19: Inflammatory Bowel Disease

Question 1

What are the two most common types of Inflammtory Bowel Disease? (IBD?)

What is their cause?

Answer 1

Both are Autoimmune-inflammtory diseases

1. Ulcerative Colitis
2. Crohn’s disease

–> can present very differently but in 10% conditions are indistiguishable, no clear diagnosis can be made

Question 2

What are the main mediators in UC?

Answer 2

Th2 mediated via IL-13+5

Question 3

What are important inflammatory mediators in Crohns diesease?

Answer 3

Th1 mediated via many factors including

• TNF-alpha
• IL-1ß
• IL-6

Question 4

What are the pathological features of Ulcerative Colitis?

Answer 4

• Continous inflammation
• Starts at rectum and progresses proximally
• Mucosal layer is affected
• Normally not associalted with fissures/fistules/ abcesses
• Surgery is curative

Question 5

What are the main pathological features of Crohn’s disease?

Answer 5

• Patchy inflammation
• In whole GI tract
• And all layers
• Commonly associated with absesses, fissures, fistules etc.
• Surgery is not always curative

Question 6

What are the supportive therapies in IBD?

Answer 6

To treat acute attack

• Fluid/electrolyte replacement
• Blood transfustion (in bloodloss, mainly Crohns)
• Nutritional support (malnutrition common)

Question 7

What kind of drugs can be used in an acute attack of UC or Crohn’s?

Answer 7

• Aminosalicylates eg Mesalazine
• Glucocorticoids eg Prednisolone
• Immunosuppressives eg Azathioprine

Question 8

What is the MOA of Aminosalicylates?

Answer 8

It is an anti-inflammtory drug

It binds to receptor and alters transcripiton in nucleus

• downregulated pro-inflammtory mediators
  
  • TFN-alpha
  • IL-6, more IL
  • Inhibits Cox2
    
    • downregulation of pro-inflammtory prostaglandins

Question 9

Compare two Aminosalicylated regarding their Pharmacokinetics and action

Answer 9

• Mesalazine or 5-aminosalicylic acid (5-ASA)
  
  • absorbed in small bowel and colon
• Olsalazine (2 linked 5-ASA molecules)
  
  • absorbed in colon
  • needs to be metabolised by gut bacteria first–> in colon so more targeted treatment

Question 10

What is the use of Aminosalicylates in Ulcerative colitis?

Answer 10

• First line of treatment
  
  • good at inducing and maintaining remission
  • better than many glococorticoids
  • PO+ rectal (combined) administration

Question 11

Explain the used of Aminosalicylates in the treatment of Crohns Disease

Answer 11

Ineffective in inducing remission of CD

• A very modest amount of evidence for effectiveness in maintenance
• However, other therapies!1 preferable for maintenance

Question 12

What are the side-effects of Aminosalicylates?

Answer 12

Common: GI disturbance

Diarrhoea; gastrointestinal discomfort; gastrointestinal disorders; nausea;

skin reactions; vestibular syndrome; vomiting

Uncommon: Agranulocytosis

Question 13

What is the MAO of Glucocorticoids?

Answer 13

Very powerful immunosupressant anti-inflammatory drug

• alters transcription of cells and pro-inflammatory mediators

Question 14

Explain the use of Glucocorticodis in the treatment of Ulcerative colitis

Answer 14

• Inducing and Maintaining Remission:
  
  • Might be Effective, but not recommended (Aminosalicylates more effective )

Question 15

Explain the use of Glucocorticoids in the treamtent of Crohns Disease?

Answer 15

1. Inducing Remission
   
   • Effective, Choice of treatment (Budesonide preferred in mild cases)
2. Maintaining Remission
   
   • Avoid due to severe side effects

Question 16

What are the side effects of the use of glucocorticoids?

Answer 16

Severe + Common

Cushing’s, electrolyte imbalance, osteoporosis, mood disturbance, hirsutism, HTN, etc. etc.

Question 17

Which glucocorticoids could you use in the treatment of Cohn’s disease?

When would you use them? Why?

Answer 17

1. Prednisolone
   
   1. in severe cases to induce remission
2. Budesonide
   
   1. in less severe cases
   2. it is less effective but also has less side effects due to local administration (gets metablised and inactivated locally)

Question 18

What is Azathioprine?

Answer 18

An immunosupressant drug used in treamtne of IBD (pruine antagonist)

Question 19

Explain the MOA of Azathioprine

Answer 19

Purine antagonist: impairs

• cell- and antibody-mediated immune responses
• lymphocyte proliferation
• mononuclear cell infiltration
• synthesis of antibodies

•It enhances

• T cell apoptosis

Question 20

What are the side effects of the use of Azathioprine?

Answer 20

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

Question 21

What is the use of Azathioprine in the treatment of Crohns disease?

Answer 21

• NOT: For active disease
• Azathioprine or other immunosuppressants recommended for maintaining remission
• Glucocorticoid-sparing
• Slow onset – 3 to 4 months treatment for clinical benefit

Question 22

When does Azathiorine develops its effects?

Answer 22

After 3-4 Month of treament

Question 23

What are the different techniques that can be used in the alteration of the Micorbiome in IBD?

Answer 23

1. Exclusive enternal nutrition
2. Probiotics
3. Fecal Transplant
4. ABX

Question 24

What is the overall mechanism of biologial treamts in the treament of IBD?

Answer 24

They are: antibodies to important inflammatory mediators (e.g. anti- TNF-alpha)

Question 25

What is Infliximab?

What is its MOA?

Answer 25

It is an anti-TNFalpha (antibody)

• Inhibits TNF-alpha and thereby
  
  • neutralizing TNF-α–mediated proinflammatory cell signaling and inhibiting the expression of inflammatory genes
  • Induces cytolysis of cells expressing TNFa
  • Promotes apoptosis of activated T cells

Question 26

Summarise the Pharmacokinetics and ROA of infliximab

Answer 26

• IV administration
• Long t1/2: 9.5 days –> adminsitration every 8 Weeks

Question 27

Explain the use of anti-TNF-alpha in treatment of Crohns disease

Answer 27

• Potentially curative, but high risk of tolerance
  
  • effective in induction and maintainance of mucosal healing in Crohns
• Successful for reduction and stabelization of fistules
• Preferable early use in combination with Azathioprine

Question 28

What are the side effects of anti-TNF alpha treatments?

Answer 28

• 4x - 5x increase in incidence of tuberculosis
• Also risk of reactivating dormant TB
• Increased risk of septicaemia
• Worsening of heart failure
• Increased risk of demyelinating disease
• Increased risk of malignancy
• Can be immunogenic – azothiaprinereduces risk, but raises TB /maligancyrisk

Question 29

What are the main problems of anti-TNF alpha drugs?

Answer 29

• High tolerance–> 50% loose response within 3 years
• •due to
  • production of anti-drug antibodies
  • and increased drug clearance.

Question 30

What is the clinical presentation of IBD?

Answer 30

• Abdominal pain and crampitng
• Diarrhoea, bloody faeces
• Mouth ulcers
• Anaemia
• Fever
• Arthritic pain
• Skin rashes
• Uveitis
• Weight loss

Question 31

How is azathioprine metabolised, and why is this clinically important in Crohn’s disease? (2 marks)

Answer 31

Prodrug activated by gut flora

Metabolised by xanthine oxidase. Coadministration with drugs that inhibit xanthine oxidase such as Allopurinol used to treat gout can cause build up of 6-mercaptopurine leading to blood disorders, hepatotoxicity.