Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) Immune-mediated chronic intestinal condition Immune-mediated chronic intestinal condition “Inflammation of the intestines” “Inflammation of the intestines” Source: p.1886

Types of IBD IBD Ulcerative Colitis (UC) Crohn’s disease (CD) Source: p.1886

Ulcerative Colitis (UC) Mucosal disease Mucosal disease Involves the rectum and extends proximally to involve all parts of the colon Involves the rectum and extends proximally to involve all parts of the colon Produces mucosal friability and areas of ulceration Produces mucosal friability and areas of ulceration Source: p.1887 Source: p.570

Crohn’s disease (CD) Chronic inflammatory disorder that produces ulceration, fibrosis, and malabsorption Chronic inflammatory disorder that produces ulceration, fibrosis, and malabsorption Can affect any part of the GI tract from the mouth to the anus Can affect any part of the GI tract from the mouth to the anus –Terminal ileum and colon are the more common sites Source: p.1888 Source: p.569

Pathophysiology

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

Predisposing factors genetic predisposition [NOD2 gene (now called CARD15), chromosomes 5 (5q31) and 6 (6p21 and 19p)] abnormal immune reactivity smoking, diet, drugs, geography and social status, the enteric flora, altered intestinal permeability, and appendectomy

Pathophysiology of IBD - pt. 2

Pathophysiology of IBD - Summary

EPIDEMIOLOGY Ulcerative ColitisCrohn’s Disease Age of onset15-30 & EthnicityJewish>non-Jewish>Caucasian>African American>Hispanic> Asian Male-female ratio1: :1 SmokingMay prevent diseaseMay cause disease OCPNo increased riskOdds ratio 1.4 AppendectomyProtectiveNot protective Monozygotic twins6% concordance58% concordance Dizygotic twins0% concordance4% concordance

CLINICAL FEATURES Ulcerative ColitisCrohn’s Disease Gross blood in stoolYesOccasionally MucusYesOccasionally Systemic symptomsOccasionallyFrequently PainOccasionallyFrequently Abdominal massRarelyYes Significant perineal disease NoFrequently FistulasNoYes

CLINICAL FEATURES Ulcerative ColitisCrohn’s Disease Small-intestinal obstruction NoFrequently Colonic obstructionRarelyFrequently Response to antibioticsNoYes Recurrence after surgery NoYes ANCA-positiveFrequentlyRarely ASCA-positiveRarelyFrequently

ENDOSCOPIC FEATURES Ulcerative ColitisCrohn’s Disease Rectal sparingRarelyFrequently Continuous diseaseYesOccasionally “Cobblestoning”NoYes Granuloma on biopsyNoOccasionally

RADIOGRAPHIC FEATURES Ulcerative ColitisCrohn’s Disease Small bowel significantly abnormal NoYes Abnormal terminal ileumOccasionallyYes Segmental colitisNoYes Asymmetric colitisNoYes StrictureOccasionallyFrequently

TREATMENT

Treatment Goals Relieve symptoms by suppressing the chronic inflammation of the intestines –Induce remission periods of time that are symptom-free periods of time that are symptom-free –Maintain remission prevent flare-ups of disease –Improve the patient's quality of life a

Treatment Options Pharmacologic Pharmacologic –5-ASA –Glucocorticoids –Antibiotics –Azathiprine and 6-MP –Methotrexate –Cyclosporine –Tacrolimus –Anti-TNF Antibody

Treatment Options Non-Pharmacologic –Nutritional Therapy Bowel Rest and TPN –Surgery ResectionStrictureplasty

Pharmacologic: 5-ASA 5-aminosalicylate acid Mainstay of therapy For mild to moderate UC and CD Effective at inducing remission in both UC and CD Maintains remission in UC

Pharmacologic: 5-ASA Example: Sulfasalazine Combined sulfapyridine and 5-ASA MOA: anti-inflammatory Side effects: allergic and hypersensitivity reactions, headache, nausea and vomiting, anorexia

Pharmacologic: 5-ASA Example: Mesalamine Example: Mesalamine Sulfa-free 5-ASA Sulfa-free 5-ASA Similar MOA to Sulfasalazine, less side effects Similar MOA to Sulfasalazine, less side effects –Olsalazine –Asacol, an enteric coated mesalamine liberates 5-ASA in pH>7.0 –Balsalazide –Claversal –Pentasa uses an ethylcellulose coating to allow water absorption

Pharmacologic: Glucocorticoids For moderate to severe UC and CD unresponsive to 5-ASA Induces remission but has no role in maintenance therapy Should be tapered once clinical remission has been induced

Pharmacologic: Glucocorticoid Oral Glucocorticoid Oral Glucocorticoid –Prednisone 40-60mg/day Parenteral Parenteral –Hydrocortisone 300mg/day –Methylprednisone mg/day –ACTH – for glucocorticoid naïve patients Side effects Side effects –Fluid retention, hyperglycemia, osteonecrosis, withdrawal symtoms

Pharmacologic: Antibiotics Indicated for post-colectomy and IPAA complication (pouchitis) in UC patients Indicated for post-colectomy and IPAA complication (pouchitis) in UC patients Metronidazole Metronidazole –15-20mg/kg/day in 3 divided doses for several months –SE: metallic taste, nausea, disulfiram-like reaction Ciprofloxacin Ciprofloxacin –500mg id –2 nd DOA for active CD after 5-ASA – 1 st DOA in perianal and fistulous CD

Pharmacologic: Azathioprine and 6-MP Purine analogs employed in the management of gluocorticoid-dependent IBD MOA: –is metabolized into thionosinic acid which inhibits the purine ribonucleotide synthesis and cell proliferation –Glucocorticoid-sparing agents Effective for post-operative prophylaxis of CD

Pharmacologic: Azathioprine and 6-MP Azathioprine –2-3 mg/kg/day 6-MP –1-1.5 mg/kg/day Side effects –Pancreatitis (reversible), nausea, fever, rash and hepatitis, dose-related leukopenia

Pharmacologic: Azathioprine and 6-MP Patients should be monitored (CBCs and liver function) since they are at a four-fold increased risk of developing a lymphoma

Pharmacologic: Methotrexate (MTX) MOA: inhibits dihydrofolate reductase leading to impaired DNA synthesis IM or SC route Effective in inducing remission and reducing glucocorticoid dosage, and in maintaining remission in active CD SE: leukopenia, hepatic fibrosis, HPS pneumonitis

Pharmacologic: Cyclosporine (CSA) For severe UC patients refractory to glucocorticoids MOA: inhibits calcineurin →blocks production of IL-2 and function of B-cells→ blocks helper T-cells→ inhibits both the cellular and humoral immune system by

Pharmacologic: Cyclosporine (CSA) Best given IV 2-4 mg/kg/day Oral 7.5 mg/kg/day only effective with 6- MP/azathioprine AE: HPN, gingival hyperplasia, etc Monitor renal function (Creatinine cleaance)

Pharmacologic: Tacrolimus Macrolide antibioitc with immunomodulatory properties similar to CSA 100x as potent as CSA, has good oral absorption For children with refractory IBD and adults with extensive small bowel involvement, steroid dependent or refractory UC or CD

Pharmacologic: Anti-TNF Ab MOA: Blocks TNF→ blocks inflammatory cytokine → blocks intestinal inflammation Examples: –Infliximab –Thalidomide –Adalimumab –Certolizumab Pegol SE: increased risk of infections, serum sickness

Non-Pharmacologic: Nutritional Therapies Bowel rest and TPN/EN Bowel rest and TPN/EN Induces remission Use of peptide-based preparations –Dietary intervention helpful in CD but not in UC a

Non-Pharmacologic: Srugery Ulcerative ColitisCrohn’s Disease Intractable disease Fulminant disease Toxic megacolon Colonic perforation Massive colonic hemorrhage Extracolonic disease Colonic obstruction Colon cancer prophylaxis Colon dysplasia or cancer Small intestine Stricture and obstruction unresponsive to medication Massive hemorrhage Refractory fistula Abscess Large inestine Intractable disease Fulminant disease Refractory fistula Colonic obstruction Cancer prohylaxis Colon dysplasia/ cancer Perianal disease unresponsive to medication

Non-Pharmacologic: Surgery Ulcerative ColitisCrohn’s Disease ResectionSmall intestine: Resection and strictureplasty Colorectal: Temporary loop ileostomy Diverting colostomy Proctocolectomy Resection

Non-Pharmacologic Reduce stress Stop smoking Do not take NSAIDs if not indicated to prevent ulcerations