Inflammatory Bowel Disease Flashcards
What are the major forms of IBD?
- ulcerative colitis
- crohn’s disease
What are the risk factors of IBD?
- Genetic predisposition – in 163 loci.
- Environmental factors – smoking (CD especially), diet/obesity, gut microbiome.
- Obesity – ONLY for CD and not for UC
Describe the pathogenesis of IBD
defective interactions between the mucosal immune system and the gut flora -> leads to disrupted innate immunity -> uncontrolled inflammation -> physical damage
What are the features of ulcerative colitis?
- Th2-mediated
- Dependant on IL-5 & IL-13 cytokines
- Affects mucosa and submucosa
- Starts in rectum, spreads proximally
- Always continuous
- Surgery can be curative
What are the features of Crohn’s disease?
- Th1-mediated -> worst inflammatory response
- Dependant on TNF-a cytokine
- Penetrates all through gut wall
- 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
What are the clinical features of IBD?
- Right iliac fossa pain
- Skin rash
- Diarrhoea, blood, mucus
- Weight loss
- Arthritis, arthralgia
- Abdominal pain
- Anaemia
What are the supportive therapies for IBD?
- Fluid/electrolyte replacement
- Blood transfusion or oral iron
- Nutritional support – as malnutrition is common
What are the symptomatic treatments?
- glucocorticoids e.g prednisolone
- aminosalicylats e.g mesalazone
- immunosuppressives e.g azathioprine
What are some potentially curative treatments/
- manipulation of microbiome
- drugs :
> anti-TNF e.g infliximab
> anti-a-4-integrins e.g natalizumab
How are aminosalcylates used in IBD?
- 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
- anti-inflammatory drugs
What are the mechanisms of action of aminosalcyates?
- Inhibition of IL-1, TNF-a and PAF (Platelet Activating Factor)
- Decrease antibody secretion
- Non-specific cytokine inhibition
- Reduce cell migration – macrophages
- Localised inhibition of immune responses
Describe the pharmakokinetics of 5-ASA (mesalazine) and derivatoves (olsalazine)
Mesalazine – does not need to be metabolised and is absorbed 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
How are glucocorticoids used in IBD?
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
Describe the pharmacokinetics of glucocorticoids
many long-term use side effects -> 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
What are examples of immunosuppressives used in IBD?
Azathioprine – Both UC and CD
- CD - used to maintain remission – superior to placebo & Budesonide in CD
- UC - useful for maintaining remission in SOME patients
- Considered a “Steroid-sparing agent”
- Slow onset of action – 3-4 months’ treatment is required before clinical benefits are seen
Methotrexate – efficacy in SOME IBD patients
- A folate antagonist
- Reduces the synthesis of thymidine and other purines
- Not widely used due to significant side effects (in over 40% of patients)
Cyclosporine – UC
What is the mechanism of action of azathioprine?
- pro-drug activated (in vivo) by the gut flora to 6-mercaptopurine (6-MP)
- 6MP is a purine antagonist – thus interferes with DNA synthesis and cell replication
- Impairs – humoral and innate immune responses, lymphocyte proliferation, mononuclear cell infiltration and synthesis of antibodies
** Promotes – T-cell apoptosis
What are the unwanted side of azathioprine? effects
Associated with:
- Pancreatitis
- Bone marrow suppression
- Hepatotoxicity
- X4 risk increase of lymphoma and skin cancer
What are the main routes of metabolism of azathioprine?
Three main routes of metabolism of 6MP:
- HPRT – beneficial but causes myelosuppression
- TPMT – hepatotoxic metabolites
- XO – inert metabolites – IDEAL and main pathway
> However, a drug called allopurinol (treats gout) inhibits CO and so blocks this pathway
How can microbiome manipulation be used to treat IBD?
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
How are anti-TNF-a antibodies used to treat IBD?
(infliximab, adalimumab)
- 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
What is the mechanism of action of anti-TNF-a antibodies?
- Reduces activation of TNF-a receptors in the gut
- As TNF-a activates other cytokines, TNF-a inactivation downregulates other cytokines, and infiltration and 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
What are the pharmacokinetics of anti-TNF-a?
- Very long T1/2 – 9.5 days
- Benefits last for 30 weeks after infusion
- Patients relapse after 8-12 weeks (repeat infusion every 8 weeks)
- Problems with anti-TNF-a antibodies:
- ~50% of patients lose response to drugs after 3 years
- Due to increased metabolism & anti-drug ABs
What are some adverse effects of anti-TNF-a antibodies?
- 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
What are other targets for therapies in IBD treatment?
- 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
