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 based on?

Answer 2

A defective interaction between the mucosal immune system + gut flora

Question 3

List 4 key environmental risk factors associated with IBD

Answer 3

Diet
Smoking
Medication
Microbiome

Question 4

Which T cell responses are involved in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 4

UC: Th2
CD: Th1

Question 5

What are the main cytokines in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 5

UC: IL-13
CD: TNF-alpha

Question 6

Which layers of the gut are affected in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 6

UC: Mucosa + Submucosa
CD: All Layers

Question 7

Describe which regions of the gut are affected in:

a. Ulcerative Colitis
b. Crohn’s Disease

Answer 7

UC: Starts at the rectum + spreads proximally (continuous inflammation)
CD: Any part of 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

UC: No
CD: Yes

Question 9

Describe the effectiveness of surgery in:

a. Ulcerative
b. Crohn’s Disease

Answer 9

UC: Curative
CD: Not always curative, even if the affected area is cut out, it often reoccurs

Question 10

Describe 3 supportive therapies that are given for IBD

Answer 10

Nutritional support
Fluid/ electrolyte replacement
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 (= 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

Bind to PPAR receptors, acting as transcription modulators
Downregulate NFKB + MAPK, thus down regulating pro-inflammatory cytokines e.g. IL-1, TNF-alpha + IL-6
Downregulate expression of COX-2 + pro inflammatory prostaglandins

Question 16

Describe the activation of aminosalicylates.

Answer 16

Mesalazine is active, absorbed in small bowel + colon

Olsalazine must be activated by colonic flora so is active in colon

Question 17

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

Answer 17

Effective at inducing + maintaining remission in UC
Better than steroids at inducing remission in UC
Ineffective in inducing remission, may help maintenance but other drugs are better in CD

Question 18

Describe the use of glucocorticoids in IBD.

Answer 18

Use in UC declining 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 + 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? Why is this?

Answer 20

Budesonide

Not absorbed, stays in gut

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 an immunosuppressive agent that could be used in IBD.

Answer 22

Azathioprine

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 is a pro-drug

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 Interferes with DNA synthesis + cell replication Impairs: Cell- + antibody-mediated immune responses Lymphocyte proliferation Mononuclear cell infiltration Synthesis of antibodies Enhances: T cell apoptosis

Question 26

What are the unwanted effects of azathioprine?

Answer 26

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

Question 27

Describe the metabolism of azathioprine.

Answer 27

3 routes of metabolism of azathioprine: Route resulting in production of beneficial active metabolites also causes myelosuppression (6-TGN) Route resulting in hepatotoxic metabolites with no beneficial effect (6-MMP) Xanthine Oxidase Pathway: produces inert metabolites (6-TU)

Question 28

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

Answer 28

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

Question 29

When is Azathioprine used in Crohn's disease?

Answer 29

Not for active disease Used for maintaining remission Glucocorticoid sparing- can reduce glucocorticoid dose

Question 30

What are the 4 potential mechanisms of manipulating the gut microbiome?

Answer 30

Exclusive enternal nutrition (EEN): Liquid diet, allows resting of mucosa + recovery of gut flora, hard to maintain + unpalatable Probiotic therapies: in maintenance of remission of UC Faecal Microbiota Replacement Therapy (FMT): in UC Antibiotics: Rifaximin Interferes with bacterial transcription by binding to RNA polymerase Induces + sustains remission in moderate CD Potentially beneficial in UC

Question 31

Give an example of an anti-TNF-alpha antibody

Answer 31

Infliximab (IV)

Question 32

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

Answer 32

60% of patients respond within 6 weeks

Question 33

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

Answer 33

Anti TNF-alpha reduces activation of TNF-alpha receptors in the gut Reduces downstream inflammatory events Induces 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-TNF-alpha therapy that may require changes in the treatment guidelines?

Answer 35

~50% of responders stopped responding after 3 years | Due to production of anti-drug antibodies + increased drug clearance

Question 36

What are the adverse effects of anti-TNF-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

List 3 local clinical features of IBD

Answer 37

Abdominal pain/ cramping Diarrhoea, bloody faeces Mouth ulcers

Question 38

List 6 systemic clinical features of IBD

Answer 38

``` Anaemia Fever Arthritic pain Skin rashes Uveitis Weight loss ```

Question 39

Name 2 glucocorticoids. What is the MOA of glucocorticoids in IBD?

Answer 39

Prednisolone + Budesonide Activate intracellular glucocorticoid receptors which then act as positive or negative transcription factors Potent anti-inflammatory + immunosuppressive actions

Question 40

List 3 strategies for minimising unwanted side effects of IBD drugs

Answer 40

Topical administration Use low dose in combination with another drug Use drug with high hepatic first pass metabolism so little escapes into systemic circulation