19. Inflammatory bowel disease Flashcards
What are the 2 main forms of IBD?
Ulcerative colitis and Crohn’s disease
How does the incidence of UC and CD compare in Western Europe to Eastern Europe?
Twice as high in Western Europe (diet and lifestyle)
In what age group does IBD most present in?
Late adolescents and young adults
What percentage of patients is the distinction between UC and CD incomplete?
10% (indeterminate colitis)
Is there a genetic risk factor to IBD?
• Crohn’s more extensively studied than UC
• Genetic predisposition to CD
- 201 loci identified
- White Europeans most susceptible
What are the 3 most important environmental in IBD?
- Smoking
- Diet
- Microbiome
How can IBD caused by an autoimmune condition?
- Begins as infection in the gut
- Defective interaction between mucosal immune system and gut flora
- Leads to pro-inflammatory compensatory responses
- Results in physical damage and chronic inflammation
How do the following compare in CD and UC: • Cell mediation • Gut layers affected • Regions of gut affected • Continuous/patchy • Abscesses/fissures present? • Surgery curative
Crohn’s | Ulcerative colitis
• Cell: Th1 mediated e.g. TNF-alpha | Th2 mediated e.g. IL-13
• Layers: all | (sub+)mucosa
• Abscess: common | not common
• Surgery: not always curative | curative
What are the systemic effects of IBD (that don’t directly affect the gut)?
- Fevers
- Sweating
- Anaemia
- Arthritis
- Weight loss
- Skin rashes
What do supportive therapies for acutely sick patients involve?
- Fluid/electrolyte replacement
- Blood transfusion/oral iron
- Nutritional support
What are the classic symptomatic treatments?
- Aminosalicylates
- Glucocorticoids
- Immunosuppressive agents
What is the active component of aminosalicylates and what do they do?
- 5-aminosalicylic acid (5-ASA) - mesalazine
- Olsalazine is 2 of these molecules linked
- Both have anti-inflammatory actions
When is it better to give mesalazine and olsalazine?
- Olsalazine (linked form) is metabolised by colonic flora
- Only works in the colon - better to use this if this is where inflammation is most serious
- Mesalazine is absorbed all the way through the gut
Which 2 pathways regulate inflammation in IBD, and how does targeting these pathways with 5-ASA affect them?
- NF-KB/MAPK: down-regulation pro-inflammatory cytokines
* COX-2: down-regulation of prostaglandins
Is it better to use topical 5-ASA or topical steroids to induce UC remission?
- Topic 5-ASA is better
* But both used together is even better
How effective are aminosalicylates in UC?
- Effective first line for inducing and maintaining remission
- Combine oral and rectal administration is more effective (rectal better for localised disease)
- Better than glucocorticoids
How effective are aminosalicylates in CD?
- Literature is unclear
- Ineffective in inducing remission
- May be better in a subgroup of patients
- Glucocorticoids are probably better
What do glucocorticoids do in IBD and how?
- Powerful anti-inflammatory and immunosuppressive drugs
- Activate intracellular glucocorticoid receptors => can act as +ve or -ve TFs
- Inhibit dendritic cells from producing IL-1 and TNF-alpha
- Down-regulate macrophages and T cells
- Related to cortisol - many unwanted effects if given systemically (chronically)
How can the unwanted effects of glucocorticoids be minimised?
- Topical administration (fluid, foam enemas, oral preparations)
- Lower dose and combine with other drugs
- Use a different drug with high hepatic first pass metabolism
How effective are glucocorticoids in treating UC?
Work, but evidence suggests that aminosalicylates are superior
How effective are glucocorticoids in treating CD?
- Drug of choice for inducing remission in Crohn’s
* Budesonide is preferred if disease is mild (less side effects)
What is azathioprine?
- Pro-drug
- Activated by gut flora to 6-mercaptopurine (can just give this directly too)
- Purine antagonist - immunosuppressive
How does azathioprine work?
- Activated to 6-MP
- Metabolised to TIMP
- Further metabolised to 6-MeMPN and 6-TGN
- 6-MeMPN inhibits to de novo purine synthesis
- 6-TGN is incorporated into DNA and disrupts synthesis
- Leads to unwanted side effects too
Which parts of the immune response does azathioprine ‘impair’ and ‘enhance’?
Impairs • cell-mediated + antibody-mediated responses • lymphocyte proliferation • mononuclear cell infiltration • synthesis of antibodies
Enhances
• T cell apoptosis
How effective is azathioprine in treating UC?
- Some success
* No reason to use if response is good with 5-ASA
How effective is azathioprine in treating CD?
- No benefit in active disease
- Can help induce remission in combination with steroid (glucocorticoid-sparing - can reduce dose of GCs to lessen side effects)
- Mainly used to maintain remission
- Slow onset (3-4 months for clinical benefit)
What are the unwanted effects of azathioprine?
- Pancreatitis
- Bone marrow suppression (myelosuppression)
- Hepatotoxicity
- Increased risk of lymphoma and skin cancers
Which inactive component of 6-MP metabolism is specifically hepatotoxic?
- 6-MeMP
* Not beneficial and is an inactive by-product, but is still toxic
Why is it toxic to take azathioprine with allopurinol (gout treatment)
- Primary metabolism of azathioprine produces 6-TU (xanthine oxidase pathway)
- Allopurinol inhibits xanthine oxidase
- Metabolism forced to go through other pathways, producing toxic metabolites
What are the different strategies for targeted drug delivery?
- Prodrugs - metabolised before an effect
- Polymer coating - dissolves at specific pH or after a specific amount of time
- Osmosis - more flows into the capsule in the small intestine, forcing the drug out
What is the problem with using time and pH as targeted drug delivery and how could this be overcome?
- Time - could be released too early if taken on a full stomach (slower gastric emptying)
- pH - small intestine has similar pH to colon, so drug could be released here (unwanted)
- Combine pH and time - greater chance of drug being released into colon
What are potential curative therapies for IBD?
Manipulation of the microbiome and biological therapies
• Anti-TNF alpha e.g. infliximab (monoclonal antibody)
• Other antibodies are effective, but some have more side-effects
• New humanised antibodies coming
New targets: • Integrins • Interleukins • Interleukin receptors • Janus kinase (JAK) cytoplasmic cell signalling
What are 3 ways the microbiome can currently be manipulated to treat IBD?
- Nutrition-based therapies
- Faecal microbiota replacement (FMT) therapies
- Antibiotic treatment with rifaximin
What do nutrition-based therapies involve?
- No evidence for probiotics to have an impact on CD
* Some evidence for probiotics inducing and sustaining remission in UC (as effectively as 5-ASA)
How effective are faecal microbiota replacement therapies in treating IBD?
- Insufficient evidence, but 2/3 studies showed benefit in UC
- More studies needed
How effective is rifaximin in treating IBD?
- Interferes with bacterial transcription - binds to RNA polymerase
- Induces and sustains remission in moderate CD
- May be beneficial in UC too
- Also reduces inflammatory mediator mRNA in experimental colitis
How do anti-TNF alpha antibodies (infliximab) work?
- Mops up any soluble TNF-alpha
- Reduces activation of TNF-alpha receptors in the gut
- Reduces downstream inflammatory events
- Also binds to membrane-associated TNF-alpha => induces cytolysis of these cells
- Promotes apoptosis of activated T cells
How is infliximab administered, what is its half life and how often is it administered?
- IV
- Half-life - 9.5 days
- Most patients relapse after 8-12 weeks - so infusion repeated every 8 weeks
How useful is anti-tumour necrosis factor alpha in IBD?
- It has been successful in treating CD
- Underlying pathology not well understood
- Potentially curative, but many patients relapse
- Successful in some patients with refractory (‘stubborn’) disease and fistulae
What is the problem with response to anti-TNF alpha antibodies over time?
- 50% of patients lose response within 3 years
* Due to anti-drug antibodies and increased drug clearance
What are the adverse effects associated with anti-TNF alpha?
- 4-5x increase in TB
- 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 (produce immune response)
Therefore it’s used as a last resort
