Inflammatory Bowel Disease Flashcards
What are the two main diseases that come under Inflammatory Bowel Disease?
Ulcerative Colitis
Crohn’s Disease
What is the underlying pathogenesis of IBD based on?
A defective interaction between the mucosal immune system + gut flora
List 4 key environmental risk factors associated with IBD
Diet
Smoking
Medication
Microbiome
Which T cell responses are involved in:
a. Ulcerative Colitis
b. Crohn’s Disease
UC: Th2
CD: Th1
What are the main cytokines in:
a. Ulcerative Colitis
b. Crohn’s Disease
UC: IL-13
CD: TNF-alpha
Which layers of the gut are affected in:
a. Ulcerative Colitis
b. Crohn’s Disease
UC: Mucosa + Submucosa
CD: All Layers
Describe which regions of the gut are affected in:
a. Ulcerative Colitis
b. Crohn’s Disease
UC: Starts at the rectum + spreads proximally (continuous inflammation)
CD: Any part of GI tract (mouth to anus). Patchy inflammation.
Are abscesses, fissures and fistulae common in:
a. Ulcerative Colitis
b. Crohn’s Disease
UC: No
CD: Yes
Describe the effectiveness of surgery in:
a. Ulcerative
b. Crohn’s Disease
UC: Curative
CD: Not always curative, even if the affected area is cut out, it often reoccurs
Describe 3 supportive therapies that are given for IBD
Nutritional support
Fluid/ electrolyte replacement
Blood transfusions/ oral iron
What are the three types of classic symptomatic treatment for IBD?
Aminosalicylates
Glucocorticoids
Immunosuppressants
What is the main aminosalicylate drug?
Mesalazine
AKA 5-aminosalicylic acid (5-ASA)
What is a slightly more complex aminosalicylate?
Olsalazine (= 2 x 5-ASA)
What type of drug are aminosalicylates?
Anti-inflammatory
Describe the mechanism of anti-inflammatory action of aminosalicylates.
Bind to PPAR receptors, acting as transcription modulators
Downregulate NFKB + MAPK, thus down regulating pro-inflammatory cytokines e.g. IL-1, TNF-alpha + IL-6
Downregulate expression of COX-2 + pro inflammatory prostaglandins
Describe the activation of aminosalicylates.
Mesalazine is active, absorbed in small bowel + colon
Olsalazine must be activated by colonic flora so is active in colon
Describe the effectiveness of aminosalicylates in Ulcerative Colitis and Crohn’s Disease.
Effective at inducing + maintaining remission in UC
Better than steroids at inducing remission in UC
Ineffective in inducing remission, may help maintenance but other drugs are better in CD
Describe the use of glucocorticoids in IBD.
Use in UC declining because aminosalicylates are better
Glucocorticoids are still the drug of choice for inducing remission in CD
However, side effects are likely if they are used to maintain remission
Describe some strategies for minimising the side effects of glucocorticoids.
Topical administration (e.g. enemas + suppositories) Low dose Use oral or topically administered glucocorticoid with a high first pass metabolism
What is an example of a glucocorticoid that has relatively few side effects? Why is this?
Budesonide
Not absorbed, stays in gut
Describe the effectiveness of budesonide compared to other glucocorticoids.
Budesonide has fewer side effects than other glucocorticoids but it is less effective at inducing remission in CD
State an immunosuppressive agent that could be used in IBD.
Azathioprine
Describe the onset of action of azathioprine.
Slow onset: can take 3-4 months
Describe the activation of azathioprine.
Azathioprine is a pro-drug
Needs to be metabolised by gut flora to 6-mercaptopurine
Describe the mechanism of action of azathioprine.
6-mercaptopurine is a purine antagonist
Interferes with DNA synthesis + cell replication
Impairs:
Cell- + antibody-mediated immune responses
Lymphocyte proliferation
Mononuclear cell infiltration
Synthesis of antibodies
Enhances: T cell apoptosis
What are the unwanted effects of azathioprine?
~ 10% of patients stop treatment because of side effects
Pancreatitis
Bone marrow suppression
Hepatotoxicity
Increased risk (4 fold) of lymphoma + skin cancer
Describe the metabolism of azathioprine.
3 routes of metabolism of azathioprine:
Route resulting in production of beneficial active metabolites also causes myelosuppression (6-TGN)
Route resulting in hepatotoxic metabolites with no beneficial effect (6-MMP)
Xanthine Oxidase Pathway: produces inert metabolites (6-TU)
In what clinical situation could there be a problem with azathioprine metabolism?
If patient is taking allopurinol
Allopurinol is used to treat gout + is a xanthine oxidase inhibitor
Results in azathioprine being shunted down the hepatotoxic + myelosuppressive routes of metabolism
When is Azathioprine used in Crohn’s disease?
Not for active disease
Used for maintaining remission
Glucocorticoid sparing- can reduce glucocorticoid dose
What are the 4 potential mechanisms of manipulating the gut microbiome?
Exclusive enternal nutrition (EEN): Liquid diet, allows resting of mucosa + recovery of gut flora, hard to maintain + unpalatable
Probiotic therapies: in maintenance of remission of UC
Faecal Microbiota Replacement Therapy (FMT): in UC
Antibiotics: Rifaximin
Interferes with bacterial transcription by binding to RNA polymerase
Induces + sustains remission in moderate CD
Potentially beneficial in UC
Give an example of an anti-TNF-alpha antibody
Infliximab (IV)
Describe the effectiveness of anti-TNF- antibodies in Crohn’s Disease.
60% of patients respond within 6 weeks
Describe the mechanism of action of anti-TNF-alpha antibodies.
Anti TNF-alpha reduces activation of TNF-alpha receptors in the gut
Reduces downstream inflammatory events
Induces cytolysis of cells expressing TNF-alpha
Promotes apoptosis of activated T cells
Describe the pharmacokinetics of anti-TNF-alpha antibodies.
Given intravenously
Long half-life: 9.5 days
Most patients relapse between 8-12 weeks
Repeat infusion given after 8 weeks
What is a problem with anti-TNF-alpha therapy that may require changes in the treatment guidelines?
~50% of responders stopped responding after 3 years
Due to production of anti-drug antibodies + increased drug clearance
What are the adverse effects of anti-TNF-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
List 3 local clinical features of IBD
Abdominal pain/ cramping
Diarrhoea, bloody faeces
Mouth ulcers
List 6 systemic clinical features of IBD
Anaemia Fever Arthritic pain Skin rashes Uveitis Weight loss
Name 2 glucocorticoids. What is the MOA of glucocorticoids in IBD?
Prednisolone + Budesonide
Activate intracellular glucocorticoid receptors which then act as positive or negative transcription factors
Potent anti-inflammatory + immunosuppressive actions
List 3 strategies for minimising unwanted side effects of IBD drugs
Topical administration
Use low dose in combination with another drug
Use drug with high hepatic first pass metabolism so little escapes into systemic circulation
