Inflammatory Bowel Disease Flashcards by Anas A

What are the Two Major Forms of Inflammatory Bowel Disease?

Ulcerative Colitis
Crohn’s Disease

Note that the distinction is incomplete in ~10% patients (Indeterminate Colitis)

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How many gene loci have been identified that are associated with IBD (i.e. genetic predisposition)?
What type of people are most susceptible?

State some important environmental risk factors?

201 loci identified

People of White European origin most susceptible

Diet (obesity esp. for Crohn’s), smoking, medication etc.

The combination of genetic and environmental factors => altered gut microbiota

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What is the underlying pathogenesis of these diseases based on?

Defective interaction between mucosal immune system and gut flora - infection

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Which T cell responses are involved in:
Crohn’s Disease
Ulcerative Colitis

Crohn’s Disease = Th1

Ulcerative Colitis = Th2

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What are the main cytokines in:
Crohn’s Disease
Ulcerative Colitis

Crohn’s Disease = TNF-alpha

Ulcerative Colitis = IL-5, IL-13

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Which layers of the gut are affected in:
Crohn’s Disease
Ulcerative Colitis

Crohn’s Disease = All Layers

Ulcerative Colitis = Mucosa + Submucosa

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Describe which regions of the gut are affected in:
Crohn’s Disease
Ulcerative Colitis

Also describe the inflammation in each.

Crohn’s Disease:
Can be anywhere on the GI tract (mouth to anus)
Patchy inflammation

Ulcerative Colitis:
Starts at the rectum and spreads proximally
Continuous inflammation

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Are abscesses, fissures and fistulae common in:
Crohn’s Disease
Ulcerative Colitis

Crohn’s Disease
Yes
Ulcerative Colitis
No

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Describe the effectiveness of surgery in:
Crohn’s Disease
Ulcerative Colitis

Crohn’s Disease:
Not always curative
Ulcerative Colitis:
Curative

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List the clinical features of IBD (systemic as well as local)

Abdominal pain and cramping
Diarrhoea, bloody faeces
Mouth ulcers 
Anaemia
Fever
Arthritic pain 
Skin rashes 
Uveitis
Weight loss

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Describe some supportive therapies that are given for IBD

Nutritional therapy
Fluid/electrolytes
Blood transfusions/oral iron

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What are the three types of classic symptomatic treatment for IBD?

Aminosalicylates
Glucocorticoids
Immunosuppressants

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What is the main aminosalicylate drug?

Mesalazine or 5-aminosalicylic acid (5-ASA)

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What is a slightly more complex aminosalicylate?

Olsalazine (2 linked 5-ASA molecules)

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What type of drug are aminosalicylates?

Anti-inflammatory

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Describe the mechanism of anti-inflammatory action of aminosalicylates.

They inhibit IL-1, TNF-alpha and PAF (inhibit transcription)
=> Decrease antibody secretion
=> Reduced cell migration (macrophages)
=> Localised inhibition of immune responses

Describe the activation and site of absorption of the two aminosalicylate drugs.

Mesalazine does not have to be activated any further; absorbed in small bowel and colon.
Olsalazine must be activated by colonic flora; absorbed in the colon.

Describe the effectiveness of aminosalicylates in Ulcerative Colitis and Crohn’s Disease.

Aminosalicylates and UC:

Effective at induction and maintenance of remission
Rectal delivery better for localised disease

Aminosalicylates and CD:
- Ineffective in inducing remission of CD

Give examples of glucocorticoid drugs used to treat IBS.

What type of drug are they?

Examples: Prednisolone, Fluticasone, budesonide

Powerful anti-inflammatory and immunosuppressive drug

What is an example of a glucocorticoid that has relatively few side effects, and why is this so?
Describe the effectiveness of budesonide compared to other glucocorticoids.

Budesonide

Because it is metabolised and inactivated locally

less effective at inducing remission in CD

How could you minimise the side effects of glucocorticoids?

Use oral or topically administered glucocorticoid with a high first pass metabolism

Describe the use of glucocorticoids in IBD (CD and UC)

Ulcerative colitis:
- Strong evidence that aminosalicylates superior

Crohn’s Disease:
- GCs are the drugs of choice for inducing remission

State three immunosuppressive agents that could be used in IBD.

Azathioprine
Methotrexate
Cyclosporin – only useful in severe UC

Describe the onset of action of azathioprine.

Slow onset – can take 3-4 months

Describe the metabolism/activation of azathioprine.

Azathioprine needs to be metabolised by gut flora to 6-mercaptopurine

Describe the mechanism of action of azathioprine - type of drug, does what, impairs what, enhances what?

``` 6-mercaptopurine is a purine antagonist; It interferes with DNA synthesis and cell replication It impairs: - Cell- and antibody-mediated immune responses - Lymphocyte proliferation - Mononuclear cell infiltration - Synthesis of antibodies It enhances: - T cell apoptosis ```

What are the unwanted effects of azathioprine?

- Nearly 10% of patients stop treatment because of the side effects - Pancreatitis - Bone marrow suppression - Hepatotoxicity - Increased risk of lymphoma and skin cancer

What are Azathioprine or other immunosuppressants recommended/ not recommended for?

Not recommended for active disease | Recommended for maintaining remission

Describe the metabolism of azathioprine.

There are three routes of metabolism of azathioprine - Route resulting in the production of beneficial active metabolites but also cause myelosuppression (HPRT pathway produces 6-TIMP => 6-TGN) - Route resulting in hepatotoxic metabolites with no beneficial effect (TPMT produces 6-MMP) - Xanthine Oxidase Pathway– produces inert metabolites (6-TU); main route

What are the three potential mechanisms of manipulating the gut microbiome as a potentially curative therapy of IBD?

Nutrition based therapies (exclusive enteral nutrition) – probiotics could be useful in UC Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC Antibiotics – Rifaximin - Interferes with bacterial transcription by binding to RNA polymerase - Induces and sustains remission in moderate CD - Potentially beneficial in UC

Give 2 examples of anti-TNF-𝛼 antibodies (biologic curative therapies) Include each ROA

Infliximab (IV) | Adalimumab (SC)

Describe the mechanism of action of anti-TNF-alpha antibodies.

Anti-TNFa reduces activation of TNFa 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

Describe the pharmacokinetics of infliximab

Given intravenously Long half-life – 9.5 days Most patients relapse between 8-12 weeks Repeat infusion given after 8 weeks

Describe the effectiveness of anti-TNF- antibodies in Crohn’s Disease.

- Used successfully in the treatment of CD - potentially curative, but many patients relapse - Very good for maintaining fistula closure

What is a problem with anti-TNA-alpha therapy that may require changes in the treatment guidelines?

Evidence showed up to 50% of responders stopped responding after 3 years This is due to production of anti-drug antibodies and increased drug clearance

What are the adverse effects of anti-TNA-alpha therapy?

- Increased risk of tuberculosis - Risk of reactivating dormant TB - Increased risk of septicaemia - Worsening heart failure - Increased risk of demyelinating disease - Increased risk of malignancy - Can be immunogenic

Give details on when infliximab should be used and how.

- Early use better than last resort | - Combined infliximab and azathioprine therapy recommended rather than monotherapy