IBD Flashcards
What are the main forms of IBD
Ulcerative Colitis (UC)
Crohn’s Disease (CD)
Distinction incomplete in ~10% patients (Indeterminate Colitis)
300,000 people in the UK
Summarise IBD in Europe
Affects children, adolescents and adults
We are only going to consider therapeutic strategies for adults
Incidence is double in Western Europe than eastern- environmental impact important
Describe the genetic risk factors for IBD
Causes incompletely understood CD more extensively studied than UC Genetic predisposition 201 loci identified People of White European origin most susceptible
Diverse mechanisms, loss of tolerance, epithelial barrier defects and impaired mucosal defence all interact with the environment
What are the environmental risk factors for IBD
Smoking Medication Diet Sleep Stress Physical Activty Air pollution UV exposure, Vit D Microbiome Appendectomy Heavy Metal
o Obesity – ONLY for CD and not for UC.
Outline the pathogenesis of UC and CD
Defective interaction between mucosal immune system and gut flora - infection
10 x more gut bacteria than host cells
Complex interplay between host and microbes
Disrupted innate immunity and impaired clearance
Pro-inflammatory compensatory responses
Physical damage and chronic inflammation
Describe the impact of the microbiome on the pathogenesis of IBD
Host genetic factors and environmental factors interact - leading to dysbiosis
Reduced mucus layer
Chronic inflammation
Describe the key features of Chron’s
Th1-mediated e.g. IL-1ß, IL-6, IFNg, TNFa, IL-17, IL-23
Florid T cell expansion
Defective T cell apoptosis
All gut layers affected
Can affect any part of G.I
Inflammed areas are patchy
Abscesses/fistulae and fissure are common
surgery not always curative- due to patchy nature
Describe the key features of UC
Th2- mediated .g. IL-5, IL-13
Limited clonal expansion
Normal T cell apoptosis
Affects mucosa and submucosa
Starts at rectum and spreads proximally
Inflammed areas are usually continuous
Absecces/fissures and fistulae are not common
surgery therefore curative
Describe the clinical features of IBD
Abdominal pain and crampitng Diarrhoea, bloody faeces Mouth ulcers Anaemia Fever Arthritic pain Skin rashes Uveitis Weight loss
can get systemic symptoms, especially with Crohn’s
Summarise the different therapies available for IBD
Supportive - fluids, bloods, nutritional support
Symptomatic (active disease and to prevent remission) - glucocorticoids, aminosalicyaltes and immunosuppressives
potentially curative- microbiome manipulation and biologic therapies
Describe the supportive therapies for the acutely sick patient
Fluid/electrolyte replacement
- Blood transfusion/ oral iron - Nutritional support (malnutrition common)
Summarise the classical symptomatic treatments
Active disease and prevention of relapse
Aminosalicylates eg Mesalazine
Glucocorticoids eg Prednisolone
- Immunosuppressives eg Azathioprine
What are the aminosalicylates
Mesalazine or 5-aminosalicylic acid (5-ASA)
Olsalazine (2 linked 5-ASA molecules)
Anti-inflammatory
Describe the pharmacokinetics of aminosalicylates
Mesalazine does not have to be activated any further and is absorbed in the small bowel and colon
Olsalazine must be activated by colonic flora - good if IBD localised to colon- as more will get there
Describe the mechanism of action of aminosalicylates
o Inhibition of IL-1, TNF-a and PAF (Platelet Activating Factor).
o Decrease antibody secretion.
o Non-specific cytokine inhibition.
o Reduce cell migration – macrophages.
o Localised inhibition of immune responses.
Binds to PPAR receptos- transcription modulator- down-regulates pro-inflammatory reactions
Inhibits COX-2:
Reducing synthesis of prostaglandins (PGE2 and PGF2)
Inhibits NFkB/MAPK
Reducing synthesis of pro-inflammatory cytokines such as TNF-a, IL-1B and IL-6
Describe the use of aminsalicyclates 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 (proctitis)
Probably better than glucortocoids
first line in inducing and maintaining remission with a good evidence base.
Describe the use of the aminosaliclates in CD
Ineffective in inducing remission of CD
A very modest amount of evidence for effectiveness in maintenance
However, other therapies preferable for maintenance
o Crohn’s disease – non-effective in active disease but may help maintain surgically-induced remission.
What are the glucocorticoids
Examples: Prednisolone, Fluticasone, budesonide
Powerful anti-inflammatory and immunosuppressive drugs
Derived from the hormone cortisol
Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors
BUDESONIDE- NOT ABSORBED- SAtYS IN GUT- FEWER SIDE EFFECTS
Describe the impact of glucocorticoids in IBD
Promotes regulatory effect on dendritic cells, M2 macrophages (which increase regulatory DCs)
Inhibits activity of IL-6, TNF-a, and IL-17
Describe how glucocorticoids work in IBD
Glucocorticoids (GCs) are anti-inflammatory drugs that activate intracellular GC receptors. The activated receptors then act as positive transcription factors, increasing the expression of antiinflammatory genes or, more frequently, negative transcription factors, reducing the expression of pro-inflammatory genes.
They act on many cell types and have powerful anti-inflammatory actions including a reduction in the influx and activation of proinflammatory cells and a reduced production of the mediators which cause vasodilation, fluid exudation (swelling), further inflammatory cell recruitment and tissue degradation.
Additionally, GCs are potent immunosuppressive drugs, causing reductions in antigen presentation, cell proliferation and clonal expansion.
What are the important side effects of glucocorticoids
Very potent anti-inflammatory and immunosuppressive actions of GCsWhen given systemically, chronic glucocorticoid administration causes many unwanted effects.
The incidence and severity of side effects are closely
related to the dose and duration of GC given.
Unwanted effects of GCs are:
Osteoporosis Increased risk of Gastric ulceration Suppression of HPA axis Type II diabetes Hypertension Susceptibility to infection Skin thinning, bruising and slow wound healing Muscle wasting and buffalo hump
What is the issue with budenoside
Budesonide has fewer side effects than other glucocorticoids but it is less effective at inducing remission in CD
Describe the use of glucocorticoids in IBD
Ulcerative colitis
Strong evidence that aminosalicylates superior
Glucocorticoids not recommended
Crohn’s Disease
GCs drugs of choice for inducing remission
Budesonide preferred if mild
Avoid as maintenance therapy due to side effects
How can we minimise the side effects of glucocorticoids in IBD
GCs play a key role in the management of CD, so strategies have been developed for minimising their unwanted effects. These strategies include the use of tapered doses, the use of drugs with
a high therapeutic index such as fluticasone, and topical administration (particularly of budesonide which has a high first pass metabolism in the liver and GIT). Because of their unwanted effects, GCs are best used to treat active disease rather than to maintain remission and prevent relapse. Despite their powerful anti-inflammatory actions, they are less effective than aminosalicylates (see below) in the treatment of UC.
State three immunosuppressive agents that can be used to treat IBD
Azathioprine
Methotrexate
Cyclosporin – only useful in severe UC
What is azathioprine
A pro-drug Activated by gut flora to 6-mercaptopurine
Give 6-mercaptopurine directly
Purine antagonist (interferes with DNA replication and synthesis)
Immunosuppressive
Describe the effect of azathioprine on the immune response
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 in Chron’s disease
Not recommended for active disease
Azathioprine or other immunosuppressants recommended for maintaining remission
Glucocorticoid-sparing
Slow onset – 3 to 4 months treatment for clinical benefit
If ineffective move to biological therapies
What are the main routes of metabolism of 6MP
Three main routes of metabolism of 6MP:
o HPRT – beneficial but causes myelosuppression.
o TPMT – hepatotoxic metabolites.
o XO – inert metabolites – IDEAL and main pathway.
However, a drug called allopurinol (treats gout) inhibits CO and so blocks this pathway.
Describe the main side effects of azathriprine
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
Outline the further metabolism of 6-MP
Converted to 6-TU inactive by Xanthine oxidase (Allopurinol inhibits)- promoting metabolism down other routes
TMPT converts to 6-MeMp which is hepatotoxic
HGPRT converts to 6-TIMP:
TPMT converts 6-TIMP to 6-MeMPN (inhibiton of de novo purine synthesis)
IMPD, GMPSa nd various kinases convert 6-TIMP to 6-TGN (incorporates into DNA)- beneficial but also causes immunosuppression
Summarise 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
Describe the strategies for targeting drug delivery b
pH dependent polymer coating
Pressure/osmotic controlled coating system (Aqueous environment in lower intestine- water moves in- pushing drug out)
Time dependent polymer coating
Prodrug based conjugates (Olsalazine)
These can reduce systemic toxicity
New complex polymers which combine time and pH
Potential to give better targeting of drugs to areas of inflammation
Summarise the potentially curative treatments
Curative (potentially) treatments: o Manipulation of the microbiome. o Drugs: Anti-TNF-a (e.g. infliximab). Anti-a-4-integrins (e.g. natalizumab).
Describe EEN as modification of the microbiome
Exclusive enteral nutrition (EEN)
- Liquid diet
- Allows “resting” of the mucosa and recovery of the gut flora
- Unpalatable and hard to maintain
- Only recommended for induction of remission if patient cannot take
steroids
Describe the role of probiotics in manipulating the microbiome
Probiotic therapies
- Different organisms have different effects so difficult to generalise - No evidence for probiotics in CD. - Weak evidence for maintenance of remission in UC
Npot tailored to individual’s microbiota
Describe the role of FMT in manipulating the microbiome
. Faecal microbiota replacement (FMT) therapies
- 2 of 3 RCTs showed benefit in UC
- Unclear if changed microbiome is cause or effect
Replace with healthy microbiota to outgrow pathogens
Describe how antibiotic treatment can manipulate the microbiome
- Antibiotic Treatment – Rifaximin
- Interferes with bacterial transcription by binding to RNA polymerase - Benefit shown in experimental models of IBD
Describe the experimental data associated with Rifaximin
Rifaximin reduces inflammatory mediator mRNA in experimental colitis (reduces expression of IL-10, IL-6 and IL-1b)
DSS = dextran sulphate sodium = induces experimental IBD
May be microbiome modulator
- Not absorbed from gut
-Some evidence for sustained remission in moderate CD
- Only recommended if complications relating to infection (i.e abscesses or fistulae)
may be useful in UC
Summarise the 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
Give two examples of anti-TNFa antibodies
Infliximab (IV)
Adalimumab (SC)
Describe the mechanism of action of anti-TNFa antibodies
Anti- TNFa reduces activation of TNF a receptors in the gut
Reduces downstream inflammatory events
Binds to membrane associated TNFa
Induces cytolysis of cells expressing TNFa
Promotes apoptosis of activated T cells
Bounds to soluble TNF and bound TNF
Describe the pharmacokinetics of infliximab
Infliximab given intravenously Very long half-life (9.5 days) Most patients relapse after 8 – 12 weeks Therefore repeat infusion every 8 weeks Can't take proteins orally
Summarise the use of anti-TNFa antibodies in IBD
Anti-TNF-Alpha Antibodies:
o CD – used successfully, 60% responsive within 6 weeks, potentially curative.
o UC – some evidence of effectiveness (but UC is not TNF-a mediated, it is mainly IL mediated).
Used successfully in the treatment of CD
Only 60% patients respond within 6 weeks
Potentially curative, but many patients relapse
Successful in some patients with refractory disease and fistulae
Very good for maintaining fistula closure
UC may be more Th1
Describe the problems with anti-TNFa antibodies
Emerging evidence that up to 50% responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance- antibodies to the antibody
Attempts being made to optimise dosing regimens (combine with azathioprine)
Describe the adverse effects of anti-TNFa antibodies
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
Summarise the use of infliximabs
Early use better than last resort
Combined infliximab and azathioprine therapy recommended rather than monotherapy
Describe the SONIC trial findings
SONIC trial findings – a study on infliximab:
o Early use of infliximab in refractory disease is better than using it as a last resort.
o CRP levels and endoscopy might allow identification of patients most likely to benefit.
o Greater risk of infection and lymphoma.
Describe some potential new targets
Integrins (needed for cells to migrate)
Interleukins (IL12; IL17;IL23)
Interleukin receptors
Janus kinase (JAK) cytoplasmic cell signalling
Explain the rationale for the new targets
Alpha-4 Integrin – cell adhesion molecule.
IL-13 – particularly in UC.
Janus kinases 1, 2, 3 – block signalling by IL-2, 4, 9, 15, 21 (lymphocyte activation and function) and IL-6 and INF-gamma (pro-inflammatory) – good in UC.
Summarise the biologic therapies
These drugs constitute the first generation of potentially curative therapies for the treatment of CD. Infliximab (anti-TNFα) is demonstrating some success in patients with previously intractable and steroid-dependent disease, although relapse is still common. The safety profile is general good, but some subjects can develop very serious side effects which can be severe. Because Crohn’s Disease (unlike UC) is a Th1-mediated autoimmune disease, TNFα plays a key role in its pathogenesis, so anti- TNFα can be of therapeutic benefit. It reduces activation of TNFα receptors in the gut and hence, other inflammatory responses downstream of TNFα such as the production of other cytokines and the infiltration and activation of leukocytes are also reduced.
Co-administration with immunomodulators reduces immunogenic side-effects, but increases the risk of serious infection (e.g. TB) and malignancy. Thus the risk/benefit equation must be
considered for each patient individually.
Infliximab and other drugs like it are likely to be very important for the future treatment of autoimmune disorders
Summarise the aminosalicylates
Aminosalicylates have fewer anti-inflammatory actions than GCs and no immunosuppressive effects and because of this, they are safer to use chronically for the maintenance of remission. They reduce the recruitment of inflammatory leukocytes and reduce the production of a number of inflammatory mediators. Aminosalicylates in current clinical use include Sulfasalazine, Mesalazine, Olsalazine.
The first to be used was sulfasalazine, but this has unwanted side effects due to its sulfapyridine moiety. These can be avoided by administering the therapeutically active component 5-aminosalicylic acid (ASA) also called mesalazine on its own. A newer drug, olsalazine, consists of 2 linked 5-ASA moieties.
Except for 5-ASA given alone, all these derivatives are activated by the gut flora.
It is therefore possible to control the site of absorption by modifying the route of drug administration and the exact formulation of the drug. You should know about the sorts of modifications which can be made to target the drugs to different parts of the GIT.
Aminosalicylates are the first line treatment for ulcerative colitis.
