IBD Flashcards by Rama Jha

2 major forms of IBD?

Ulcerative Colitis (UC)

Crohn’s Disease (CD)
• more studied of the 2

Distinction incomplete in ~10% of pop.
• Indeterminate Colitis

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Risk factors for IBD?

Genetic Predisposition
• in 201 loci

Environmental factors
• smoking (CD especially)
• diet/obesity
• gut microbiome

Obesity
• ONLY for CD (NOT for UC)

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Pathogenesis of IBD?

Defective interactions between the mucosal I.S & the gut flora
• leads to disrupted innate immunity –> uncontrolled inflammation –> physical damage

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UC?

AI disease
Gut layers affected
Regions of gut affected
Inflamed areas are:
Abcesses/fissures/fistulae
Surgery

Th2-mediated
• limited clonal expansion
• normal T-cell apoptosis

Dependant on IL-5 & IL-13 cytokines

Affects mucosa and submucosa

Starts in rectum, spreads proximally

Inflamed areas are usually: CONTINOUS

Abcesses/fissures etc: NOT COMMON

Surgery can be curative

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CD?

AI disease
Gut layers affected
Regions of gut affected
Inflamed areas are:
Abcesses/fissures/fistulae
Surgery

Th1-mediated
• worst inflammatory response
• florid T-cell expansion
• defective T-cell apoptosis

Dependant on TNF-a cytokine

Penetrates all through gut wall
• aka. ALL LAYERS affected

Affects any point of the GI tract

Causes patchy (not continuous) inflammation
 • hard to cure with surgery and often reoccurs

Abscesses, fissures and fistula MORE COMMON

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Clinical features of IBD?

Can be systemic as well as local

	Right iliac fossa pain.
	Skin rash.
	Diarrhoea, blood, mucus.
	Weight loss.
	Arthritis, arthralgia.
	Abdominal pain.
	Anaemia.

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Summary of the therapies available for IBD - for adults only

SUPPORTIVE therapies:
o Fluid/electrolyte replacement
o Blood transfusion or oral iron
o Nutritional support – as malnutrition is common

Classic SYMPTOMATIC treatments – we can’t cure these diseases outright:
o Glucocorticoids – e.g. prednisolone
o Aminosalicylates – e.g. mesalazine
o Immunosuppressives – e.g. azathioprine

CURATIVE (potentially) treatments:
 o Manipulation of the microbiome
 o Drugs:
   Anti-TNF-a (e.g. infliximab)
   Anti-a-4-integrins (e.g. natalizumab)

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Describe the use of Aminosalicylates for the treatment of UC & CD

•

Ulcerative colitis
– first line in inducing and maintaining remission with a good evidence base

Crohn’s disease
– non-effective in active disease but may help maintain surgically-induced remission

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Example Aminosalicylates drugs?

Mesalazine

Olsalazine

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General information regarding Aminosalicylates & its drugs?

Mesalazine (5-aminosalicyclic acid / 5-ASA)
• Olsalazine (2 linked 5-ASA molecules)

These are anti-inflammatory drugs.

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MoA 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

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Explain the pharmacokinetics of 5-ASA and its derivatives

Mesalazine – does NOT need to be metabolised & is ABOSRBED by small bowel and colon

Good at maintaining remission in UC.
Topical 5-ASA is better than topical steroids at inducing UC remission
Combined topical 5-ASA and oral steroids better at inducing remission than oral 5-ASA alone

Olsalazine – metabolised by gut flora and absorbed by the colon

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Describe the treatment of Glucocorticoids for UC & CD

Ulcerative colitis
– use is in decline
– can be used topically or via IV
– 5-ASA seems to be superior

Crohn’s disease
– drug of choice for inducing remission
– SEs likely if used to maintain remission

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General information surrounding Glucocorticoids and its use?

o Powerful anti-inflammatories
o Powerful Immunosuppressives

o Activate intra-cellular GC receptors –> ±transcription factors

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Example glucocorticoid drugs?

Prednisolone

Fluticasone

Budesonide

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Explain the pharmacokinetics of glucocorticoids

Glucocorticoids have many long-term use side effects SO methods for reducing SEs:

 Administer topically.
 Use a low-dose in combination with another drug (steroid-sparing agent)
 Use an oral/topical drug with HIGH first-pass metabolism (e.g. Budesonide), so little escapes systemically –> Budesonide has fewer SEs than Prednisolone

Oral GCs are better than Budesonide at inducing remission in ACTIVE Crohn’s disease.
Budesonide is a better than placebo at preventing CD relapse

Example Imuunosuppresive drugs that are used?

Azathioprine

Methotrexate

Cyclosporine

General information about Azathioprine and its use?

CD
• used to maintain remission – superior to placebo & Budesonide in CD

UC
• useful for maintaining remission in SOME patients

o Considered a “Steroid-sparing agent”
o Slow onset of action
– 3-4 months’ treatment is required before clinical benefits are seen

General information about Methotreaxate and its use?

Efficacy in SOME IBD patients.
o A folate antagonist.
o Reduces the synthesis of thymidine and other purines.
o NOT widely used due to significant side effects (in over 40% of patients).

General information about Cyclosporine?

Used in severe UC

MoA of Azathioprine

Aza is a pro-drug activated (in vivo) by the gut flora to 6-mercaptopurine (6-MP)
• can give 6MP DIRECTLY

6MP is a purine antagonist - thus interferes with:
• DNA synthesis & cell replication

What does Azathioprine impair?

Humoral and innate immune responses
Lymphocyte proliferation
Mononuclear cell infiltration
Synthesis of antibodies

What does Azathioprine enhance?

• T-cell apoptosis

Unwanted effects associated with Azathioprine?

~10% patients experience side effects.

Associated with:
	Pancreatitis
	Bone marrow suppression.
	Hepatotoxicity.
	x4 risk increase of lymphoma and skin cancer.

There are 3 main routes of metabolism of Azathioprine - what are they and explain

Azathioprine is activated to 6-MP which then: 1. HPRT • beneficial BUT causes myelosuppression 2. TPMT • produces hepatotoxic metabolites 3. XO • produces inert metabolites - IDEAL & MAIN pathway BUT • a drug called ALLOPURINOL (treats gout) inhibits Xanthine Oxidase = blocks this pathway

One potential curative therapy is microbiome manipulation - explain the different kinds that can be used

Nutrition-based therapies: • CD – no evidence for probiotics. • UC – evidence for probiotics in the induction and maintenance of remission Faecal microbiota replacement (FMT): • Insufficient evidence for FMT – 1 study showing remission/cure in UC Antibiotic treatment (Rifaximin): • CD – induces and sustains remission in moderate cases • UC – may be beneficial • Interferes with bacterial transcription by binding to RNA polymerase – reduces mRNA coding by inflammatory mediators.

What is the drug used as the Antibiotic Treatment for microbiome manipulation?

Rifaximin

What biological therapies are there for the curative treatment of IBD?

Approved for use in IBD: • Anti TNF-alpha Abs - Infliximab (IV) - Adalimumab (SC) • Other Abs are also effective BUT have more SEs

Explain the use of Anti-TNF-alpha Abs in both UC & CD

CD – used successfully – 60% responsive within 6 weeks – potentially curative UC – some evidence of effectiveness (but UC is NOT TNF-a mediated, it is mainly IL mediated)  Infliximab – binds to soluble TNF-a and receptor bound TNF-a --> it can strip away already TNF-a bound onto cells

Drugs used as Anti-TNF-a Abs biological therapy?

Infliximab - IV Adalimumab - SC

Explain the MoA of the Anti-TNF-a Abs biological therapy

Reduces activation of TNF-a receptors in the gut As TNF-a activates other cytokines, TNF-a inactivation: • downregulates other cytokines • infiltration & activation of leukocytes Binds to membrane associated TNF-a as well as soluble TNF-a  Induces CYTOLYSIS of cells expressing TNF-a  Promotes APOPTOSIS of activated T-cells

Pharmacokinetics of Anti-TNF-a Abs?

o Very long T1/2 – 9.5 days o Benefits last for 30 weeks after infusion o Patients relapse after 8-12 weeks (repeat infusion every 8 weeks)

Problems associated with Anti-TNF-a Abs?

~50% of patients lose response to drugs after 3 years due to: • increased metabolism (i.e. drug clearance) & • production of anti-drug ABs

Why do adverse effects from Anti-TNF-a Abs arise?

Due to consequences of knocking out KEY CYTOKINES in the INFLAMMATORY CASCADE

What are the adverse effects of Anti-TNF-a Abs?

4-5x increase incidence of TB and other infections – and risk of reactivating dormant TB Increased risk of septicaemia – downregulates inflammation Worsening of heart failure Increased risk of demyelinating disease and malignancy Can be immunogenic – Azathioprine reduces risk but raises TB/malignancy risk

Explain the SONIC trial

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

What are other possible targets of biological therapies?

 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

In IBD, budesonide causes fewer unwanted systemic effects than prednisolone because: A. It can be administered topically B. It can be co-administered with another drug C. It has a higher potency at therapeutic doses D. It has a lower potency at therapeutic doses E. It is metabolised and inactivated locally

E A. It can be administered topically True but so can other glucocorticoids B. It can be co-administered with another drug True but not unique to budesonide C. It has a higher potency at therapeutic doses Potencies are similar D. It has a lower potency at therapeutic doses Potencies are similar E. It is metabolised and inactivated locally Best answer

The mechanism of action of Azathioprine in IBD: A. Interferes with purine biosynthesis B. Is a direct reduction of protein synthesis in the GI tract C. Is blocked by co-administration with allopurinol D. Means that it increases side-effects caused by infliximab E. Needs activation of the drug by metabolism to 5-ASA

A A. Interferes with purine biosynthesis True B. Is direct reduction of protein synthesis in the GI tract it will reduce protein synthesis indirectly C. Is blocked by co-administration with allopurinol untrue - allopurinol inhibits metabolism D. Means that it increases side-effects of infliximab untrue – it reduces side effects of infliximab E. Needs pro-drug activation by metabolism to 5-ASA untrue – it needs activation to 6-mercaptopurine