Inflammatory Bowel Disease Flashcards
What are the Two Major Forms of Inflammatory Bowel Disease?
Ulcerative Colitis
Crohn’s Disease
Note that the distinction is incomplete in ~10% patients (Indeterminate Colitis)
How many gene loci have been identified that are associated with IBD (i.e. genetic predisposition)?
What type of people are most susceptible?
State some important environmental risk factors?
201 loci identified
People of White European origin most susceptible
Diet (obesity esp. for Crohn’s), smoking, medication etc.
The combination of genetic and environmental factors => altered gut microbiota
What is the underlying pathogenesis of these diseases based on?
Defective interaction between mucosal immune system and gut flora - infection
Which T cell responses are involved in:
Crohn’s Disease
Ulcerative Colitis
Crohn’s Disease = Th1
Ulcerative Colitis = Th2
What are the main cytokines in:
Crohn’s Disease
Ulcerative Colitis
Crohn’s Disease = TNF-alpha
Ulcerative Colitis = IL-5, IL-13
Which layers of the gut are affected in:
Crohn’s Disease
Ulcerative Colitis
Crohn’s Disease = All Layers
Ulcerative Colitis = Mucosa + Submucosa
Describe which regions of the gut are affected in:
Crohn’s Disease
Ulcerative Colitis
Also describe the inflammation in each.
Crohn’s Disease:
Can be anywhere on the GI tract (mouth to anus)
Patchy inflammation
Ulcerative Colitis:
Starts at the rectum and spreads proximally
Continuous inflammation
Are abscesses, fissures and fistulae common in:
Crohn’s Disease
Ulcerative Colitis
Crohn’s Disease
Yes
Ulcerative Colitis
No
Describe the effectiveness of surgery in:
Crohn’s Disease
Ulcerative Colitis
Crohn’s Disease:
Not always curative
Ulcerative Colitis:
Curative
List the clinical features of IBD (systemic as well as local)
Abdominal pain and cramping Diarrhoea, bloody faeces Mouth ulcers Anaemia Fever Arthritic pain Skin rashes Uveitis Weight loss
Describe some supportive therapies that are given for IBD
Nutritional therapy
Fluid/electrolytes
Blood transfusions/oral iron
What are the three types of classic symptomatic treatment for IBD?
Aminosalicylates
Glucocorticoids
Immunosuppressants
What is the main aminosalicylate drug?
Mesalazine or 5-aminosalicylic acid (5-ASA)
What is a slightly more complex aminosalicylate?
Olsalazine (2 linked 5-ASA molecules)
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 (inhibit transcription)
=> Decrease antibody secretion
=> Reduced cell migration (macrophages)
=> Localised inhibition of immune responses
Describe the activation and site of absorption of the two aminosalicylate drugs.
Mesalazine does not have to be activated any further; absorbed in small bowel and colon.
Olsalazine must be activated by colonic flora; absorbed in the colon.
Describe the effectiveness of aminosalicylates in Ulcerative Colitis and Crohn’s Disease.
Aminosalicylates and UC:
- Effective at induction and maintenance of remission
- Rectal delivery better for localised disease
Aminosalicylates and CD:
- Ineffective in inducing remission of CD
Give examples of glucocorticoid drugs used to treat IBS.
What type of drug are they?
Examples: Prednisolone, Fluticasone, budesonide
Powerful anti-inflammatory and immunosuppressive drug
What is an example of a glucocorticoid that has relatively few side effects, and why is this so?
Describe the effectiveness of budesonide compared to other glucocorticoids.
Budesonide
Because it is metabolised and inactivated locally
less effective at inducing remission in CD
How could you minimise the side effects of glucocorticoids?
Use oral or topically administered glucocorticoid with a high first pass metabolism
Describe the use of glucocorticoids in IBD (CD and UC)
Ulcerative colitis:
- Strong evidence that aminosalicylates superior
Crohn’s Disease:
- GCs are the drugs of choice for inducing remission
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 metabolism/activation of azathioprine.
Azathioprine needs to be metabolised by gut flora to 6-mercaptopurine
Describe the mechanism of action of azathioprine - type of drug, does what, impairs what, enhances what?
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
What are the unwanted effects of azathioprine?
- Nearly 10% of patients stop treatment because of the side effects
- Pancreatitis
- Bone marrow suppression
- Hepatotoxicity
- Increased risk of lymphoma and skin cancer
What are Azathioprine or other immunosuppressants recommended/ not recommended for?
Not recommended for active disease
Recommended for maintaining remission
Describe the metabolism of azathioprine.
There are three routes of metabolism of azathioprine
- Route resulting in the production of beneficial active metabolites but 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); main route
What are the three potential mechanisms of manipulating the gut microbiome as a potentially curative therapy of IBD?
Nutrition based therapies (exclusive enteral nutrition) – 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-𝛼 antibodies (biologic curative therapies)
Include each ROA
Infliximab (IV)
Adalimumab (SC)
Describe the mechanism of action of anti-TNF-alpha antibodies.
Anti-TNFa reduces activation of TNFa receptors in the gut
=> Reduces downstream inflammatory events
=> Binds to membrane associated TNFa
=> Induces cytolysis of cells expressing TNFa
=> Promotes apoptosis of activated T cells
Describe the pharmacokinetics of infliximab
Given intravenously
Long half-life – 9.5 days
Most patients relapse between 8-12 weeks
Repeat infusion given after 8 weeks
Describe the effectiveness of anti-TNF- antibodies in Crohn’s Disease.
- Used successfully in the treatment of CD - potentially curative, but many patients relapse
- Very good for maintaining fistula closure
What is a problem with anti-TNA-alpha therapy that may require changes in the treatment guidelines?
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
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
Give details on when infliximab should be used and how.
- Early use better than last resort
- Combined infliximab and azathioprine therapy recommended rather than monotherapy
