Inflammatory Inflammatory Bowel Bowel

DiseaseDisease

Inflammatory Bowel Disease Inflammatory Bowel Disease (IBD)(IBD)

• Immune-mediated chronic intestinal Immune-mediated chronic intestinal conditioncondition

• ““Inflammation of the intestines”Inflammation of the intestines”

Source:p.1886

Types of IBDTypes of IBD

Source:p.1886

Ulcerative Colitis (UC)Ulcerative Colitis (UC)

• Mucosal disease Mucosal disease • Involves the rectum Involves the rectum

and extends and extends proximally to involve proximally to involve all parts of the colonall parts of the colon

• Produces mucosal Produces mucosal friability and areas of friability and areas of ulcerationulceration

Source:p.1887

Source:p.570

Crohn’s disease (CD) Crohn’s disease (CD)

• Chronic inflammatory Chronic inflammatory disorder that produces disorder that produces ulceration, fibrosis, and ulceration, fibrosis, and malabsorptionmalabsorption

• Can affect any part of the GI Can affect any part of the GI tract from the mouth to the tract from the mouth to the anus anus – Terminal ileum and colon are Terminal ileum and colon are

the more common sitesthe more common sitesSource:p.1888

Source:p.569

PathophysiologyPathophysiology

Possible factorsPossible factors

a pathogenic organism (as yet a pathogenic organism (as yet unidentified) unidentified) an immune response to an intraluminal an immune response to an intraluminal antigen (eg, protein from cow milk)antigen (eg, protein from cow milk)or an autoimmune process whereby an or an autoimmune process whereby an appropriate immune response to an appropriate immune response to an intraluminal antigen and an inappropriate intraluminal antigen and an inappropriate response to a similar antigen is present on response to a similar antigen is present on intestinal epithelial cells. intestinal epithelial cells.

Predisposing factorsPredisposing factors

genetic predisposition [NOD2 gene (now genetic predisposition [NOD2 gene (now called CARD15), chromosomes 5 (5q31) called CARD15), chromosomes 5 (5q31) and 6 (6p21 and 19p)] and 6 (6p21 and 19p)]

abnormal immune reactivity abnormal immune reactivity

smoking, diet, drugs, geography and smoking, diet, drugs, geography and social status, the enteric flora, alteredsocial status, the enteric flora, alteredintestinal permeability, and appendectomy intestinal permeability, and appendectomy

Pathophysiology of IBD - pt. 2Pathophysiology of IBD - pt. 2

Pathophysiology of IBD - SummaryPathophysiology of IBD - Summary

EPIDEMIOLOGYEPIDEMIOLOGY

Ulcerative Colitis Crohn’s Disease

Age of onset 15-30 & 60-80 15-30 & 60-80

Ethnicity Jewish>non-Jewish>Caucasian>African American>Hispanic> Asian

Male-female ratio 1:1 1.1-1.8:1

Smoking May prevent disease May cause disease

OCP No increased risk Odds ratio 1.4

Appendectomy Protective Not protective

Monozygotic twins 6% concordance 58% concordance

Dizygotic twins 0% concordance 4% concordance

CLINICAL FEATURESCLINICAL FEATURESUlcerative Colitis Crohn’s Disease

Gross blood in stool Yes Occasionally

Mucus Yes Occasionally

Systemic symptoms Occasionally Frequently

Pain Occasionally Frequently

Abdominal mass Rarely Yes

Significant perineal disease

No Frequently

Fistulas No Yes

CLINICAL FEATURESCLINICAL FEATURESUlcerative Colitis Crohn’s Disease

Small-intestinal obstruction

No Frequently

Colonic obstruction Rarely Frequently

Response to antibiotics No Yes

Recurrence after surgery

No Yes

ANCA-positive Frequently Rarely

ASCA-positive Rarely Frequently

ENDOSCOPIC FEATURESENDOSCOPIC FEATURES

Ulcerative Colitis Crohn’s Disease

Rectal sparing Rarely Frequently

Continuous disease Yes Occasionally

“Cobblestoning” No Yes

Granuloma on biopsy No Occasionally

RADIOGRAPHIC FEATURESRADIOGRAPHIC FEATURES

Ulcerative Colitis Crohn’s Disease

Small bowel significantly abnormal

No Yes

Abnormal terminal ileum Occasionally Yes

Segmental colitis No Yes

Asymmetric colitis No Yes

Stricture Occasionally Frequently

TREATMENTTREATMENT

Treatment GoalsTreatment Goals

Relieve symptoms by suppressing the Relieve symptoms by suppressing the chronic inflammation of the intestineschronic inflammation of the intestines– Induce remissionInduce remission

periods of time that are symptom-free periods of time that are symptom-free

– Maintain remission Maintain remission prevent flare-ups of disease prevent flare-ups of disease

– Improve the patient's quality of lifeImprove the patient's quality of life

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Treatment OptionsTreatment Options

• PharmacologicPharmacologic– 5-ASA5-ASA– GlucocorticoidsGlucocorticoids– AntibioticsAntibiotics– Azathiprine and 6-MPAzathiprine and 6-MP– MethotrexateMethotrexate– CyclosporineCyclosporine– TacrolimusTacrolimus– Anti-TNF AntibodyAnti-TNF Antibody

Treatment OptionsTreatment Options

Non-PharmacologicNon-Pharmacologic– Nutritional TherapyNutritional Therapy

Bowel Rest and TPNBowel Rest and TPN

– SurgerySurgeryResectionResection

Strictureplasty Strictureplasty

Pharmacologic: 5-ASAPharmacologic: 5-ASA

5-aminosalicylate acid5-aminosalicylate acid

Mainstay of therapy Mainstay of therapy

For mild to moderate UC and CDFor mild to moderate UC and CD

Effective at inducing remission in both UC Effective at inducing remission in both UC and CD and CD

Maintains remission in UCMaintains remission in UC

Pharmacologic: 5-ASAPharmacologic: 5-ASA

Example: SulfasalazineExample: Sulfasalazine

Combined sulfapyridine and 5-ASACombined sulfapyridine and 5-ASA

MOA: anti-inflammatory MOA: anti-inflammatory

Side effects: allergic and hypersensitivity Side effects: allergic and hypersensitivity reactions, headache, nausea and reactions, headache, nausea and vomiting, anorexiavomiting, anorexia

Pharmacologic: 5-ASAPharmacologic: 5-ASA

• Example: Mesalamine Example: Mesalamine • Sulfa-free 5-ASASulfa-free 5-ASA• Similar MOA to Sulfasalazine, less side Similar MOA to Sulfasalazine, less side

effectseffects– OlsalazineOlsalazine– Asacol, an enteric coated mesalamine liberates Asacol, an enteric coated mesalamine liberates

5-ASA in pH>7.05-ASA in pH>7.0– BalsalazideBalsalazide– ClaversalClaversal– Pentasa uses an ethylcellulose coating to allow Pentasa uses an ethylcellulose coating to allow

water absorptionwater absorption

Pharmacologic: GlucocorticoidsPharmacologic: Glucocorticoids

For moderate to severe UC and CD For moderate to severe UC and CD unresponsive to 5-ASAunresponsive to 5-ASA

Induces remission but has no role in Induces remission but has no role in maintenance therapymaintenance therapy

Should be tapered once clinical remission Should be tapered once clinical remission has been inducedhas been induced

Pharmacologic: GlucocorticoidPharmacologic: Glucocorticoid

• Oral GlucocorticoidOral Glucocorticoid– Prednisone 40-60mg/day Prednisone 40-60mg/day

• ParenteralParenteral– Hydrocortisone 300mg/dayHydrocortisone 300mg/day– Methylprednisone 40-60 mg/dayMethylprednisone 40-60 mg/day– ACTH – for glucocorticoid naïve patientsACTH – for glucocorticoid naïve patients

• Side effectsSide effects– Fluid retention, hyperglycemia, osteonecrosis, Fluid retention, hyperglycemia, osteonecrosis,

withdrawal symtomswithdrawal symtoms

Pharmacologic: AntibioticsPharmacologic: Antibiotics

• Indicated for post-colectomy and IPAA Indicated for post-colectomy and IPAA complication (pouchitis) in UC patientscomplication (pouchitis) in UC patients

• Metronidazole Metronidazole – 15-20mg/kg/day in 3 divided doses for several 15-20mg/kg/day in 3 divided doses for several

monthsmonths– SE: metallic taste, nausea, disulfiram-like reactionSE: metallic taste, nausea, disulfiram-like reaction

• CiprofloxacinCiprofloxacin– 500mg id500mg id– 22ndnd DOA for active CD after 5-ASA DOA for active CD after 5-ASA– 11stst DOA in perianal and fistulous CD DOA in perianal and fistulous CD

Pharmacologic: Azathioprine and 6-Pharmacologic: Azathioprine and 6-MPMP

Purine analogs employed in the management Purine analogs employed in the management of gluocorticoid-dependent IBD of gluocorticoid-dependent IBD

MOA: MOA: – is metabolized into thionosinic acid which inhibits is metabolized into thionosinic acid which inhibits

the purine ribonucleotide synthesis and cell the purine ribonucleotide synthesis and cell proliferationproliferation

– Glucocorticoid-sparing agentsGlucocorticoid-sparing agents

Effective for post-operative prophylaxis of CDEffective for post-operative prophylaxis of CD

Pharmacologic: Azathioprine and 6-Pharmacologic: Azathioprine and 6-MPMP

AzathioprineAzathioprine– 2-3 mg/kg/day2-3 mg/kg/day

6-MP6-MP– 1-1.5 mg/kg/day1-1.5 mg/kg/day

Side effectsSide effects– Pancreatitis (reversible), nausea, fever, rash Pancreatitis (reversible), nausea, fever, rash

and hepatitis, dose-related leukopeniaand hepatitis, dose-related leukopenia

Pharmacologic: Azathioprine and 6-Pharmacologic: Azathioprine and 6-MPMP

Patients should be monitored (CBCs and Patients should be monitored (CBCs and liver function) since they are at a four-fold liver function) since they are at a four-fold increased risk of developing a lymphomaincreased risk of developing a lymphoma

Pharmacologic: Methotrexate Pharmacologic: Methotrexate (MTX)(MTX)

MOA: inhibits dihydrofolate reductase MOA: inhibits dihydrofolate reductase leading to impaired DNA synthesisleading to impaired DNA synthesis

IM or SC routeIM or SC route

Effective in inducing remission and Effective in inducing remission and reducing glucocorticoid dosage, and in reducing glucocorticoid dosage, and in maintaining remission in active CDmaintaining remission in active CD

SE: leukopenia, hepatic fibrosis, HPS SE: leukopenia, hepatic fibrosis, HPS pneumonitispneumonitis

Pharmacologic: Cyclosporine Pharmacologic: Cyclosporine (CSA)(CSA)

For severe UC patients refractory to For severe UC patients refractory to glucocorticoidsglucocorticoids

MOA: inhibits calcineurin →blocks MOA: inhibits calcineurin →blocks production of IL-2 and function of B-cells→ production of IL-2 and function of B-cells→ blocks helper T-cells→ inhibits both the blocks helper T-cells→ inhibits both the cellular and humoral immune system bycellular and humoral immune system by

Pharmacologic: Cyclosporine Pharmacologic: Cyclosporine (CSA)(CSA)

Best given IV 2-4 mg/kg/dayBest given IV 2-4 mg/kg/day

Oral 7.5 mg/kg/day only effective with 6-Oral 7.5 mg/kg/day only effective with 6-MP/azathioprineMP/azathioprine

AE: HPN, gingival hyperplasia, etcAE: HPN, gingival hyperplasia, etc

Monitor renal function (Creatinine Monitor renal function (Creatinine cleaance)cleaance)

Pharmacologic: TacrolimusPharmacologic: Tacrolimus

Macrolide antibioitc with Macrolide antibioitc with immunomodulatory properties similar to immunomodulatory properties similar to CSACSA

100x as potent as CSA, has good oral 100x as potent as CSA, has good oral absorptionabsorption

For children with refractory IBD and adults For children with refractory IBD and adults with extensive small bowel involvement, with extensive small bowel involvement, steroid dependent or refractory UC or CDsteroid dependent or refractory UC or CD

Pharmacologic: Anti-TNF AbPharmacologic: Anti-TNF Ab

MOA: Blocks TNF→ blocks inflammatory MOA: Blocks TNF→ blocks inflammatory cytokine → blocks intestinal inflammationcytokine → blocks intestinal inflammation

Examples:Examples:– InfliximabInfliximab– ThalidomideThalidomide– AdalimumabAdalimumab– Certolizumab PegolCertolizumab Pegol

SE: increased risk of infections, serum SE: increased risk of infections, serum sicknesssickness

Non-Pharmacologic: Nutritional Non-Pharmacologic: Nutritional TherapiesTherapies

Bowel rest and TPN/ENBowel rest and TPN/EN

Induces remissionInduces remission

Use of peptide-based preparationsUse of peptide-based preparations– Dietary intervention helpful in CD but not in Dietary intervention helpful in CD but not in

UCUC

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Non-Pharmacologic: SrugeryNon-Pharmacologic: Srugery

Ulcerative Colitis Crohn’s Disease

Intractable diseaseFulminant diseaseToxic megacolonColonic perforationMassive colonic hemorrhageExtracolonic diseaseColonic obstructionColon cancer prophylaxisColon dysplasia or cancer

Small intestineStricture and obstruction unresponsive to medicationMassive hemorrhage Refractory fistulaAbscess

Large inestineIntractable disease Fulminant diseaseRefractory fistula Colonic obstructionCancer prohylaxis Colon dysplasia/ cancerPerianal disease unresponsive to medication

Non-Pharmacologic: SurgeryNon-Pharmacologic: Surgery

Ulcerative Colitis Crohn’s Disease

Resection Small intestine: Resection and strictureplasty

Colorectal:Temporary loop ileostomyDiverting colostomyProctocolectomyResection

Non-PharmacologicNon-Pharmacologic

Reduce stressReduce stress

Stop smokingStop smoking

Do not take NSAIDs if not indicated to Do not take NSAIDs if not indicated to prevent ulcerationsprevent ulcerations