease (CD) is relapsing, discontinuous, and transmural granulomatous disease.
• Usually involves the small intestine and colon.
• Ulcerative Colitis (UC) is a diffuse inflammatory disease, continuous, limited to the colon (usually beginning with rectum, commonly extending proximally).

Crohn's Disease: Patterns

• Inflammatory (no stricturing or fistulizing disease)
• Fibrostenotic-obstructing
• Penetrating-fistulous

Crohn's Disease Pathology

• Aphthous or small superficial ulcerations: characterize mild disease.
• Ulcerations, in more active disease, fuse longitudinally (serpentine linear ulcers).
• Fissurations, more extensive in depth lead to fistula formation.
• Active CD (focal transmural inflammation) forms fistula tracts which turn to fibrosis, causing strictures.

Crohn's Disease Pathology: Microscopic Features

• Sharply delimited and typically nonconfluent inflammatory process.
• Sarcoid-like granulomas, potentially deep into the muscularis propria.
• Focal neutrophils in epithelium.
• Also plasmacytosis, cryptitis, and crypt abscesses.
• Superficial or deep ulceration.
• Often serositis and thickened bowel wall

Crohn's Disease Pathology: Microscopic Features

-Late changes include architectural distortion (e.g., villus blunting), crypt atrophy.

• Areas of stricture may have thick and continuous muscle layer, sometimes called "obliterative muscularization of submucosa".
• Isolated colonic Crohn's may mimic ulcerative colitis, showing minimal endoscopic/microscopic features.

Ulcerative Colitis Pathology

-Early stages: mucosa is hemorrhagic, granular, and friable.

• Late stages: extensive ulceration along the bowel axis, but not serpentine, common pseudopolyps (isolated islands of regenerating mucosa) and flat mucosa.
• Normal wall thickness and normal serosa in many types of disease. -Severe cases may have megacolon or become fibrotic, narrow and shortened.

Ulcerative Colitis Pathology: Microscopic Features

• Absence of goblet cells in mucosal layer, crypt distortion and crypt abscess.

IBD Pathology: Microscopic Features

• Comparison of microscopic features of Crohn's disease and ulcerative colitis:
• Goblet cells (present in normal, absent/reduced in UC)
• Crypt abscesses (common in CD, less in UC)
• Granulomas (common and deep in CD, rare in UC)
• Inflammation extent (transmural in CD, mucosal in UC)

Crohn's Disease: Clinical Patterns

• Enteroenteric
• Enterovesical
• Retroperitoneal
• Enterocutaneous
• Perianal

Perianal Crohn's Disease

• Perianal involvement in Crohn's disease.
• Pain, incontinence, bleeding, purulent discharge, tags, fissures, fistulae, or abscesses are signs.
• Types: simple, complex, suprananal
• Classification: superficial, intersphincteric, transsphincteric, suprasphincteric, extrasphincteric
• Affected patients often exhibit incontinence, large hemorrhoidal tags and perirectal abscesses

Extraintestinal Manifestations

• IBD often involves systems other than the digestive tract.
• EIMs can arise from (but is not necessarily dependent on) inflammation.
• Common EIMs include skin, eye, joint and kidney conditions.
• Some EIMs might precede the development of colonic symptoms.

Major extraintestinal immune related manifestations of IBD

• Skin: Erythema nodosum, pyoderma gangrenosum, aphtous ulcers, psoriasis, Alopecia areata
• Eyes: Episcleritis and Iritis /uveitis
• Joints: Arthritis, ankylosing spondylitis, reactive arthritis
• Kidneys: stones, hydronephrosis
• Liver: steatosis, biliary tract abnormalities

Autoimmune disorders associated to IBD

-Many autoimmune disorders are more common in patients with IBD.

• These include ankylosing spondylitis, psoriasis, inflammatory bowel disease, autoimmune hepatitis, etc.
• The link between IBD and autoimmune disorders is complex but may involve genetic predisposition, shared antigens, or immune dysregulation.

Pathogenesis of immune-related extraintestinal manifestation in IBD

-Genetic predisposition plays a significant role.

• Enteric flora's role is crucial in activating the immune system which leads to antigenic cross-reactivity toward organs outside the GI tract.
• Antigen mimicry may lead to immune attack on these organs.

Extraintestinal complications in IBD

-Anaemia: Iron deficiency and inflammation. -Thromboembolic events: Hypercoagulopathies and platelet activation. -Osteopathy: steroid therapy, deficiency in vitamin D. -Growth failure and malnutrition: dehydration, hyperoxaluria, low urinary PH. -Cholelithiasis: intestinal loss of bile acids. -Amyloidosis: acute phase reaction, chronic inflammation. -Fatty liver: malnutrition.

IBD Diagnosis

-History of symptoms to analyze clinical profile. -Physical examination including evaluation skin, eyes, and joints -Laboratory tests -Endoscopy and biopsies (ileum colonoscopy) -Radiographic investigations -Histological examination of tissue taken from biopsy.

IBD Diagnosis - Staging, etc.

• Scoring systems for endoscopic stages.
• Detailed analyses of endoscopic and radiographic findings, allowing for more refined assessment of disease severity and extent.
• Including imaging methods and testing (e.g., CT or MRI enterography).

Ileocolitis, Jejunileitis, and Colitis in Crohn's Disease

• Ileocolitis: Crohn's disease affecting the terminal ileum and colon.
• Jejunileitis: Crohn's disease affecting the jejunum.
• Colitis: Crohn's disease affecting the colon. Often the rectum is spared.

Ileocolitis (L3 B1), Ileocolitis (L3 B2-B3), Jejunoileitis (L4-L3), and Colitis (L2) in Crohn's Disease

• Ileocolitis (L3 B1): Typical presentation, involves terminal ileum/colon; presents chronically with diarrhea and right lower quadrant pain
• Ileocolitis (L3 B2-B3): Prolonged inflammation may lead to strictures, microperforations and fistulae to adjacent structures.
• Jejunoileitis (L4-L3): Extensive inflammation, malabsorption, and other nutritional deficiencies are significant.
• Colitis (L2): Presents with lower gastrointestinal symptoms, such as lower abdominal pain and diarrhea, gross bleeding in some.

Perianal Disease in Crohn's Disease

• Perianal Crohn's disease (PCD) is frequent.
• Pain, incontinence, bleeding, purulent discharge, tags, fissures, fistulae, or abscesses can be part of the clinical presentation.

Montreal Classification (CD)

• Classification system used for Crohn's disease based on age at diagnosis, location/extent, and behavior.
• Factors include age, disease pattern, extent and presence of complications.

IBD and Colon Cancer

• Risk of colon cancer is increased in patients with IBD. -Risk is dependent on the severity of Crohn's disease, extent of colitis, and duration.

True-love & Witts Severity Index

• Diagnostic assessment score for ulcerative colitis.
• Scoring system used for severity stages (Mild, Moderate, Severe, Fulminant).
• Disease severity and inflammation are calculated using indices such as temperature, stool number and types, and blood in stool

Mayo Scoring System for Ulcerative Colitis (UC) Activity

• Diagnostic assessment score for ulcerative colitis.
• Scoring system used to assess disease activity.
• Based on variables including bowel movement frequency, rectal bleeding, endoscopic findings, and physician global assessment

FULMINANT COLITIS

• A severe and life-threatening kind of ulcerative colitis (UC).
• More than 10 stools per day, continuous bleeding, abdominal distention, severe pain, and fever.

Natural History of Ulcerative Colitis

• Disease evolves between quiescence and acute inflammation, often with a fluctuation of activity
• Proctitis, left sided colitis, or pancolitis are the different extent classifications.
• Mild cases may spontaneously resolve with remission; others can progress to severe disease or potentially with complications.

Ulcerative Colitis Therapy

• Initial treatment: oral mesalazine in mild/moderate cases; enemas may be effective -Escalation strategies are helpful when response to initial treatment is poor.
• Severe cases may require systemic corticosteroids (IV) and biologic treatments.

Crohn's Disease Therapy

• Various approaches for Crohn's disease treatment are available; initial treatment can involve various aminosalicylate derivatives, antibiotics, corticosteroids, immunomodulator therapies, and anti-TNF agents.
• Treatment options are adjusted based on disease activity, location (i.e. perianal, fistulous, stricturing)

Treatment Paradigm Shift: Decision Making in IBD

• The previous approach to IBD treatment focused on symptom relief.
• New paradigm emphasizes treating based on objective markers of inflammation.
• This improved approach includes biomarkers for monitoring disease, treatment response, and disease course.

Objectives for the Treatment of Crohn's Disease (CD)

• Rapid induction of remission
• Sustained remission off steroids
• Mucosal healing
• Fewer surgeries and hospitalizations
• Effective treatment of fistulae
• Effective treatment of extra-intestinal manifestations
• Improvement of patient's quality of life -Acceptable benefit/risk ratio at an affordable cost.

Crohn's Disease Therapy

• 5-aminosalicylic acid derivatives: sulfasalazine, mesalamine
• Antibiotics: metronidazole, ciprofloxacin, rifaximin
• Corticosteroids: budesonide, prednisone, methylprednisolone
• Immunomodulators: azathioprine, 6-mercaptopurine, methotrexate, cyclosporine
• Tumor necrosis factor inhibitors (anti-TNF): infliximab, adalimumab, certolizumab
• Anti-integrin agents: vedolizumab
• Anti-IL12/23 agents: ustekinumab

Safety and Toxicity Considerations of Anti-TNF Agents

• Infection and malignancy
• Reactivation of hepatitis B
• Skin cancer
• Psoriasis
• Autoimmunity
• Immunogenicity

Safety and Toxicity Considerations

-Anti-integrin agents: Multiple adverse effects, including but not limited to: -progressive multifocal leukoencephalopathy (PML) -Other treatments: diverse side effects (e.g., liver issues, infections, etc)

Conventional Approach. Step-up Induction Therapy

• Stepwise approach to manage Crohn's Disease, beginning with mildest regimens, like topical corticosteroids or aminosalicylates.
• Escalation of treatments if response is poor, progressing through more intensive therapies like systemic corticosteroids, immunomodulators, or anti-TNF inhibitors.

Ulcerative Colitis: New Therapies

• Agents that directly target the underlying pathological processes of ulcerative colitis are more prevalent treatment options
• Biologics, such as anti-TNF agents and anti-integrin agents, may be able to significantly improve patient management and outcomes.

Ulcerative Colitis Complications

• Intestinal complications
• Hemorrhage: Bleeding from the intestines.
• Strictures: Narrowing of the intestinal lumen.
• Perforation: Hole in the intestine.
• Toxic megacolon: Widening of the colon.
• Colonic cancer

Toxic Megacolon

• A severe and life-threatening complication in ulcerative colitis (UC).
• Characterized by dilatation of the colon (>5.5 cm), with associated increased risk of perforation, shock
• Requires emergency colectomy in many cases

Colectomy in Ulcerative Colitis

• Surgical removal of the colon and rectum.
• Various approaches exist, including ileostomy, restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA).

IBD and Colon Cancer Risk Factors

-Equal risk for ulcerative colitis (UC) and Crohn's disease (CD).

• Risk increases over time based on type and extent of IBD.
• Screening should be tailored to the specific patient, to assess individual risk and need.

Inflammatory Bowel Disease (IBD) Diagnosis: Diagnostic Statements

• No single test diagnose IBD.
• Diagnosis depends on multiple factors.
• Additional tests (e.g., stool cultures) needed for infections (e.g., CDI).
• Visualizing the small intestine may be essential for suspected Crohn's disease.

IBD Diagnosis: Diagnostic Tools

• Endoscopic procedures (e.g., colonoscopy, capsule endoscopy).
• Imaging techniques (e.g., CT or MRI enterography).
• Biomarkers to assess disease activity or inflammation.
• Laboratory analysis, including stool tests, blood tests, and other clinical analyses

Inflammatory Bowel Disease (IBD) Treatment Paradigm

• Transitioning from subjective symptom management to marker-driven therapy.
• Emphasis is on treating and monitoring inflammation, not just relieving symptoms.
• Objective criteria (e.g., CRP reduction) are used for monitoring disease activity.

Treatment of Mild Ulcerative Colitis

• Initial choice of treatment varies; oral 5-ASA suppositories, enemas, and combination therapy are helpful.

Treatment of Left Side Ulcerative Colitis

• Combination of oral and topical therapies, with escalation to more complex options if needed.

Ulcerative Colitis Therapy: Pancolitis

-Oral 5-aminosalicylate (5-ASA) and topical mesalazine are first line -Additional therapies might be needed, e.g., systemic corticosteroids, ciclosporin, infliximab, tacrolimus.

• Emergency surgical measures are an option if treatment fails

Test your knowledge on inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. This quiz covers definitions, symptoms, and factors related to these conditions, along with key terminology used in microbiome studies. Explore the nuances of IBD and its impact on health.