Inflammatory bowel disease Flashcards
1
Q
What are the two major forms of IBD?
A
Ulcerative colitis (UC) Crohn's disease (CD)
2
Q
In what percentage of patients is the distinction between UC and CD incomplete?
A
10%
3
Q
How many people in the UK currently have IBD?
A
300,000
4
Q
Why is CD more extensively studied?
A
It is more serious and difficult to treat
5
Q
What are the risk factors for IBD?
A
Genetic predispositions
Environmental factors which could include smoking and diet/obesity (it’s a disease of affluence)
6
Q
What is obesity a risk factor for?
A
CD but not UC
7
Q
What is the simple point of the disease’s pathogenesis?
A
Defective interaction between mucosal immune system and gut flora
8
Q
Explain the basic development of IBD?
A
Complex interplay between host and microbes
Disrupted innate immunity
Uncontrolled inflammation
Physical damage to epithelium and leakiness of tight junctions
9
Q
What mediates UC?
A
TH2
10
Q
What is UC dependent on?
A
Cytokines such as IL-5 and IL-13
11
Q
What does UC tend to affect?
A
Just mucosa and submucosa
12
Q
Where does UC always start?
A
It always starts in the rectum and spreads proximally- it’s always continuous
13
Q
How can you cure UC in worst case scenario?
A
Surgery- remove affected piece of bowel and it doesn’t reoccur
14
Q
What is CD mediated by?
A
TH1
15
Q
What is the main cytokine in CD?
A
TNF-alpha
16
Q
What is the effect of CD being TH1 mediated?
A
It causes a more severe inflammatory response
17
Q
What does CD affect?
A
It can penetrate all the way through the gut and can affect any point of GI tract from mouth to anus
18
Q
What is the main problem with CD?
A
It causes patchy inflammation which means you can’t remove affected area as easily as UC
19
Q
What happens if you cut out affected area in CD?
A
It is likely to reoccur
20
Q
What are you more likely to develop in CD than UC?
A
Abscesses, fissures and fistulae
21
Q
What is chrohn’s physically characterised by in terms of appearance?
A
Cobblestone appearance
22
Q
What is a fistula?
A
Abnormal or surgically made passage between a hollow tubular organ and body surface or between two hollow or tubular organs
23
Q
What are the clinical features of IBD?
A
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
24
Q
What does someone need if they have very bloody diarrhoea?
A
Fluid/electrolyte replacement
Blood transfusion/oral iron
Nutritional support
25
How is IBD treated?
Symptomatically:
Glucocorticoids e.g. prednisolone
Aminosalicylates e.g. mesalazine
Immunosuppressives e.g. azathioprine
26
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
27
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
28
What is mesalazine?
5-aminosalicylic acid (5-ASA)
29
What is olsalazine?
Slightly more complex molecules- consists of 2 linked 5-ASA molecules (no benefit compared to mesalazine)
Anti-inflammatory
30
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
```
31
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
32
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
33
What is better between topical 5-ASA and topical steroids at inducing remission in UC?
Topical-5-ASA
| Combined with steroids is even better
34
Why is the use of glucocorticoids for UC in decline?
It has been shown that aminosalicylates are better than glucocorticoids ar doing the job
35
How can glucocorticoids be used?
Topically (enema) or IV if severe
36
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
37
Give some examples of glucocorticoids?
Prednisolone, fluticasone and budesonide
38
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
39
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
40
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
41
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
42
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
43
What is azathioprine mainly used for?
Maintain remission in CD
44
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
45
How is azathioprine activated?
It is a pro-drug that is activated in vivo by gut flora to 6-mercaptopurine
46
What is 6-mercaptopurine?
Purine antagonist so it interferes with DNA synthesis and cell remplication
47
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
```
48
What percentage of patients on azathioprine have to stop treatment because of side effects?
10%
49
What unwanted effects is azathioprine associated with?
Pancreatitis
Bone marrow suppression
Hepatotoxicity
Increased risk (4 fold) of lymphoma and skin cancer
50
How many routes of metabolism are there for azathioprine?
3
51
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
52
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
53
Which pathway is preferred for azathioprine metabolism?
Xanthine oxidase- its metabolites are inert so won't cause any problems
54
What does allopurinol inhibit?
Xanthine oxidase
55
What is allopurinol used to treat?
Gout
56
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
57
How effective is azathioprine at maintaining remission in CD?
Clear benefit over placebo
58
How effective is methotrexate at maintaining remission in CD?
It has a demonstrable effect
59
What does methotrexate do?
It is a folate antagonist which reduces the synthesis of thymidine and other purines
60
Why is methotrexate not widely used?
There are significant unwanted side effects
61
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
62
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
63
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
64
What biological therapies have been approved for use in IBD?
Anti-TNF-alpha antibodies:
- Infliximab (IV)
- Adalimumab (SC)
65
How effective are anti-TNF alpha antibodies in treating CD?
They are used very effectively
66
What percentage of patients will respond within 6 weeks to anti-TNF-alpha antibodies?
60% (potentially curative
67
What does refractory disease mean?
It describes disease that doesn't respond to attempted forms of treatment
68
How effective are anti-TNF alpha antibodies in treating UC?
Some evidence of effectiveness which is surprising because TNF-alpha is a Th1 cytokine
69
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
70
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)
71
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
72
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
73
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
