Overview of Inflammatory Bowel

DiseaseCrohn’s Disease

andUlcerative Colitis

Definitions

• “Inflammatory bowel disease (IBD) is an idiopathic and chronic intestinal inflammation.” Harrison’s Textbook of Internal Medicine

• Ulcerative Colitis (UC) is a mucosal disease that usually involves the rectum and extends proximally to involve part of or the entire colon.

• Crohn’s Disease (CD) is a disease that can effect any portion of the luminal GI tract and usually presents in two patters: obstructive/fibrostenotic and penetrating/fistulizing

IBD - Epidemiology

• Men = Women ; Jews > non-Jews

• Peak incidence is 15 - 25 years old

• Incidence is 5-15/100,000 but prevalence is much higher (133-181/100,000) and rising (Crohn’s/UC)

• 17% of UC and 23% of Crohn’s patients have a relative with IBD (usually same type of IBD)

UC

Terminal Ileum

Ulcerative Colitis• Inflammatory disease of the colon mucosa affecting the

rectum and to varying degrees extending proximally to the cecum

• Presents with bloody diarrhea (rarely constipation) and abdominal pain

• 77% (Danish cohort) experience chronic relapsing disease

• 30% will undergo colectomy over 30 years

• Approximately 18% (Mayo Clinic data) will develop colon cancer over 30 years

• Up to 4% will develop Primary Sclerosing Cholangitis

• 6-11% will develop osteopenia, venous thrombosis, arthritis/arthralgias, pyoderma, E. nodosum, iritis, uveitis, hepatobiliary complications, asymptomatic abnormal PFTs

UC

UC- Endoscopic

Mucosal Inflammation in UC

Crohn’s Disease

• A pan-enteric transmural inflammatory disease involving the terminal ileum and right colon, terminal ileum alone or colon alone (in a patchy distribution)

• Abdominal pain and diarrhea in > 70%

• 2 subtypes: inflammatory/obstructive, penetrating/fistulous

• 80% will need surgery by 15-30 years

Transmural Inflammation

The Elusive Granuloma

CD- endoscopic

Crohn’s

Etio-pathogenesis in IBD• Abnormal function of the gut mucosal barrier results in

chronic intestinal inflammation

• Genetic susceptibility conferred by mutations at distinct chromosomal loci

• Dysregulation of mucosal proinflammatory immunity (Th1 responses) with resulting overactivity of effector immune mechanisms

• Decreased regulatory T cell populations (suppressor T cells) lead to unfettered Th1 inflammatory responses to luminal antigens (loss of tolerance)

• Microbial antigens can lead to self-perpetuating inflammation in genetically susceptible hosts

Bacteria Antigen presenting cell

Macrophage

Type 1 helperT cell

Macrophagemigration inhibitorfactorInterleukin-12Interleukin-18

Tumor necrosis factorInterleukin-1Interleukin-6

Normal epithelium

Epithelialbarrier

Interferon-γ

Toll-likereceptor

Bacterial LPS

NOD2

TNF and receptor

Interleukin-1 and receptor

NFk -B

Anti-apoptosis

NIK, MEKK1, or MEKK3

IKKcomplex

Receptor-interacting protein 2

Genetranscription

IkB

Environmental Influences

• Clean Kid hypothesis• Crohn’s > UC are smokers; are s/p

appendectomy• IBD more common in cold climates• IBD more common in industrialized areas• Active disease increases risk to fetus and

mother in pregnancy; relapse not increased by pregnancy

Symptoms

Infectious Mimics of IBD

• Bacteria: Shigella species, Enterohemorrhagic E. coli, Enteroinvasive E. coli, Campylobacter jejuni, Salmonella (gastroenteritis and typhoid fever), Yersinia enterocolitica, MTB, C. difficile, Vibrio parahaemolyticus, Chlamydia (lymphogranuloma venereum serotypes)

• Parasites: Entamoeba histolytica, Schistosoma species, Balantidium coli, Trichinella spiralis

• Viruses: Cytomegalovirus• Causing proctitis: Neisseria gonorrhoeae,

Herpes simplex virus, Chlamydia trachomatis, Treponema pallidum, Cytomegalovirus

Colorectal Cancer in Ulcerative Colitis

• Increased risk above general population (5%) 1-3% at 10 yrs and 18% at 30 years with pancolitis

• Flat or depressed adenomas—fields of dysplasia. • Increased risk with:

– Disease proximal to splenic flexure– > 8 years duration; young age at diagnosis– Primary sclerosing cholangitis (1-4% of IBD patients)– Family history of CRC– Pseudopolyps at colonoscopy

• 5-ASA treatment is protective

Capsule Endoscopy

CD in Small Bowel

Common extraintestinal manifestations

• Musculoskeletal: Arthritis, ankylosing spondylitis, clubbing, periostitis, osteoporosis, aseptic necrosis, polymyositis

• Skin and mouth: erythema nodosum, pyoderma gangrenosum, aphthous ulcers, vesiculopustular eruption, necrotizing vasculitis, fissures and fistulas, oral Crohn's disease, drug rashes, nutritional deficiencies, vitiligo, psoriasis, amyloidosis, epidermolysis bullosa acquisita

• Hepatobiliary: Primary sclerosing cholangitis and bile duct carcinoma , autoimmune chronic active hepatitis, pericholangitis, portal fibrosis and cirrhosis, granulomatous inflammation, fatty liver, gallstones associated with ileal Crohn's disease

• Ocular: Uveitis (iritis), episcleritis, scleromalacia, corneal ulcers, retinal vascular disease

• Metabolic: Growth retardation in children and adolescents, delayed sexual maturation, osteoporosis, vitamin D deficiency

Obstruction in CD

Fistulae in CD

Current Expectations for IBD Therapy

• Induce clinical remission

• Maintain clinical remission

• Improve patient quality of life

PLUS

• Heal mucosa

• Decrease hospitalization/surgery and overall costs

• Minimize disease-related and therapy-related complications

IBD Therapeutic Pyramid

Severe

Moderate

MildAminosalicylates / Antibiotics

Budesonide/ Oral prednisone

Azathioprine / 6-MP

IV Corticosteroids

Infliximab / anti-TNF Rx

Cyclosporine

Tacrolimus

Surgery

Methotrexate

Refractory

AMINOSALICYLATES

Steroid Toxicities

• Ocular – cataracts, glaucoma• Skin – striae, atrophy, acne• Endocrine – growth failure (pediatric),

hypothalamic-pituitary-adrenal (HPA) axis suppression; glucose intolerance

• Cardiovascular – hypertension• Other – Infection (abcess); myopathy• Mortality, increased hospitalization

(outcomes studies ??confounders)

ORAL BUDESONIDE IN ACTIVE CROHN’S

DISEASE

IBD Therapeutic Pyramid

Severe

Moderate

MildAminosalicylates / Antibiotics

Budesonide/Oral prednisone

Azathioprine / 6-MP

Systemic Corticosteroids

Infliximab / anti-TNF Rx

Cyclosporine

Tacrolimus

Surgery

Methotrexate

Refractory

6-MERCAPTOPURINE IN ACTIVE CROHN’S

DISEASE

Biologic Therapy

Infliximab

TNF-α Inhibitors

Infliximab for UC

INDICATIONS FOR SURGERY IN ULCERATIVE

COLITIS

SURGICAL OPTIONS IN ULCERATIVE COLITIS

INDICATIONS FOR SURGERY IN CROHN’S

DISEASE