L10 Management of Inflammatory Bowel Disease

Question 1

Non-Pharmacological Management of Chron’s Disease?

Answer 1

• Smoking cessation
• Early Surgery (ie. Disease localized to distal ileum)

Question 2

Pharmaceutical Management of Chron’s Disease?

FIRST LINE: ____________________=> Induces remission in first presentation

____________________ may be considered when above is unsuitable or in patients with distal ileal, ileocecal or right-sided colonic disease

_______________________: ONLY for mild presentations (less effective but have fewer side effects)

Answer 2

FIRST LINE: Corticosteroids: Prednisolone, Methylprednisolone, IV Hydrocortisone=> Induces remission in first presentation

Budesonide may be considered when corticosteroid unsuitable or in patients with distal ileal, ileocecal or right-sided colonic disease

Aminosalicylates (sulfasalazine and mesalazine): ONLY for mild presentations (less effective than corticosteroids or budesonide but have fewer side effects)

Question 3

First-line therapy for Chron’s Disease?

Answer 3

Oral Prednisolone for reducing over 6-8 weeks

May be combined with Azathioprine (two or more inflammatory exacerbations in a 12-month period, or the corticosteroid dose cannot be reduced)

Question 4

Pharmaceutical therapy for MILD vs. SEVERE cases of Crohn’s Disease?

Mild Cases (confined to ileum/ascending colon): __________________

SEVERE Cases: __________________ or ___________________

Answer 4

Mild Cases (confined to ileum/ascending colon): Budesonide (Less effective, fewer side effects)

SEVERE Cases: IV Hydrocortisone or Methylprednisolone

Question 5

Metabolic effects of glucocorticoids involve transcriptional _________

Anti-inflammatory effects involve transcriptional ____________

• Exception?

Answer 5

Metabolic effects of glucocorticoids involve transcriptional activation

Anti-inflammatory effects involve transcriptional inhibition ( ie. COX-2)

• Upregulation of Annexin A1: directly inhibits PLA2 and COX2

Question 6

Side Effects of Systemic Corticosteroids?

How to Limit these effects?

Answer 6

CUSHINGOID

Cataracts

Ulcers

Skin: striae, thinning, bruising

Hypertension/ hirsusm/ hyperglycemia

Infections

Necrosis, avascular necrosis of the femoral head

Glycosuria

Osteoporosis, obesity

Immunosuppression

Diabetes

TAPERING is required to prevent secondary adrenal insufficiency (Cushing’s Syndrome)

Question 7

Budesonide Indications/Benefits/Delivery?

Answer 7

Corticosteroid that exerts significant local anti-inflammatory effects used to treat Chron’s Disease

Benefits: High topical potency and extensive first pass=> Limited severe side effects

Delivery:

• Topically as a rectal foam or enema (Sigmoid colon/Rectum)
• Orally for mild/moderate CD (Ileum/Ascending colon)

Question 8

What can be added to a corticosteroid to induce remission of Chron’s Disease?

Answer 8

Azathioprine or Mercaptopurine can be added to a corticosteroid to induce remission or if there are 2+ inflammatory exacerbations

MOA: Converted to the purine analog 6-thioinosine monophosphate (TIMP), interfering with lymphocyte replication

Helps w/ steroid sparing

Question 9

____________ and _________________ are converted to the purine analog 6-thioinosine monophosphate (TIMP), interfering with lymphocyte replication. Can be added to a corticosteroid to induce remission in Chron’s Disease (Helps w/ steroid sparing)

Side Effects?

Contraindications?

Answer 9

Azathioprine and Mercaptopurine (6-MP) are converted to the purine analog 6-thioinosine monophosphate (TIMP), interfering with lymphocyte replication. Can be added to a corticosteroid to induce remission in Chron’s Disease (Helps w/ steroid sparing)

Side effects:

• Bone marrow suppression
• Opportunistic infections
• Alopecia

Contraindication: Drug interaction with allopurinol (gout)

Question 10

______________ and ____________ are TNFα inhibitors used for the treatment of severe, active Crohn’s disease, following inadequate response to conventional therapies. They also help with ___________

Cautions?

Answer 10

Infliximab (Chimeric IgG1 monoclonal antibody to TNFα) and Adalimumab (Fully Human) are TNFα inhibitors used for the treatment of severe, active Crohn’s disease, following inadequate response to conventional therapies.

Help with Steroid sparing’

Cautions:

• Caution in active/dormant TB
• Antigenic: body creates antibodies against limiting its effectiveness

Question 11

____________ and _______________ block the action of integrins on the surface of circulating activated CD4+ cells preventing interaction with endothelial cell adhesion molecules.

Anti-Integrin Therapy is indicated for Moderate/Severe Crohn’s when TNFα antibody therapy with _________ or ________ is unsuccessful, contra-indicated, or not tolerated

Answer 11

Vedolizumab and Ustekinumab block the action of integrins on the surface of circulating activated CD4+ cells preventing interaction with endothelial cell adhesion molecules.

Anti-Integrin Therapy is indicated for Moderate/Severe Crohn’s when TNFα antibody therapy with Adalimumab or Infliximab is unsuccessful, contra-indicated, or not tolerated

Question 12

________________: targets the p40 subunit of both IL-12 and IL-23 and prevents them from binding to IL-12Rβ1 receptors on T cells. Fewer T1 and T17 helper cells are recruited and activated, reducing inflammation in the gut (Used to Treat Chron’s Disease)

Contraindication?

Answer 12

Ustekinumab: targets the p40 subunit of both IL-12 and IL-23 and prevents them from binding to IL-12Rβ1 receptors on T cells. Fewer T1 and T17 helper cells are recruited and activated, reducing inflammation in the gut

ACTIVE INFECTION is a contraindication for Ustenumbad!!

Question 13

___________________ are Prodrugs => Mesasaline (5-ASA) (Active Drug) which exerts a potent inhibitory effect on a number of pro-inflammatory mediators released by intestinal mucosa (acts as a PPAR γ agonist)

• Much stronger evidence for their benefit in _____ vs ____

Answer 13

Amino Salicylates (-alazine) are Prodrugs => Mesasaline (5-ASA) (Active Drug) which exerts a potent inhibitory effect on a number of pro-inflammatory mediators released by intestinal mucosa (acts as a PPAR γ agonist)

• Much stronger evidence for their benefit in UC vs CD

Question 14

Mainstay Therapy of Ulcerative Colitis

Answer 14

Aminosalicylates are the mainstay of maintenance therapy

• If the inflammation is distal, use rectal preparation otherwise systemic medication required
• Diarrhea sometimes treated with anti-diarrhoeal drugs
• Laxatives can be useful in proctitis

Question 15

Acute Severe Ulcerative Colitis (medical emergency)

• _________________________ is required.
• _____________________ given to induce remission

Mild-to-Moderate Presentation/Inflammatory Exacerbation:

• __________________ is first-line

No remission in 4 weeks:

• _____________________________________
• _____________________________________

Answer 15

Acute Severe Ulcerative Colitis (medical emergency)

• Immediate hospital admission is required.
• IV Corticosteroids (Hydrocortisone) to induce remission

Mild-to-Moderate Presentation/Inflammatory Exacerbation: Topical Aminosalicylate is first-line

No remission in 4 weeks:

• Topical/Oral Aminosalicytate (Extensive Disease)
• 4-8 weeks of Topical/Oral corticosteroids

Question 16

_____________________: (JAK1 and JAK3 inhibitor) used in active moderate to severe Ulcerative Colitis in patients who have had an inadequate or lost response to, or are intolerant to either conventional therapy or a biologic agent.

Answer 16

Tofacitinib: (JAK1 and JAK3 inhibitor) used in moderate to severe active disease in patients who have had an inadequate or lost response to, or are intolerant to either conventional therapy or a biologic agent.

Highly effective in UC but not in CD

Question 17

Treatments of IBD that are more effective for Ulcerative Collitits than Chrons’ Disease?

Answer 17

Golimumab: TNF alpha blocking mAb

Tofacitinib: JAK1 and JAK3 inhibitor

Aminosalicylates (-alazine) Prodrugs => Mesasaline (5-ASA) (Active Drug) exerts a potent inhibitory effect on a number of pro-inflammatory mediators released by intestinal mucosa (acts as a PPAR γ agonist)

Question 18

Evolution of IBD Therapy

• Early treatment focused on agents that prevented TNF-α signaling (______________)
• Newer agents target IL-12/IL-23 (_________) as well as the integrin α4β7 (__________) and prevent leukocyte adhesion and migration.

Other new therapies include:

• Inhibitors of the JAK/STAT pathway (_______________)
• Stem cells to treat fistulizing disease
• Probiotics
• Fecal transplantation

Answer 18

Early treatment focused on agents that prevented TNF-α signaling. (Golimumab)

Newer agents target IL-12/IL-23 (Ustekinumab) as well as the integrin α4β7 (Vedolizumab) and prevent leukocyte adhesion and migration.

Other new therapies include:

• Inhibitors of the JAK/STAT pathway (Tofacitinib)
• Stem cells to treat fistulizing disease
• Probiotics
• Fecal transplantation

Question 19

_________________: specific inhibitor of α4β7 integrin. By not blocking CD4+ lymphocytes with α4β1receptors, the risk of progressive multifocal leukoencephalopathy (PML) is vastly reduced (Used to Treat Chron’s Disease)

Answer 19

Vedolizumab: specific inhibitor of α4β7 integrin. By not blocking CD4+ lymphocytes with α4β1receptors, the risk of progressive multifocal leukoencephalopathy (PML) is vastly reduced

Question 20

_________________ (TNF alpha blocking mAb): Given by SC injection at increasing intervals to treat ulcerative colitis

Answer 20

Golimumab (TNF alpha blocking mAb): Given by SC injection at increasing intervals to treat ulcerative collitis