Inflammatory bowel disease Flashcards
What are the two major forms of IBD?
Ulcerative colitis (UC) Crohn's disease (CD)
In what percentage of patients is the distinction between UC and CD incomplete?
10%
How many people in the UK currently have IBD?
300,000
Why is CD more extensively studied?
It is more serious and difficult to treat
What are the risk factors for IBD?
Genetic predispositions
Environmental factors which could include smoking and diet/obesity (it’s a disease of affluence)
What is obesity a risk factor for?
CD but not UC
What is the simple point of the disease’s pathogenesis?
Defective interaction between mucosal immune system and gut flora
Explain the basic development of IBD?
Complex interplay between host and microbes
Disrupted innate immunity
Uncontrolled inflammation
Physical damage to epithelium and leakiness of tight junctions
What mediates UC?
TH2
What is UC dependent on?
Cytokines such as IL-5 and IL-13
What does UC tend to affect?
Just mucosa and submucosa
Where does UC always start?
It always starts in the rectum and spreads proximally- it’s always continuous
How can you cure UC in worst case scenario?
Surgery- remove affected piece of bowel and it doesn’t reoccur
What is CD mediated by?
TH1
What is the main cytokine in CD?
TNF-alpha
What is the effect of CD being TH1 mediated?
It causes a more severe inflammatory response
What does CD affect?
It can penetrate all the way through the gut and can affect any point of GI tract from mouth to anus
What is the main problem with CD?
It causes patchy inflammation which means you can’t remove affected area as easily as UC
What happens if you cut out affected area in CD?
It is likely to reoccur
What are you more likely to develop in CD than UC?
Abscesses, fissures and fistulae
What is chrohn’s physically characterised by in terms of appearance?
Cobblestone appearance
What is a fistula?
Abnormal or surgically made passage between a hollow tubular organ and body surface or between two hollow or tubular organs
What are the clinical features of IBD?
Diarrhoea, blood, mucus Weight loss Skin rash Right iliac fossa mass/pain Primary sclerosing cholangitis Aphthous ulcers Anaemia, uveitis, fevers, sweats and jaundice Abdominal pain Arthritis arthralgia
What does someone need if they have very bloody diarrhoea?
Fluid/electrolyte replacement
Blood transfusion/oral iron
Nutritional support
How is IBD treated?
Symptomatically:
Glucocorticoids e.g. prednisolone
Aminosalicylates e.g. mesalazine
Immunosuppressives e.g. azathioprine
What potentially curative therapies are there?
Manipulation of gut microbiome
Biological therapies:
Anti-TNF alpha e.g. infliximab
Anti alpha-4-integrin e.g. natalizumab
How effective are aminosalicylates in UC and CD?
In UC:
First line inducing and maintaining remission
Good evidence base
Crohn’s disease:
Unsure effectiveness in active disease
May help maintain surgically induced remission
Less clear cut than utility in UC
What is mesalazine?
5-aminosalicylic acid (5-ASA)
What is olsalazine?
Slightly more complex molecules- consists of 2 linked 5-ASA molecules (no benefit compared to mesalazine)
Anti-inflammatory
What is the mechanism of anti-inflammatory action?
Inhibition of: -IL-1 -TNF-alpha -Platelet activating factor (PAF) Decreased antibody secretion Non-specific cytokine inhibition Reduced cell migration (macrophages) Localised inhibition of immune responses
What is anti-inflammatory action more effective in?
UC than CD which is weird as it seems to be targeting Th1 and UC is mainly governed by Th2 system
What is the pharmacokinetics of 5-ASA derivatives? (mesalazine and olsalazine)
Mesalazine doesn’t need to be metabolised so is absorbed in small bowel and colon
Olsalazine is more complex and needs to be activated by colonic flora so is only absorbed in colon
What is better between topical 5-ASA and topical steroids at inducing remission in UC?
Topical-5-ASA
Combined with steroids is even better
Why is the use of glucocorticoids for UC in decline?
It has been shown that aminosalicylates are better than glucocorticoids ar doing the job
How can glucocorticoids be used?
Topically (enema) or IV if severe
What are the drugs of choice for inducing remission in Crohn’s?
Glucocorticoids but you’re likely to get side effects if they’re used to maintain remission
Give some examples of glucocorticoids?
Prednisolone, fluticasone and budesonide
What are glucocorticoids?
Powerful anti-inflammatory and immunosuppressive drugs derived from cortisol that activate intracellular glucocorticoid receptors which then act as positive or negative transcription factors
What strategies are there for minimising side effects of glucocorticoids?
Topical administration- fluid or foam enemas
Low dose in combination with another drug
Oral or topically administered drug with high hepatic first pass metabolism e.g. budesonide- so relatively little active glucocorticoid escapes into systemic circulation
How does budesonide compare to standard glucocorticoids?
Budesonide has fewer side effects but standard oral glucocorticoids are better at inducing remission in active Crohn’s disease and budesonide is a little better than placebo at preventing CD relapse
How effective have immunosuppressive agents been at inducing remission in UC and CD?
A number of drugs have been tried but have not been successful
Which immunosuppressive drugs have been tried ad how effective have they been?
Azathioprine has shown significant degree of success in UC and CD
Methotrexate has demonstrable efficacy in some IBD patients
Cyclosporin is useful only in severe UC
What is azathioprine mainly used for?
Maintain remission in CD
What is the onset of azathioprine like?
Slow- 3-4 months of treat required before clinical benefits seen which can be problematic as patients may relapse between starting treatment and seeing benefits
How is azathioprine activated?
It is a pro-drug that is activated in vivo by gut flora to 6-mercaptopurine
What is 6-mercaptopurine?
Purine antagonist so it interferes with DNA synthesis and cell remplication
What does 6-mercaptopurine impair and enhance?
It impairs: Cell and antibody mediated immune responses Lymphocyte proliferation Mononuclear cell infiltration Synthesis of antibodies It enhances: T cell apoptosis
What percentage of patients on azathioprine have to stop treatment because of side effects?
10%
What unwanted effects is azathioprine associated with?
Pancreatitis
Bone marrow suppression
Hepatotoxicity
Increased risk (4 fold) of lymphoma and skin cancer
How many routes of metabolism are there for azathioprine?
3
Why don’t you want too much use of the metabolism of azathioprine pathway that involves HRPT?
It produces active metabolites that are beneficial but cause myelosuppression
Why don’t you want too much use of the metabolism of azathioprine pathway that involves TPMT?
It will produce metabolites that aren’t beneficial and hepatotoxic
Which pathway is preferred for azathioprine metabolism?
Xanthine oxidase- its metabolites are inert so won’t cause any problems
What does allopurinol inhibit?
Xanthine oxidase
What is allopurinol used to treat?
Gout
What happens if the xanthine oxidase is inhibited?
You will shunt azathioprine through other pathways so patients need to be monitored to make sure they aren’t making too many toxic metabolites
How effective is azathioprine at maintaining remission in CD?
Clear benefit over placebo
How effective is methotrexate at maintaining remission in CD?
It has a demonstrable effect
What does methotrexate do?
It is a folate antagonist which reduces the synthesis of thymidine and other purines
Why is methotrexate not widely used?
There are significant unwanted side effects
How effective are nutrition based therapies/probiotics at obtaining and maintaining remission in UC and CD?
No evidence for probiotics in CD
Evidence for probiotics in UC
What is the rationale for Faecal microbiota replacement therapies (FMT)?
There is insufficient evidence for it but rational is gut flora is out of control and there are organisms that you don’t want there causing harm so wipe them out and replace them with good normal microbiota
How does antibiotic treatment (rifaximin) have an effect on CD and UC?
It induces and sustains remission in moderate CD
It may be beneficial in UC
It interferes with bacterial transcription by binding to RNA polymerase and it reduces the amount of mRNA coding for inflammatory mediators in UC
What biological therapies have been approved for use in IBD?
Anti-TNF-alpha antibodies:
- Infliximab (IV)
- Adalimumab (SC)
How effective are anti-TNF alpha antibodies in treating CD?
They are used very effectively
What percentage of patients will respond within 6 weeks to anti-TNF-alpha antibodies?
60% (potentially curative
What does refractory disease mean?
It describes disease that doesn’t respond to attempted forms of treatment
How effective are anti-TNF alpha antibodies in treating UC?
Some evidence of effectiveness which is surprising because TNF-alpha is a Th1 cytokine
What is the mechanism of action of anti-TNF-alpha antibodies?
Anti-TNF alpha reduces activation of TNF-alpha receptors in the gut, TNF-alpha is right at the top of inflammatory cascade so you get general down regulation of other cytokines as well
It also reduces infiltration and activation of leukocytes
Also bind to membrane associated TNF-alpha
Induces cytolysis of cells expressing TNF-alpha
Promotes apoptosis of activated T cells
What is the half life of infliximab like?
It has a very long half life of 9.5 days which means benefits can last for 30 weeks after a single infusion (most patients relapse after 8-12 weeks so there is a repeat infusion every 8 weeks)
What is a big problem with anti-TNF-alpha antibodies?
There is emerging evidence showing that upto 50% of responders lose response within 3 years due to production of anti-drug antibodies and increased drug clearance
What adverse effects of anti-TNF-alpha antibodies are there and what causes this?
All of these are consequences of knocking out the key cytokine in the inflammatory cascade:
4-5x increase in incidence of tuberculosis and other infections
Risk of reactivating dormant TB
Increased risk of septicaemia
Worsening of heart failure
Increased risk of demyelinating disease
Increased risk of malignancy
Immunogenic- azathioprine reduces risk but raises risk of TB/malignancy
What was the SONIC study and what did it show?
It was a study on infliximab- 500 patients with CD were monitored for 30 weeks- it showed that early use of infliximab in patients with refractory disease is better than last resort. CRP levels and endoscopy might allow identification of patients that are most likely to benefit
