20 - Inflammatory Bowel Disease Flashcards
What are the two major forms of inflammatory bowel disease (IBD)?
Ulcerative Colitis (UC)
Crohn’s Disease (CD)
However, approximately 10% of patients have ‘indeterminate colitis’ in which the distinction between the two conditions is incomplete. This makes treatment decisions difficult.
How many people in the UK have IBD?
300,000 people in the UK
In what percentage of patients is the distinction of IBD type incomplete and what is this called?
Interdeterminate Colitis
Distinction incomplete in ~10% patients
Outline the incidence of IBD in Europe
Affects children, adolescents and adults
Only consider therapeutic strategies for adults in this lecture
Prevalence is greater in Western Europe than Eastern Europe
What are the genetic risk factors for IBD?
Causes incompletely understood
CD more extensively studied than UC
Genetic predisposition
- 201 loci identified
- People of White European origin most susceptible
- Which loci are the most important is still not known
Describe the cell types and molecular mechanisms involved in the pathogenesis of IBD
INNER CIRCLE
Cell types and components involved in IBD pathogenesis
MIDDLE CIRCLE
Depicts the molecular mechanisms affected by mutations in genes presenting with an IBD phenotype
OUTER CIRCLE
Represents the molecular pathomechanisms leading to IBD
What are the environmental risk factors for IBD?
Most important environmental risk factors are:
- smoking
- diet
- microbiome
Explain how autoimmune diseases can cause chronic inflammation in the gut
Defective interaction between mucosal immune system and gut flora - infection
10x more gut bacteria than host cells - therefore, the microbiome is really important
- Complex interplay between host and microbes
- Disrupted innate immunity and impaired clearance
- Pro-inflammatory compensatory responses
- Physical damage and chronic inflammation
Explain the impact of the microbiome in the pathology of IBD
Summarise the differences between Crohn’s Disease and Ulcerative Colitis
CROHN’S DISEASE
- Th1-Mediated
- Affects all layers of the gut, can go all way through the gut
- Can get abcesses and fistulae
- Can affect any part of the GI
ULCERATIVE COLITIS
- Th2-Mediated
- Always starts at the rectum and spreads proximally
- Surgery is curative
What are the clinical features of Ulcerative Colitis and Crohn’s Disease?
CLINICAL FEATURES - SYSTEMIC AS WELL AS LOCAL
Summarise the therapies available for IBD
Read the table vertically
What supportive therapies can be used for acutely sick patients with IBD?
Fluid/Electrolyte Replacement
Blood Transfusion/Oral Iron
Nutritional Support (malnutrition is common)
- food doesn’t remain in the gut long enough for nutrients to be absorbed
What are classic symptomatic treatments used for people with active IBD?
For people with the active disease and prevention of relapse
Aminosalicylates
- eg. Mesalazine
Glucocorticoids
- eg. Prednisolone
Immunosuppressives
- eg. Azathioprine
What are Aminosalicylates?
They are anti-inflammatory agents
Mesalazine (5-aminosalicylic acid, 5-ASA)
- continuous action
Olsalazine (2 linked 5-ASA molecules)
- metabolised in the colon by colonic flora
- then has action in the colon and onwards
Outline the pharmacokinetics of 5-ASA derivatives
Olsalazine must be metabolised by colonic flora (split into its two halves) before it can have action
Describe the anti-inflammatory actions of aminosalicylates
Downregulated NF-κB/MAPK pathways
- reduce a family of pro-inflammatory cytokines
Downregulated COX-2
- reduce prostaglandins
Can scavenge oxidants
Is oral 5-ASA an effective treatment for ulcerative colitis?
THERE WAS A META-ANALYSIS OF ORAL 5-ASA VS. PLACEBO FOR MAINTENANCE OF REMISSION IN UC
There are slightly better than placebo and are reasonably safe
Are aminosalicylates recommended for the treatment of ulcerative colitis (UC)?
Yes, aminosalicylates are recommended for the treatment of ulcerative colitis
- Effective at induction and maintenance of remission
- Combined oral and rectal administration probably more effective than either alone for generalised disease
- Rectal delivery better for localised disease
- Probably better than glucortocoids in terms of efficacy and safety
Are aminosalicylates recommended for the treatment of Crohn’s Disease (CD)?
Literature is unclear
Ineffective in inducing remission
Less clear cut than utility in UC
Glucorticoids probably better
May be effective in a subgroup of patients
Physician beliefs and patient preferences are the major driving factors in prescribing
What is the impact of glucocorticoids in IBD?
IMPACT OF GLUCOCORTICOIDS IN IBD
Many Points of Action:
Modulate T-Cell Activation
- downregulate cytokine production
Modulate Macrophage Activity
- downregulate cytokine production
Downregulate Dendritic Cells
- modulate production of Th1 cytokines
Compare the side effects from treatment of CD with Prednisolone versus Budesonide
Budesonide is metabolised locally and doesn’t escape into the systemic circulation as much as Prednisolone
Therefore, Budesonide is safer and has fewer side effects
However, the downside of this is that standard oral glucocorticoids like Prednisolone are better than Budesonide at inducing remission in active CD
Why is Azathioprine highly immunosuppressive?
Azathioprine interferes with DNA synthesis and cell replication
However, it has a lot of side effects, especially in cells with a high turnover
What aspect of Azathioprine can cause hepatotoxicity?
6-MeMP metabolite is hepatotoxic
Outline strategies for targeted drug delivery
TARGETED DRUG DELIVERY
Different Forms of Packaging:
e.g.
- only degrade at certain pHs
- self destructs at a certain time
- type that depends on osmosis, drug gets pushed out at higher osmotic pressures
Some new complex polymers which combine time and pH
- potentially to give better targeting of drugs to areas of inflammation
- get drug closer to where it needs to be
What is the impact of Rifaximin on experimental colitis?
Rifaximin reduces inflammatory mediator mRNA in experimental colitis
Outline the mechanism of therapeutic effects of anti-tumour necrosis factor alpha (TNF-a) antibodies in IBD
These drugs work by ‘mopping up’ TNF-alpha
Because TNF-alpha is high up in pathways, it can downregulate many pathways
Anti-TNFa reduces activation of TNF a receptors in thegut
Reduces downstream inflammatory events
Also binds to membrane associated TNFa
Induces cytolysis of cells expressing TNFa
Promotes apoptosis of activated T cells
Has usage of Anti-Tumour Necrosis Factor α (biologic therapy) been successful in IBD treatment?
Used successfully in the treatment of CD
Only 60% patients respond within 6 weeks
Potentially curative, but many patients relapse
Successful in some patients with refractory disease and fistulae
Very good for maintaining fistula closure
Outline the efficacy of anti-TNFα for induction and maintenance of mucosal healing in UC controlled trials
No real evidence for efficacy for indcution and maintenance of mucosal healing in UC
