IBD

What is Inflammatory Bowel Disease (IBD)?

A spectrum of remitting and relapsing, chronic, inflammatory intestinal conditions causing significant GI symptoms.

What are the two major subtypes of IBD?

Ulcerative Colitis (UC) and Crohn's Disease (CD).

Where is Ulcerative Colitis (UC) primarily located?

Mostly limited to the colon and rectum (95%).

Where is Crohns Disease primarily located?

any portion of the GI tract

almost always affects the terminal ileum and cecum

ileocecal valve

What is the first-line treatment for mild-to-moderate Ulcerative Colitis?

Mesalamine-based therapy.

Is Mesalamine generally used in Crohn's Disease?

No

What is Sulfasalazine?

A prodrug that contains 5-ASA linked to sulfapyridine by an azo bond

What is the function of the azo bond in Sulfasalazine?

It prevents absorption in the stomach or small intestine, releasing active 5-ASA in the colon after colonic bacterial azoreductase cleave the bond

Name two second generation prodrug 5-ASA compounds.

Olsalazine and Balsalazide.

Role of coated mesalamine

delayed release, releases drug throughout the GI tract

Role of PH sensitive mesalamine

◦Releases drug in the small intestine and colon

A mesalamine suppository works where?

rectum

A mesalamine enema works where?

distal colon

what is canasa?

mesalamine suppository

what is asacol?

delayed release resin tablet

what is pentasa?

microgranule controlled-release capsule

what is lialda?

MMX formulated pH-dependent polymer film coated tablet

what is aspriso?

enteric coated granules in polyermatrix

where do apriso, balsalazide, lialda, olsalazine, and delzicol work>

proximal colon

where does asacol HD work?

all the way to terminal ileum

where does pentase work?

all the way to jejunum

What are the adverse effects associated with Sulfasalazine?

Nausea, GI upset, headaches, arthralgias, myalgias, bone marrow suppression, malaise, impaired folate absorption, and hypersensitivity to sulfapyridine.

What percentage of patients discontinue Sulfasalazine due to adverse effects?

Up to 40%.

What patients have higher risk of ADEs with sulfasalazine?

◦Slow acetylators have a higher incidence of adverse effects than fast acetylators

How do corticosteroids function in the treatment of IBD?

They suppress acute inflammation and modulate the immune system by inhibiting cytokine production.

How can corticosteroids be administered for IBD?

Parenterally, orally, or rectally.

What is unclear about the effects of corticosteroids in IBD?

Whether the most important effects are systemic or local (mucosal).

corticosteroids role in IBD

Used for the treatment of active UC or CD to induce remission

◦Should not be used chronically to maintain disease remission

Corticosteroids MOA

modulates immune system and inhibits production of cytokines and mediators

corticosteroids used for sevre vs mild IBD

severe disease: burst and taper 1-2 weeks

◦Oral- Prednisone and prednisolone

◦IV- methylprednisolone

Mild to Moderate: topical hydrocortisone, budenoside, oral/topical enteric coated budenoside

enteric coated budenoside ADME

◦Undergoes extensive first pass metabolism that reduces systemic absorption

◦Drug is delivered primarily at the ileocecal junction

can be used for up to 8 weeks

name the synethic glucocorticoid used for retaining UC/Crohns remission

budenoside

*not preferred to be used for maintenance

budenoside ADEs

HA, acnea, nausea, CYP3A4

What are the immunomodulators used in IBD?

Azathioprine, 6-mercaptopurine (6-MP), and methotrexate.

What is the purpose of immunomodulators in IBD treatment?

Monotherapy or adjunctive therapy for patients not responding to mesalamine-based therapy, can help maintain remission achieved with corticosteroids (steroid-sparing effect)

Adjunct to biologics and anti-integrin therapies to add efficacy and reduce risk of antibody formation

immunomodulators

Are immunomodulators used for induction therapy?

no - takes 6 months

What is the MOA of azathioprine and 6-MP?

Purine antimetabolites with immunosuppressive properties

Impair purine biosynthesis and inhibit cell proliferation

What should be tested before initiating azathioprine treatment?

TPMT activity to assess risk of bone marrow suppression

azathioprine DDI caution

xanthine oxidase inhibitors

azathioprine ADE

◦Idiosyncratic

◦Pancreatitis (5%)

◦N/V, fever, rash arthralgias

- bone marrow suppression

What is the MOA of methotrexate?

Inhibition of dihydrofolate reductase, reducing thymidine and purines production.

◦Used in many chronic inflammatory conditions as maintenance therapy

Methotrexate onset of action

8 weeks

Methotrexate administration

PO, IM, or SubQ once weekly

What are common adverse effects of methotrexate at higher doses?

Bone marrow suppression, megaloblastic anemia, alopecia, mucositis.

*folate supplentation reduces risk

cyclosporine MOA

Calcineurin inhibitor

What is the primary role of cyclosporine in IBD?

Limited to treating specific problems like fistulous complications or severe UC failing corticosteroids over short term

What are the significant adverse effects of cyclosporine?

Renal toxicity, cardiovascular risks, hyperglycemia, gum hyperplasia, hepatotoxicity, hyperuricemia, hirsuitism, hyperlipidemia, hypertension.

*CYP3A4

Name the classes of biologic agents used in IBD.

TNF-α inhibitors

leukocyte adhesion inhibitors

anti- IL23

Anti-IL12/IL23

Which TNF-a inhibitors are used fro both UC and Crohn's

◦Infliximab:

Adalimumab

Which TNF-a inhibitors are used for only Crohn's?

Certolizumab

Which TNF-a inhibitors are used for only UC?

Golimumab

What is the therapeutic effect of TNF-α inhibitors in Crohn's disease?

They lead to improvement in 60% and disease remission in 30% of patients with moderate to severe crohns disease

*Median time to clinical response is 2 weeks

What are the 'big four' things to worry about with TNF-alpha therapy?

Infection risk, malignancy, heart failure, and hypersensitivity disorders.

What should be tested prior to initiating TNF-alpha therapy?

Screening for tuberculosis (TB) and hepatitis B.

name the leukocyte adhesion inhibitors (anti-integrins)

natalizumab

vedolizumab

natalizumab MOA

◦Anti- α4 integrin that binds to CNS-tropic and gut-tropic T cells

Vedolizumab MOA

◦Anti- α4 integrin that binds to only gut-tropic T cells

What is the role of leukocyte adhesion inhibitors (anti-integrins) in IBD?

◦In patients who have failed or cannot tolerate TNF inhibitors

ADEs of anti-integrin therapy

◦Infusion-related reactions

◦Hypersensitivity

What is a serious risk associated with Natalizumab?

Risk of Progressive Multifocal Leukoencephalopathy (PML).

What are the common adverse effects of Vedolizumab?

Headache and nasopharyngitis.

screening specification for anti-integrin therapy

Do not need to screen for TB or Hepatitis with these agents

* Risk of lymphoma is much less than with the TNF inhibitors

Name three IL-23 agents.

Risankizumab, Mirikizumab, and Guselkumab.

*Mike, Gus, and Ris are all 23

Name the IL-12/IL-23 agent

ustekinumab

IL-inhibitors MOA

monoclonal antibody that binds to the p40 subunits preventing activation of interlukin 23 +/-12 which are pro-inflammatory cytokines on lymphocytes

What are IL-23 agents used for in Crohn's disease?

They are used as second-line therapy crohns disease

What are common adverse effects of IL-inhibitor therapy?

Hypersensitivity, infusion-related reactions, TB (test prior), HA, fatigue, injection site reaction, and herpes infections.

What antibiotics are commonly used in Crohn's disease?

Metronidazole and Ciprofloxacin.

What is the mechanism of action of antibiotics in crohns disease?

It may interrupt the inflammatory process directed at the endogenous flora.

when are antibiotics often added to crohns therapy?

◦Often used in patients when fistulas or abscesses are present

What is a potential complication of ileal pouch anal anastomosis (IPAA) in UC?

Pouchitis.

What are common adverse effects of Ciprofloxacin?

Nausea, vomiting, diarrhea, headache, dizziness, and phototoxicity, QT prolongation, increases levels of warfarin and theophylline

Ciprofloxacin BBW

Tendonitis and tendon rupture.

What are common adverse effects of Metronidazole?

Gastrointestinal upset, metallic taste, dark urine, vertigo, ataxia, disulfiram-like reaction, incteractions with warfarin, phenytoin, phenobarbitol

What is the initial treatment for distal mild to moderate active UC?

Oral/topical 5-ASA agents.

 Consider reducing ASA to lowest possible effective dose

What is the initial treatment for extensive mild to moderate active UC?

oral mesalamine or budesonide

What is the treatment for moderate to severe active UC?

Budesonide or high-dose prednisone, possibly combined with infliximab or vedolizumab +/- AZA

*need to quickly suppress inflamation

 If taking budesonide, try to stop after _ weeks after remission achieved

8

What is the treatment for acute severe or fulminant UC?

Hospitalization with methylprednisolone or hydrocortisone.

What is the treatment for acute severe or fulminant UC with no response to steroids?

infliximab or cyclosporine

What is the treatment for mild to moderate active Crohn's disease - extensive?

Sulfasalazine

What is the treatment for mild to moderate active Crohn's disease - perianal?

metronidazole +/- infliximab

What is the treatment for mild to moderate active Crohn's disease - small bowel?

budesonide

Treatment for Moderate to Severe Active Crohn's Disease

◦Prednisone + infliximab

◦Adalimumab

◦Vedolizumab +/- MTX

◦AZA/6-MP

* off 2-4 weeks after response achieved

Treatment for Moderate to Severe to fulminant

◦Hospitalization

◦Steroids

◦Infliximab prior to surgery as last option

What is the last option for severe Crohn's disease treatment?

Ustekinumab.