Inflammatory Bowel Disease

Question 1

What are the two main diseases that come under Inflammatory Bowel Disease?

Answer 1

Ulcerative Colitis

Crohn’s Disease

Question 2

What is the underlying pathogenesis of IBD diseases based on?

Answer 2

It boils down to a defective interaction between the mucosal immune system and gut flora- an autoimmune condition

Question 3

What type of IBD is obesity a risk factor for?

Answer 3

Crohn’s Disease

Question 4

Which T cell responses are involved in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 4

a. Ulcerative Colitis
Th2
b. Crohn’s Disease
Th1

Question 5

What are the main cytokines in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 5

a. Ulcerative Colitis
IL-5
IL-13
b. Crohn's Disease
TNF-alpha

Question 6

Which layers of the gut are affected in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 6

a. Ulcerative Colitis
Mucosa + Submucosa
b. Crohn’s Disease
All Layers

Question 7

Describe which regions of the gut are affected in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 7

a. Ulcerative Colitis
Starts at the rectum and proceeds proximally (continuous inflammation)
b. Crohn’s Disease
Can be anywhere on the GI tract (mouth to anus)
Patchy inflammation

Question 8

Are abscesses, fissures and fistulae common in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 8

a. Ulcerative Colitis
No
b. Crohn’s Disease
Yes

Question 9

Describe the effectiveness of surgery in:

a. Ulcerative
b. Crohn’s Disease

Answer 9

a. Ulcerative Colitis
Curative
b. Crohn’s Disease
Not always curative, even if the affected area is cut out, it often reoccurs

Question 10

Describe some supportive therapies that are given for IBD

Answer 10

Nutritional therapy
Fluid/electrolytes
Potentially even blood transfusions/oral iron

Question 11

What are the three types of classic symptomatic treatment for IBD?

Answer 11

Aminosalicylates
Glucocorticoids
Immunosuppressants

Question 12

What is the main aminosalicylate drug?

Answer 12

Mesalazine

AKA 5-aminosalicylic acid (5-ASA)

Question 13

What is a slightly more complex aminosalicylate?

Answer 13

Olsalazine (this is 2 x 5-ASA)

Question 14

What type of drug are aminosalicylates?

Answer 14

Anti-inflammatory

Question 15

Describe the mechanism of anti-inflammatory action of aminosalicylates.

Answer 15

They inhibit IL-1, TNF-alpha and PAF
Decrease antibody secretion
Reduced cell migration (macrophages)
Localised inhibition of immune responses

Question 16

Describe the activation of aminosalicylates.

Answer 16

Mesalazine does not have to be activated any further

Olsalazine must be activated by colonic flora

Question 17

Describe the effectiveness of aminosalicylates in Ulcerative Colitis and Crohn’s Disease.

Answer 17

They are effective at inducing and maintaining remission in UC
They are better than steroids at inducing remission in UC
They are less effective in CD

Question 18

Describe the use of glucocorticoids in IBD.

Answer 18

Use of glucocorticoids in UC is in decline because aminosalicylates are better
Glucocorticoids are still the drug of choice for inducing remission in CD
However, side effects are likely if they are used to maintain remission

Question 19

What is an example of a glucocorticoid that has relatively few side effects?

Answer 19

Budesonide as tends to remain in gut

Question 20

Describe the effectiveness of budesonide compared to other glucocorticoids.

Answer 20

Budesonide has fewer side effects than other glucocorticoids but it is less effective at inducing remission in CD

Question 21

State three immunosuppressive agents that could be used in IBD.

Answer 21

Azathioprine
Methotrexate
Cyclosporin – only useful in severe UC

Question 22

Describe the onset of action of azathioprine.

Answer 22

Slow onset – can take 3-4 months

Question 23

Describe the activation of azathioprine.

Answer 23

Azathioprine needs to be metabolised by gut flora to 6-mercaptopurine

Question 24

Describe the mechanism of action of azathioprine.

Answer 24

6-mercaptopurine is a purine antagonist
It interfered with DNA synthesis and cell replication
It impairs:
 Cell- and antibody-mediated immune responses
 Lymphocyte proliferation
 Mononuclear cell infiltration
 Synthesis of antibodies
It enhances:
 T cell apoptosis

Question 25

What are the unwanted effects of azathioprine?

Answer 25

Nearly 10% of patients stop treatment because of the side effects Pancreatitis Bone marrow suppression Hepatotoxicity Increased risk (4 fold) of lymphoma and skin cancer

Question 26

What is the mechanism of action of Methotrexate?

Answer 26

Folate antagonist It reduces the production of thymidine and other purines NOTE: not widely used because of significant side effects

Question 27

What are the three potential mechanisms of manipulating the gut microbiome?

Answer 27

Nutrition based therapies – probiotics could be useful in UC Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC Antibiotics – Rifaximin  Interferes with bacterial transcription by binding to RNA polymerase  Induces and sustains remission in moderate CD  Potentially beneficial in UC

Question 28

Give 2 examples of anti-TNF-alpha antibodies.

Answer 28

Infliximab (IV) | Adalimumab (SC)

Question 29

Describe the effectiveness of anti-TNF- antibodies in Crohn’s Disease.

Answer 29

60% of patients will respond within 6 weeks are it is potentially curative

Question 30

Describe the mechanism of action of anti-TNF-alpha antibodies.

Answer 30

Knocking out TNF-alpha leads to general downregulation of other inflammatory cytokines downstream Induced cytolysis of cells expressing TNF-alpha Promotes apoptosis of activated T cells

Question 31

Describe the pharmacokinetics of anti-TNF-alpha antibodies.

Answer 31

Given intravenously Long half-life – 9.5 days Most patients relapse between 8-12 weeks Repeat infusion given after 8 weeks

Question 32

What is a problem with anti-TNA-alpha therapy that may require changes in the treatment guidelines?

Answer 32

Evidence showed up to 50% of responders stopped responding after 3 years This is due to production of anti-drug antibodies and increased drug clearance

Question 33

What are the adverse effects of anti-TNA-alpha therapy?

Answer 33

``` Increased risk of tuberculosis Risk of reactivating dormant TB Increased risk of septicaemia Worsening heart failure Increased risk of demyelinating disease Increased risk of malignancy Can be immunogenic ```

Question 34

Use of azathioprine

Answer 34

Not recommended for active disease use in CD but maintaining remission

Question 35

How to minimise unwanted effects of azathioprine

Answer 35

Administer locally in fluid or foam form Reduce doses by combining with other drug Give drug with high metabolic first pass metabolism