1. Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis

Chronic inflammation of the gastrointestinal (GI) tract

Pathophysiology

• Severity varies - asymptomatic remission to mild and manageable to severe where surgeries are needed 

• Two hypothesis:

  • Primary dysregulation of the mucosal immune system resulting in excessive immunologic responses to normal microflora

  • Changes in the composition of the gut microflora and/or deranged epithelial barriers function that causes pathologic responses (inflammation) from the normal mucosal immune system 

• Etiology poorly understood, but potential factors include

  • Genetics (first degree relatives have a 4- to 20-fold greater risk), predisposing immunological factors, infection, emotional stress, environment (eg. diet, smoking, etc)

• Chronic inflammation of the GI tract leading to diarrhea 

  • Exact cause of inflammation is unknown 

  • Inflammation is considered secondary to an antigen driven response 

Etiology

Ulcerative Colitis

• Location 

  • Colon, rectum

  • Backwash ileitis = rare involvement of the terminal ileum

• Mucosal penetration 

  • Superficial

• Distribution 

  • Continuous 

Crohn’s Disease 

• Location

  • Anywhere from mouth to anus

  • Terminal ileum (most common)

• Mucosal penetration

  • Deep transmural lesions; affecting mucosa, submucosa, muscle, and serosa

• Distribution 

  • Discontinuous

  • Patchy “cobblestone” appearance

Signs and symptoms

• Diarrhea and frequent bowel movements

• Abdominal pain

• Fatigue

• Fever

• Weight loss 

UC complications

• Hemorrhoids

• Anal fissures

• Perirectal abscess

• Toxic megacolon 

  • colonic distension of > 6 cm plus acute colitis and systemic toxicity (fever, tachycardia, elevated WBC)

CD complication 

• Structure

• Abscess

• Fistula

• Nutritional deficiencies 

Agents

Aminosalicylates

• Drugs

  • Sulfasazine (Azulfidine, Sulfazine)

  • Mesalamine (Canasa, Rowasa, Apriso, Asacol, Lialda, Pentasa)

  • Olsalazine (Dipentum)

  • Balsalazide (Colazal, Giazp)

• MOA: unclear; likely involves inhibition of several inflammatory mediators, like leukotrienes, tumor necrosis factor (TNF), and free radicals 

• ADME

  • Mesalamine is the active drug 

  • Prodrug formulations are designed to deliver mesalamine to various distal segments of the small bowel or colon, and are generally better tolerated

Corticosteroids 

• Drug:

  • Budesonide (Entocort EC, Uceris)

  • Prednisone, prednisolone, and methyl prednisolone for systemic use 

• MOA: glucocorticoid, which depresses the captivity of endogenous chemical mediators of inflammation 

  • Budesonide used for mild disease

  • Systemic steroids used for acute flares 

Immunomodulators 

• Drugs:

  • Azathioprine (Azasan, Imuran)

  • Mercaptopurine (Purinethol)

  • Methotrexate (Trexall) 

• MOA:

  • Unclear with respect to immune modulators and anti-inflammatory activity; however, these agents interfere with purine nucleic acid metabolism (different mechanisms)

  • Known as antimetabolites

Azathioprine (AZA)/6-mercaptopurine (6-MP) metabolism 

TPMT polymorphism have been shown to influence patient responsiveness to therapy - specifically, TMPT deficiency increases risk for ADE

Selective adhesion-molecules inhibitors (AKA integrin inhibitors)

• Drugs:

  • Natalizumab (Tysabri) - MS

  • Vedolizumab (Entyvio) - IBD

• MOA: antibody generated against integrins, which interferes with adhesion and migration cells form the vasculature into inflamed tissue 

Sphingosine 1-phosphate (S1P) Receptor Modulators 

• Ozanimod (Zeposia), Etrasimod (Velsipity), Fingolimod (Gilenya), Ponesimod (Ponvory)

• ORAL

• MOA: internalization of S1P receptors leading to prevention of lymphocyte mobilization to inflammatory sites; basically prevent lymphocytes from leaving the lymph nodes

Warning: S1P receptors affect multiple organ systems which is why they cause eye and CV adverse effects