Inflammatory Bowel Disease Flashcards
What are the two main diseases that come under Inflammatory Bowel Disease?
- Ulcerative Colitis
- Crohn’s Disease
What is the underlying pathogenesis of these diseases based on?
- It boils down to a defective interaction between the mucosal immune system and gut flora
What type of IBD is obesity a risk factor for?
- Crohn’s Disease
Which T cell responses are involved in:
1) Ulcerative Colitis?
2) Crohn’s Disease?
1) Ulcerative Colitis - Th2
2) Crohn’s Disease - Th1
What are the main cytokines in:
1) Ulcerative Colitis?
2) Crohn’s Disease?
1)
- Ulcerative Colitis - IL-5, IL-13
2)
- Crohn’s Disease - TNF-alpha
Which layers of the gut are affected in:
1) Ulcerative Colitis?
2) Crohn’s Disease?
1)
- Ulcerative Colitis - Mucosa + Submucosa
2)
- Crohn’s Disease - All Layers
Describe which regions of the gut are affected in:
1) Ulcerative Colitis
2) Crohn’s Disease
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
Are abscesses, fissures and fistulae common in:
1) Ulcerative Colitis?
2) Crohn’s Disease?
1)
- Ulcerative Colitis - No
2)
- Crohn’s Disease - Yes
Describe the effectiveness of surgery in:
1) Ulcerative Colitis
2) Crohn’s Disease
1)
- Ulcerative Colitis - Curative
2)
- Crohn’s Disease - Not always curative, even if the affected area is cut out, it often reoccurs
Describe some supportive therapies that are given for IBD
- Nutritional therapy Fluid/electrolytes
- Potentially even blood transfusions/oral iron
What are the three types of classic symptomatic treatment for IBD?
- Aminosalicylates
- Glucocorticoids
- Immunosuppressants e.g. azathioprines
What is the main aminosalicylate drug?
- Mesalazine AKA 5-aminosalicylic acid (5-ASA)
What is a slightly more complex aminosalicylate?
- Olsalazine (this is 2 x 5-ASA)
What type of drug are aminosalicylates?
- Anti-inflammatory
Describe the mechanism of anti-inflammatory action of aminosalicylates
- They inhibit IL-1, TNF-alpha and PAF secreted by dendritic cells
- Decrease antibody secretion
- Reduced cell migration (macrophages)
- Localised inhibition of immune responses
Describe the activation of 2 types of aminosalicylates and thus the sites where they are active
- Mesalazine does not have to be activated any further - all over GI
- Olsalazine must be activated by colonic flora - only in colon
Describe the effectiveness of aminosalicylates in Ulcerative Colitis and Crohn’s Disease
- 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
Describe the use of glucocorticoids in IBD
- 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
Describe some strategies for minimising the side effects of glucocorticoids
- Topical administration (e.g. enemas and suppositories)
- Low dose
- Use oral or topically administered glucocorticoid with a high first pass metabolism
What is an example of a glucocorticoid that has relatively few side effects?
- Budesonide
Describe the effectiveness of budesonide compared to other glucocorticoids
- Budesonide has fewer side effects than other glucocorticoids but it is less effective at inducing remission in CD
State three immunosuppressive agents that could be used in IBD
- Azathioprine
- Methotrexate
- Cyclosporin – only useful in severe UC
Describe the onset of action of azathioprine
- Slow onset – can take 3-4 months
Describe the activation of azathioprine
Azathioprine needs to be metabolised by gut flora to 6-mercaptopurine
Describe the mechanism of action of azathioprine
- 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
What are the unwanted effects of azathioprine?
- Pancreatitis
- Bone marrow suppression
- Hepatotoxicity
- Increased risk (4 fold) of lymphoma and skin cancer
Describe the metabolism of azathioprine
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
In what clinical situation could there be a problem with azathioprine metabolism?
- 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
What is the mechanism of action of Methotrexate?
- Folate antagonist
- It reduces the production of thymidine and other purines
- NOTE: not widely used because of significant side effects
What are the three microbiome manipulation therapies for IBD?
- 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
Give 2 examples of anti-TNF-alpha antibodies
- Infliximab (IV)
- Adalimumab (SC)
Describe the mechanism of action of anti-TNF-alpha antibodies
- 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
What is a problem with anti-TNA-alpha therapy that may require changes in the treatment guidelines?
- Production of anti-drug antibodies
- Increased drug clearance
What are the adverse effects of anti-TNA-alpha therapy?
- 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
What were the key findings from the SONIC trial?
- 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
