Lecture 5: Treatments for IBD

Question 1

What 4 agents can be used to treat Ulcerative Colitis? (5A/J/T/a4)

Answer 1

1. 5-ASA (have “-sala-“ in the middle)
   
   • all convert to Mesalamine
2. Janus Kinase (JAK) Inhibitors
3. TNF-a Inhibitors
4. a-4 Integrin Inhibitors

Question 2

What 3 agents can be used to treat Crohn Disease? (ILI/T/a4)

Answer 2

1. IL-12/23 inhibitors
2. TNF-a Inhibitors
3. a-4 Integrin Inhibitors

Question 3

What are the two MOA’s for 5-ASA agents and what are their two contraindications?

Answer 3

MOA:

1. block cyclooxygenase and lipoxygenase
   
   • no prostaglandin/leukotriene production (COX)
2. dec. PMN/macrophage chemotaxis (block NFkB)

Contraindications:

1. all 5-ASA agents in ASA-allergic patients
2. Sulfasalazine in sulfonamide-allergic patients

Question 4

What are the 4 5-ASA drugs (S/M/O/B) and what are their components?

Answer 4

1. Sulfasalazine (sulfapyridine + 5-ASA)
2. Mesalamine (single 5-ASA)
3. Olsalazine (2 molecules of 5-ASA)
4. Balsalazide (inert carrier + 5-ASA)

all get converted to mesalamine

Question 5

What is the difference in area of 5-ASA affect if given orally, through rectal enemas, or by rectal suppository?

Answer 5

Oral: distal/terminal ileum, colon, throughout GI tract
- varies by agent

RE: may reach splenic flexure; does not frequently concentrate in rectum

RS: reaches upper rectum (15-20 cm beyond anal verge)

Question 6

What are 5-ASA agents indicated for and what are Olsalazine and Balsalazide specifically indicated for?

Answer 6

• mild-moderate Ulcerative Colitis

Olsalazine: ONLY for maintenance of remission
Balsalazide: ONLY for active disease

Question 7

What is the MOA of TNF-a Inhibitors and what are the 4 drugs in this family? (A/I/G/C)

What is their major side-effect?

Answer 7

• binds/neutralizes membrane-associated/soluble human TNF-a-mediated pro-inflammatory cell signaling = blocks leukocyte migration to inflammation site

Adalimumab, Infliximab, Golimumab, Certolizumab

Side Effect: infections (do TB-testing pre-therapy)
- also liver toxicity; malignancy/derm. (RARE)

Question 8

What are indications for Adalimumab, Infliximab, Golimumab, Certolizumab and when are they administered?

When are ALL TNF-a inhibitors used?

Answer 8

A: moderate-severe U.C. and C.D. (SubQ every 2 wks)

I: moderate-severe C.D./severe U.C. (IV every 8 wks)

G: moderate-severe U.C. ONLY (SubQ every 4 wks)
C: moderate-severe C.D. ONLY (SubQ every 4 wks)

all inhibitors used after inadequate response to conventional or immunosuppressant therapy

Question 9

What 3 other conditions are TNF-a inhibitors also indicated for?

Answer 9

rheumatoid/psoriatic arthritis, psoriasis, ankylosing spondylitis

Question 10

What is the MOA of a-4 Integrin Inhibitors and what are the two drugs in this family? (N/V)

What is their major side effect and which drug are cases only seen with?

Answer 10

MOA: limit integrin-associated cell adhesion, preventing migration of leukocytes to site of inflammation

Natalizumab and Vedolizumab (IV injections)
- N (IgG4k Ab) and V (IgG1 Ab)

SE: Progressive Multifocal Leukoencephalopathy

• cases ONLY in natalizumab (TOUCH program)
• associated with John Cunningham Virus (JCV)

Question 11

What are 3 risk factors for Progressive Multifocal Leukoencephalopathy? What drug is it associated with?

Answer 11

1. treatment > 2 years
2. prior imunosuppressant treatment
3. anti-JCV antibodies

infections associated with natalizumab

Question 12

What are the indications for Natalizumab and Vedolizumab, and when are they administered?

When are ALL a-4 Integrin inhibitors recommended?

Answer 12

N: moderate-severe C.D. (IV every 4 wks)
- NOT recommended in combination w/immunosupp.

V: moderate-severe C.D. and U.C. (IV every 8 wks)

ALL a-4 Integrin Inhibitors recommended after inadequate response to conventional or TNF-a therapy

Question 13

What is the MOA of Interleukin-12/23 Inhibitors, what drug is in this family, and what is its major side-effect?

Answer 13

MOA: binds to P40-subunit of IL’s = block activation/differentiation of NAIVE T-CELLS and activation of NK cells (no proinflammatory cytokines)

Ustekinumab
- other IL-inhibitors for plaque psoriasis/psor. arthritis

SE: Infections (TB-testing pre-therapy recommended)
- also: infusion allergic rxn/malignancy (RARE)

Question 14

What are the indications for IL-12/23 Inhibitors and how is Ustekinumab administered?

Answer 14

U: moderate-severe U.C. and C.D.
- pts. intolerant/resistant to other therapies

• administered SubQ every 8 wks (AFTER single IV infusion for induction)

Question 15

What is the MOA of JAK Inhibitors, what is the drug of this family, and what other disease is it indicated for BESIDES Ulcerative Colitis?

Answer 15

MOA: bind to/inhibit free-floating and bound JAK-1/JAK-3 (lesser extent JAK-2)
- inhibits gene transcription and cytokine release

Tofacitinib (Xeljanz) - oral JAK-1/3 inhibitor
- also indicated for psoriatic/rheumatoid arthritis

Question 16

What is the major indication for Tofacitinib (Xeljanz), how is it administered, and what two therapies should NOT be given with it?

Answer 16

T: moderate-severe U.C. (orally 2x daily)

• do not use cocomitantly with Biological therapies or potent immunosuppressant’s

Question 17

When are Steroid Agents used for Ulcerative Colitis and Crohn Disease and how are they dosed?

Answer 17

I: acute or severe U.C/C.D. UNCONTROLLED by other means

• NOT FOR maintenance of remission unless ABSOLUTELY required

Dose: use lowest dose for shortest duration possible