Inflammatory bowel disease Flashcards
What are the two major forms of IBD?
Ulcerative colitis (UC) Crohn's Disease (CD)
Indeterminate colitis (~10% of patients)
What are the environmental risk factors?
Smoking* Medication Diet * Sleep Stress Physical activity Air pollution UV exposure to vitamin D Microbiome * Appendectomy Heavy metal
Describe autoimmune disease
A defective interaction between mucosal immune system and gut flora - infection
10x more gut bacteria than host cells
How does autoimmune disease leads to IBD
1) Complex interplay between host and microbes
2) Disrupted innate immunity and impaired clearance
3) Pro-inflammatory compensatory responses
4) Physical damage and chronic inflammation
Compare the pathologies of CD and UC
See slide 9
Learn the table
What are the clinical features of UC and CD?
Systemic as well as local
- Skin rash
- Diarrhoea, blood in stool
- Right iliac fossa pain
- Weight loss
- Abdominal pain
- Anaemia, fever, jaundice, sweats
- apthous ulcers
Summarise the therapies used for IBD?
Supportive (for the acutely sick)
- Fluids/electrolyte replacement
- Blood transfusion/oral iron
- Nutritional support (malnutrition is common)
Symptomatic (active disease and prevention of relapse)
- Glucocorticoids: Prednisolone
- Aminosalicylates: Mesalazine
- Immunosuppressives: Azathioprine
Potentially curative
- Microbiome manipulation
- Biologic therapies
Describe aminosalicylates
Mesalazine or 5-aminosalicylic acid (5-ASA)
Olsalazine (2linked 5-ASA molecules)
These are anti-inflammatory
What is mesalazine and olsalazine metabolised and where is the site of absorption?
Mesalazine: absorbed in the small bowel and colon
Olsalazine: metabolised by colonic flora and absorbed in the colon
Describe the anti-inflammatory actions of aminosalicylates
Downregulate NF-kappaB/MAPK pathways –> decrease in pro-inflammatory cytokines
Downregulate prostaglandins
Describe the use of aminosalicylates in UC
- 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
Describe the use aminosalicylates in CD
- Literature 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
Give examples of glucocorticoids
Prednisolone, Fluticasone, budesonide
What are glucocorticoids?
Powerful anti-inflammatory and immunosuppressive drugs derived from the hormone cortisol.
They activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors.
What is the impact of glucocorticoids in IBD?
Very potent anti-inflammatory and immunosuppressive actions of GCs
When given systemically, chronic glucocorticoid administration causes many unwanted effects.(Endocrinology teaching)
Describe the use of glucocorticoids in IBD?
Ulcerative colitis
- Use of glucocorticoids in decline
- Evidence that aminosalicylates superior
- Glucocorticoids best avoided
Crohn’s Disease
- GCs remain drugs of choice for inducing remission
- Budesonide preferred if mild
- Likely to get side effects if used to maintain remission
What is azathioprine?
A pro-drug activted by gut flora to 6-mercaptopurine
Give 6-mercaptopurine directly
Purine antagonist - it interferes with DNA synthesis and cell replication.
Immunosuppressive
What are the effects of azathioprine on immune responses?
It impairs:
- cell- and antibody-mediated immune responses
- lymphocyte proliferation
- mononuclear cell infiltration
- synthesis of antibodies
It enhances:
- T cell apoptosis
Describe the use of azathioprine for IBD?
Ulcerative Colitis:
- Some success in Ulcerative Colitis
Crohn’s Disease:
- Weak benefit in inducing remission unless in combination
- Mainly used to maintain remission
- Recent Cochrane review shows it be glucocorticoid-sparing
Slow onset – 3 to 4 months treatment for clinical benefit
What are the unwanted effects of azathioprine?
- 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
What are the strategies for minimising the unwanted effects of drugs?
Administer topically - fluid or foam enemas or suppositories
Use a low dose in combination with another drug
Use an oral or topically administered drug with high hepatic first pass metabolism
e.g.Budesonide so little escapes into the systemic circulation
What are the different strategies for targeted drug delivery?
Produce packaging for the drugs than only degrade at certain pHs. So it can get through the stomach
Packaging that is purely time dependent. Self destructs after a certain time
Prodrugs –> metabolisbed into their active forms.
Releys on osmosis. Fluid gets into the intestine. More fluid gets into the capsule when it reaches the intestine pushing the drug out.
New complex polymers which combine time and pH - delivers the drugs directly to the inflamed colon.
What are the potentially curative therapies
- manipulation of the microbiome
- biologic therapies
1) Anti-TNF alpha e.g Infliximab
2) Many others
What are the three methods of manipulating the microbiome?
- Nutrition-based therapies
- Different organisms have different effects so difficult to generalise
- No evidence for probiotics in CD.
- Some evidence for maintenance of remission in UC, but less for induction. - Faecal microbiota replacement (FMT) therapies
- 2 of 3 RCTs showed benefit in UC
- Weak evidence for induction in UC, none for maintenance - Antibiotic Treatment - Rifaximin
- Interferes with bacterial transcription by binding to RNA polymerase
- Induces and sustains remission in moderate CD
- May be beneficial in UC
- May be microbiome modulator
- It reduces inflammatory mediator mRNA in experimental colitis
Describe biologic therapies
Approved for use in IBD
- Anti- TNFa antibodies
- Example: Infliximab (iv)
- Other antibodies effective but some have more side-effects
- New humanised antibodies coming on stream eg Entanacept
What is the mechanism of action of action of anti-TNF alpha?
- Anti- TNFa reduces activation of TNF a receptors in the gut
- Reduces downstream inflammatory events
- Also binds to membrane associated TNFa
- Induces cytolysis of cells expressing TNFa
- Promotes apoptosis of activated T cells
What are the pharmacokinetics of infliximab?
- I.V
- Very long half-life (9.5 days)
- Most patients relapse after 8 – 12 weeks
- Therefore repeat infusion every 8 weeks
What are the problems with anti-TNF aplha antibodies and adverse effects
Emerging evidence that up to 50% responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance.
Attempts being made to optimise dosing regimens.
- 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 – azothiaprine reduces risk, but raises TB /maligancy risk
