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 these diseases based on?

Answer 2

It boils down to a defective interaction between the mucosal immunesystem and gut flora

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 remissio

Question 19

Describe some strategies for minimising the side effects of glucocorticoids.

Answer 19

Topical administration (e.g. enemas and suppositories) 
Low dose  
Use oral or topically administered glucocorticoid with a high first pass metabolism

Question 20

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

Answer 20

Budesonide

Question 21

Describe the effectiveness of budesonide compared to other glucocorticoids.

Answer 21

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

Question 22

State three immunosuppressive agents that could be used in IBD.

Answer 22

Azathioprine
Methotrexate
Cyclosporin – only useful in severe UC

Question 23

Describe the onset of action of azathioprine.

Answer 23

Slow onset – can take 3-4 months

Question 24

Describe the activation of azathioprine.

Answer 24

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

Question 25

Describe the mechanism of action of azathioprine.

Answer 25

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 26

What are the unwanted effects of azathioprine?

Answer 26

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 27

Describe the metabolism of azathioprine.

Answer 27

There are three routes of metabolism of azathioprine  Route resulting in the production of beneficial active metabolites that also cause myelosuppression (HPRT pathway produces 6-TIMP --> 6-TGN)  Route resulting in hepatotoxic metabolites with no beneficial effect (TPMT produces 6-MMP) Xanthine Oxidase Pathway– produces inert metabolites (6-TU) Xanthine oxidase is, fortunately, the main route of azathioprine metabolism

Question 28

In what clinical situation could there be a problem with azathioprine metabolism?

Answer 28

If the patient is taking allopurinol Allopurinol is used to treat gout and is a xanthine oxidase inhibitor This will result in the azathioprine being shunted down the hepatotoxic and myelosuppressive routes of metabolism

Question 29

What is the mechanism of action of Methotrexate?

Answer 29

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

Question 30

What are the three potential mechanisms of manipulating the gutmicrobiome?

Answer 30

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 31

Give 2 examples of anti-TNF-alpha antibodies.

Answer 31

Infliximab (IV) | Adalimumab (SC)

Question 32

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

Answer 32

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

Question 33

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

Answer 33

Knocking out TNF-alpha leads to general downregulation of other inflammatory cytokines Reduced infiltration and activation of leukocytes Induced cytolysis of cells expressing TNF-alpha Promotes apoptosis of activated T cells

Question 34

Describe the pharmacokinetics of anti-TNF-alpha antibodies.

Answer 34

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

Question 35

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

Answer 35

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 36

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

Answer 36

``` 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 37

What were the key findings from the SONIC trial?

Answer 37

Early use of infliximab is better than last resort use in patients with refractory disease CRP levels and endoscopy may allow identification of patients that aremost likely to benefit There is a greater risk of infection and lymphoma