Inflammatory Bowel Disease

Question 1

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

Answer 1

1. Ulcerative Colitis
2. 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 immune system 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:

1) Ulcerative Colitis?
2) Crohn’s Disease?

Answer 4

1) Ulcerative Colitis - Th2
2) Crohn’s Disease - Th1

Question 5

What are the main cytokines in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

Answer 5

1)

• Ulcerative Colitis - IL-5, IL-13

2)

• Crohn’s Disease - TNF-alpha

Question 6

Which layers of the gut are affected in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

Answer 6

1)

• Ulcerative Colitis - Mucosa + Submucosa

2)

• Crohn’s Disease - All Layers

Question 7

Describe which regions of the gut are affected in:

1) Ulcerative Colitis
2) Crohn’s Disease

Answer 7

1)

• Ulcerative Colitis - starts at the rectum and proceeds proximally (continuous inflammation)

2)

• Crohn’s Disease - can be anywhere on the GI tract (mouth to anus) - patchy inflammation

Question 8

Are abscesses, fissures and fistulae common in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

Answer 8

1)

• Ulcerative Colitis - No

2)

• Crohn’s Disease - Yes

Question 9

Describe the effectiveness of surgery in:

1) Ulcerative Colitis
2) Crohn’s Disease

Answer 9

1)

• Ulcerative Colitis - Curative

2)

• 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

1. Aminosalicylates
2. Glucocorticoids
3. Immunosuppressants e.g. azathioprines

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 secreted by dendritic cells
• Decrease antibody secretion
• Reduced cell migration (macrophages)
• Localised inhibition of immune responses

Question 16

Describe the activation of 2 types of aminosalicylates and thus the sites where they are active

Answer 16

• Mesalazine does not have to be activated any further - all over GI
• Olsalazine must be activated by colonic flora - only in colon

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

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

1. Azathioprine
2. Methotrexate
3. 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

* Azathioprine is converted into 6-mercaptopurine * **6-mercaptopurine is a purine antagonist**. It interferes 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 * 6-mercaptopurine is also converted into **6-MeMPN which inhibits de novo purine synthesis** * **6-TU which is a 'fake purine' which inserts into DNA**

Question 26

What are the unwanted effects of azathioprine?

Answer 26

* 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 or 6-MePN) * Route resulting in hepatotoxic metabolites with no beneficial effect (TPMT produces 6-MeMP) * 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, rather than forming the inactive metabolite 6-TU

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 microbiome manipulation therapies for IBD?

Answer 30

1. Nutrition based therapies – probiotics could be useful in UC 2. Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC 3. 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

1. **Infliximab (IV)** 2. Adalimumab (SC)

Question 32

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

Answer 32

* 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 33

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

Answer 33

* Production of anti-drug antibodies * Increased drug clearance

Question 34

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

Answer 34

* 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 35

What were the key findings from the SONIC trial?

Answer 35

* 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