Inflammatory Bowel Disease Flashcards
What are the two major forms of IBD? What is a problem with the distinction
Ulterative colitis
Crohn’s disease - most studied of the two
The distinction is incomplete in ~10% of the patients (intermediate colitis)
What are risk factors for IBD
- genetic predisposition
- environmental factors eg smoking, diet, obesity, gut microbiome
- obesity
What is the pathogenesis of IBD
Defective interactions between the mucosal immune system and the gut flora leading to disrupted innate immunity -> uncontrolled inflammation -> physical damage
What are the differences between ulcerative colitis and crohn’s disease? - 6 points
what mediates it? dependent on? affects? surgery effect? ect
Ulcerative colitis:
o Th2-mediated. o Dependant on IL-5 & IL-13 cytokines. o Affects mucosa and submucosa. o Starts in rectum, spreads proximally. o Always continuous. o Surgery can be curative.
Crohn’s disease:
o Th1-mediated -> worst inflammatory response.
o Dependant on TNF-a cytokine.
o Penetrates all through gut wall.
o Affects any point of the GI tract.
o Causes patchy (not continuous) inflammation.
- Hard to cure with surgery and often reoccurs.
o Abscesses, fissures and fistula more common.
What are clinical features of inflammatory bowel disease: name 10
Right iliac fossa pain Skin rash Diarrhoea, blood, mucus Weight loss Arthritis, arthralgia Abdominal pain Anaemia
What are classic symptomatic treatments of IBD
Glucocorticoids eg prednisolone
Aminosalicylates eg mesalazine
Immunosuppressives eg azathioprine
What are supportive therapies of IBD
Fluid/electrolyte replacement
Blood transfusion or oral iron
Nutritional support - as malnutrition is common
what are curative (potentially) treatments of IBD
Manipulation of gut microbiome
Drugs - anti-TNF-a eg infliximab or anti-a-4-integrins eg natalizumab
When are aminosalicyates used as therapy in UC and crohn’s?
UC - first line in inducing and maintaining remission with good evidence base
Crohn’s - non effective in active disease but may help maintain surgically induced remission
What are examples of aminosalicylates
Masalazine
Olsalazine
What is the mechanism of action of aminosalicylates
- Inhibition of IL-1, TNF alpha, and PAF (platelet activating factor)
- Decrease antibody secretion
- Non specific cytokine inhibition
- Reduced cell migration - macrophages
- Localised inhibition of immune responses
What is the effectiveness of mesalazine at inducing and maintaining remission in UC
It is good at maintaining remission, and topical mesalazine is better than topical steroids at inducing remission. Combined topical mesalazine and oral steroids are better at inducing remission than oral 5-ASA alone
How is mesalazine metabolised
It does not need to be metabolised and is absorbed by small bowel and colon
How is olsalazine metabolised
By gut flora and absorbed by the colon
What are examples of glucocorticoids
Prednisolone, fluticasone, budesonide
How are glucocorticoids used as treatment in UC and crohns?
In UC - use is in decline, can be used topically or via IV but mesalazine is superior
In Crohn’s it is the drug of choice for inducing remission. SEs likely if used to maintain remission
What are the effects of glucocorticoids when used in IBD
Powerful antiinflammatories and immunosuppressives that activate intra cellular GC receptors causing TF +/-
How are glucocorticoids administered in IBD to reduce side effects in long term use
Administer topically
Use a low dose in combination with another drug eg a steroid sparing agent
Use an oral/topical drug with HIGH first pass metabolism eg budesonide so little escapes systemically -> budesonide has fewer Ses than prednisolone
What GC are best at inducing crohn’s remission and which are better at preventing relapse
Oral GCs are better than budesonide at inducing remission in active crohn’s disease
Budesonide is a better placebo at preventing CD relase
What are examples of immunosuppressives used in IBD
Azathioprine, methotrexate, cyclosporine
When is Azathioprine used as therapy in UC and crohn’s?
CD - maintain remission and is superior to placebo and budesonide in CD
UC - useful for maining remission in some patients
What is the onset of action of azathioprine for IBD
3-4 months treatment needed before clinical benefits are seen
What is methotrexate
A folate antagonist that reduces the synthesis of thymidine and other purines
Why is methotrexate not used to treat IBD often
Due to significant side effects in over 40% of patients
What condition is cyclosporine used in
UC
What is the mechanism of action of azathioprine
Aza is a pro drug activated in vivo by the gut flora into 6 mercaptopurine (6-MP) which is a purine antagonist that interferes with DNA synthesis and cell replication. 6MP can also be given directly
What does azathioprine impair
Humoural and innate immune responses, lymphocyte proliferation, mononuclear cell infiltration and synthesis of antibodies
What does azathioprine promote
T cell apoptosis
What are unwanted effects of azathioprine
Pancreatitis, bone marrow suppression, hepatotoxicity and a x4 risk increase of lymphoma and skin cancer
What are the 3 main routes of metabolism of 6Mp
HPRT- beneficial but causes myelosuppression
TPMT - hepatotoxic metabolites
XO - inert metabolites - ideal and main pathway but a drug allopurinol inhibits CO and blocks the pathway (treats gout)
What are the ways of using microbiome manipulation to treat IBD
(adults only)
Nutrition based therapies
Faecal microbiota replacement (FMT)
Antibiotic treatment (rifaximin)
What IBD is affected by probiotics
UC has evidence for probiotics in the induction and maintenance of remission
What is the problem with using faecal microbiota replacement as a treatment for IBD
Insufficient evidence for FMT - 1 study showing remission/cure
What does antibiotic treatment do in IBD
CD - induces and sustains remission in moderate cases
UC - may be beneficial
How does antibiotic treatment work for IBD
Interferes with bacterial transcription by binding to RNA polymerase - reducing mRNA coding by inflammatory mediators
What are biological therapies used for IBD
Anti TNF alpha:
Infliximab (IV) or Adalimumab (SC)
Other antibodies are effective but also have more side effects
What happens when anti TNF alpha antibodies are used in different IBDs?
CD - used successfully and 60% response
UC - some evidence of effectiveness but UC is not TNF alpha mediated and mainly IL mediated
How does Infliximab used to treat IBD
It binds to soluble TNFa and receptor bound TNFa and it can strip away already TNFa bound onto cells
MoA of biological therapies for IBD - anti TNFa
Reduces activation of TNFa receptors in the gut
As TNFa activates other cytokines, TNFa inactivation downregulates other cytokines and infiltration and activation of leukocytes
It binds to membrane associated TNFa as well as soluble TNFa, (inducing cytolysis of cells expressing TNFa and promotes apoptosis of activated T cells)
What is the effect of biological therapies of IBD?
Induces cytolysis of cells expressing TNFa and promotes apoptosis of activated T cells
What are the half life, benefits and relapse time of biological IBD therapies?
very long half life 9.5 days, benefits last 30 weeks after infusion and patients relapse after 8-12 weeks
What are problems with anti TNF a antibodies used in IBD
~50% of patients lose response to drug after 3 years and due to an increased metabolism and anti drug ABs
What are adverse effects of biological therapies for IBD due to
Due to consequences of knocking out the key cytokine inflammatory cascades
what are the adverse effects of biological therapies for IBD
- 4-5x increased incidence of Tb and other infections - and risk of reactivating dormant TB
- increased risk of septicaemia - downregulates inflammation
- worsening 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 used for IBD
- 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 IL6 and INF gamma (pro inflammatory) good in UC
