IBD Flashcards
Types of IBD
Ulcerative Colitis (UC)
Crohn’s Disease (CD)
Distinction incomplete in ~10% patients (Indeterminate Colitis)
Where is IBD most common
Western europe more than eastern
Are there genetic risk factors for IBD?
Genetic predisposition
201 loci identified
People of White European origin most susceptible
Cell types and molecular mechanisms
Treg IL10: T‐cell immunodeficiencies with bowel inflammation and Defects in Tregs or IL10 signaling.
Phagocytes: Congenital defects of phagocyte number or function.
Complement: Complement deficiencies.
Bacterial recognition: Defects in host‐microbiota interactions, bacterial sensing.
Epithelial barrier: Epithelial barrier defects.
B cells and antibodies: Predominantly antibody deficiencies with IBD.
Innate immune cells: Systemic autoinflammatory diseases and IBD.
PRR: pattern‐recognition receptor
What are the main environmental risk factors for IBD
Smoking
Diet
MICROBIOME
How many gut bacteria
10 x more gut bacteria than host cells
Outline the autoimmune basis of IBD
Complex interplay between host and microbes
Disrupted innate immunity and impaired clearance
Pro-inflammatory compensatory responses
Physical damage and chronic inflammation
What occurs in each of the following layers in IBD:
Intestinal lumen
Mucus layer
Epithelial barrier
Lamina propria
lumen:
Increased pathogen number. Diet/antibiotics/stress. Dysbiosis
mucus:
Reduces mucus in IBD. Reduced anti-inflammatory bacteria in the mucus
Epithelial layer:
Tight junctions inpaired so pathogens can permeate the epithelial barrier
Lamina propria:
Normally there would be physiological inflammation with upregulated Th17/Th1/barrier function and also increased Tregs and IL-10 (anti-inflammatory)
In IBD, TH17 and TH1 greatly increased, reduced Treg, IL10 though
Differentiate Crohns and UC
AI disease: Chrohn’s is Th1 (TNF-a), UC is Th2 (IL-13). Chrohn’s is T cell expansion, defective T cell apoptosis. In UC, limited clonal expansion and normal T cell apoptosis.
Gut layers: Chrohn’s- all layers, UC: mucosa/submucosa
Regions: Crohn’s any part of GI, UC rectum spreading proximally
Inflamed areas patchy in chrohn’s but continuous in UC
Abcesses and fissures and fistulae are common in Crohn’s but not in UC
Surgery is curative in UC but not crohn;s
What are the systemic and GI effects of IBD
SYSTEMIC
Skin rashes, night sweats, fevers, arthritis, weight loss
GI:
Pain
Diarrhoea
Mouth ulcers
Types of therapy for IBD
Supportive,
Symptomatic:
Active disease
Symptomatic:
prevention of remission
Potentially curative
What are supportive therapies
Acutely unwell
- Fluid/electrolyte replacement
- Blood transfusion/ oral iron
- Nutritional support (malnutrition common)
What are the
Symptomatic:
Active disease
therapy
Aminosalicylates eg
Mesalazine
Glucocorticoids eg Prednisolone
Immunosuppressives eg Azathioprine
Give examples of aminosalicylates
Mesalazine or 5-aminosalicylic acid (5-ASA)
Olsalazine (2 linked 5-ASA molecules)
Anti-inflammatory
What is the difference between mesalazine and olsalazine in terms of where they are absorbed and their metabolism
Olsalazine must be metabolised to active form in the colon by COLONIC FLORA
Mesalizine absorbed throughout small bowel and colon
Olsalazine only absorbed in the colon
Mechanism of action of aminosalicylates, including the receptor they act on
PPAR receptor activation by 5-ASA.
- Downregulate NFkB/MAPK and thus TNFa, IL1 and IL6
- Downregulate COX2 and thus PGE2 and PGF2
- Also scavenge oxidants
What is the effectiveness 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 across colon
Rectal delivery better for localised disease
Probably better than glucortocoids
What is the effectiveness of aminosalicylates in CD
Unclear
Ineffective in inducing remission
Glucorticoids probably better
May be effective in a subgroup of patients
Examples of glucocorticoids
Prednisolone, Fluticasone, budesonide
What is the action of glucocorticoids
Powerful anti-inflammatory and immunosuppressive drugs
Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors
Why might GC be useful in IBD
GC come through blood stream,
can downregulate dendritic cells and the TNFa and IL1 they produce
Downregulate production of Th1/Th2 and Th17 cytokines
Modulate macrophage an downregulate their cytokines (TNFa, IL12, IL6)
Inhibit inflammatory effects
Promote regulatory effects
What is the problem with GCs
When given systemically, chronic glucocorticoid administration causes many unwanted effects
(endo)
SO YOU GIVE IT TO INDUCE REMISSION AND THEN MAINTAIN THE REMISSION WITH SOMETHING ELSE.
Why is budesonide good over prednisolone
Why isn’t it
It is metabolised locally (HIGH fpm) and doesn’t escape into systemic circulation so less side effects.
Not as effective though compared to prednisiolone in inducing remission
When is comparison of GCs useful
In Crohn’s patients (not using GCs in UC patients as they have aminosalicylates working well )
What is the drug treatment for chrohn’s
GCs remain drugs of choice for inducing remission
Budesonide preferred if mild
Likely to get side effects if used to maintain remisson
What is azathioprine
Prodrug
Immunosuppressive
How does azathrioprine work
A pro-drug
Activated by gut flora to 6-mercaptopurine
Give 6-mercaptopurine directly
Purine antagonist
Immunosuppressive
How can Azathriprine work on DNA
6-MP converted o 6-TIMP which can then inhibit de novo pruine synthesis
and can be incoroporated into the DNA
Azathioprine impacts what
It impairs:
1. cell- and antibody-mediated immune responses
- lymphocyte proliferation
- mononuclear cell infiltration
- synthesis of antibodies
It enhances:
1. T cell apoptosis
When is azathiprine used in IBD
Not really needed in UC
Weak benefit in inducing remission, but better in inducing remission when combined for Crohn’s
Maintains remission
Downside of azathioprine
Slow onset – 3 to 4 months treatment for clinical benefit
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 is causing hepatoxicity and myelosuppression
6-MeMP (an inactive metabolite of 6-MP) is hepatotoxic
Even the wanted metabolite of 6-TGN causes myelosuppression
What are the strategies for minimising unwanted effects of the IBD 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 strateiges for targeted drug dlivery
Packaging that degrades at certain pH
Packaging that degrades at a certain time (self destructs after a period of time)
Prodrugs (i.e activated by enzymatic degradation in colon lumen incl. azathiprine (to 6MP) and olsalazine (to 5ASA) both by gut flora)
Osmosis (fluid flows into the tablet and pushes drug out the other side)
How else can drugs be targeted
E.g nanoparticles
Those that are time dependent might have premature release into the release into stomach
Those that are pH dependent you could get complete drug release at small intestine (as it is the same pH as the colon)
If pH/time, the nanoparticals avoid complete drug release and seliver drug to inflamed colon
What are the potentally curative therapies
- Manipulation of the microbiome
2. Biologic Therapies
How can the microbiome be manipulated as a curative therapy
- Nutrition based therapies
- No evidence for probiotics in CD
- Some evidence for maintaining remission for UC (but not for induction) - Faecal microbiota replacement (weak evidence)
- Antibiotics RIFAXIMIN
How does rifaximin work
- 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
Bear in mind don’t want to kill off the commensals
What are the biologic therapies in IBD
Infliximab (iv)
Anti- TNFa antibodies
Many others
Have to do repeatedly
New humanised antibodies coming on stream eg Entanacept
How does infliximab work
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
How is infliximab given
Infliximab given intravenously
Very long half-life (9.5 days)
Most patients relapse after 8 –
12 weeks
Therefore repeat infusion every 8 weeks
When is anti-TNF useful in Chrohn’s
What proportion of CD patients respond to TNFa
Used successfully in the treatment of CD
Only 60% patients respond within 6 weeks
Successful in some patients with refractory disease and fistulae
Very good for maintaining fistula closure
Why might Anti-TNFa be less useful in UC than Chroh’s
Because in Crohn’s it’s TNF-a mediated due to Th1,
but in UC it’s mainly Th2 where there’s less role for TNFa
Problems with TNFa
50% responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance.
Adverse effects of TNFa
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 – combination with azothiaprine reduces risk, but raises TB /maligancy risk
(I Said Hi To Dr Carrot….. Immunogenic, Septicaemia, Heart failure, TB, Demyelinating disease, Cancer)
When is infliximab best used in IBD
Early use better than last resort
Combined infliximab and azathioprine therapy may be more effective than antibody alone
(but think of malignancy/TB risk)
Remember it maintains remission, and may induce remission in moderate CD
Potential new targets for IBD
Integrins (needed for cells to migrate)
Interleukins (IL12; IL17;IL23)
Interleukin receptors
Janus kinase (JAK) cytoplasmic cell signalling
T/f azathriopine increases side effects of infliximab
F…. it reduces them
T/F azathiopine needs pro-drug activation by metabolism to 5-ASA
Olsalazine needs pro-drug activation by metabolism to 5-ASA
untrue becaise azathioprine– it needs activation to 6-mercaptopurine
