what are the 2 main forms of IBD?
ulcerative colitis
crohn’s disease
when does IBD most commonly first present and occur?
in late adolescents and young adults
what environmental factors are risks in IBD?
smoking
diet
microbiome
why does IBD occur?
- occurs as a result of a defective interaction between the mucosal immune system and the gut flora
- the conditions begin as an infection
- if the innate immunity becomes disrupted you get pro-inflammatory compensatory responses –> physical damage and chronic inflammation
what is the difference between crohn’s disease and ulcerative colitis?
- CD is Th1-mediated whereas UC is Th2-mediated
- in CD all layers of the gut are affected, in UC only the mucosa and submucosa are affected
- in CD any part of the GI can be affected, in UC primarily the rectum is affected (spreading proximally)
- abscesses/fissures are common in CD not UC
- surgery is curative in UC but not necessarily in CD
what are the clinical features of CD and UC?
- fevers
- sweating
- anaemia
- arthritis
- weight loss
- skin rashes
what types of treatments are there for UC and CD?
supportive: fluids, blood, nutritional support
symptomatic (active disease/prevention of remission): glucocorticoids, aminosalicylates, immunosuppressives
potentially curative: microbiome management, biologic therapies
what are aminosalicylates?
compounds that contain mesalazine (5-aminosalicylic acid (5-ASA))
this is the active component which interferes with the body’s ability to control inflammation
what is olsalazine?
drug consisting of 2 linked 5-ASA molecules
also has anti-inflammatory actions
describe the pharmacokinetics of aminosalicylates
OLSALAZINE: has to be activated by gut flora (metabolised by colonic flora) so only works in the colon - if the inflammation is most serious in the colon it is best to give this
MESALAZINE: will be absorbed all the way through the gut
what is inflammation regulated by?
- NF-KB/MAPK pathway: down-regulates pro-inflammatory cytokines (TNF-a, IL-1B, IL-6)
- COX-2 pathway: down-regulates prostaglandins (PGE2 and PGF2)
how effective is the treatment of UC with aminosalicylates?
first line for inducing and maintaining remission
how effective is the treatment of CD with aminosalicylates?
- ineffective in inducing remission
- may be effective in a subgroup of patients
what do glucocorticoids do? give some examples of glucocorticoids
- powerful anti-inflammatory and immunosuppressive drugs
- activate intracellular glucocorticoid receptors which can act as positive or negative TFs
prednisolone, fluticasone, budesonide
what is the impact of glucocorticoids in IBD?
- inhibit the production of IL-1 and TNF-a by dendritic cells (dendritic cells have an important role in IBD)
- inhibit the production of IL-6, IL-12 and IL-17
what strategies are there for minimising unwanted effects of glucocorticoids?
- topically administer glucocorticoids (fluid, foam enemas, suppositories, oral preparations)
- use a lower dose in combination with another drug
- use an oral or topically administered drug with high hepatic first pass metabolism
how effective is the treatment of UC with glucocorticoids?
- use is in decline due to evidence that aminosalicytes are better
- avoided due to their side effects
how effective is the treatment of CD with glucocorticoids?
- drug of choice
- budesonide is preferred if the disease is mild
- likely to get side effects if glucocorticoids are used to maintain remission (long-term use)
what is azathioprine?
- a pro-inflammatory drug that has to be activated by the gut flora to 6-mercaptopurine
- 6-mercaptopurine can be given directly - it is a purine antagonist that is therefore immunosuppressive
what can 6-mercaptopurine be metabolised to form?
- can be metabolised by multiple routes
- when it is metabolised to 6-TIMP it is further metabolised to 6-MeMPN or 6-TGN
- 6-MeMPN inhibits de novo purine synthesis
- 6-TGN acts like a false purine molecule and gets incorporated into DNA
what are the effects of azathioprine on immune response?
IMPAIRS:
- cell-mediated and antibody-mediated immune responses
- lymphocyte proliferation
- mononuclear cell infiltration
- synthesis of antibodies
ENHANCES:
- T-cell apoptosis
how effective is the treatment of UC with azathioprine?
- some success
- no real reason to use it if response is good with 5-ASA
how effective is the treatment of CD with azathioprine?
- no benefit at all in active disease
- mainly used to maintain remission
what are the unwanted effects of azathioprine?
- pancreatitis
- bone marrow suppression
- hepatotoxicity
- increased risk of lymphoma and skin cancers
what metabolites of azathioprine specifically cause unwanted effects?
- 6-MeMPN is hepatotoxic
- 6-TU becomes toxic when taken with allopurinol (used to treat gout)
- 6-TGN causes myelosuppression
how can the microbiome be manipulated?
- nutrition based therapies (e.g. consuming probiotic-rich foods)
- faecal microbiota replacement therapies (FMT) - repopulating a patient’s bowel with healthy gut flora
- antibiotic treatment with rifaximin - interferes with bacterial transcription by binding to RNA polymerase, induces and sustains remission in moderate Crohn’s disease
what biologic therapies now exist to treat IBD?
- anti-TNF-a antibodies
- other antibodies (though some have more side-effects)
- humanised antibodies
how do anti-TNF-a antibodies work in IBD?
- antibodies mop up any soluble TNF-a before it can bind and activate receptors
- reduces downstream inflammatory events
- also binds to membrane associated TNF-a –> induces cytolysis of cells expressing TNF-a
- promotes apoptosis of activated T cells
describe the pharmacokinetics of infliximab (anti-TNF-a antibody)
- given intravenously
- has a very long half life (9.5 days)
- most patients relapse after 8-12 weeks so an infusion needs to be repeated every 8 weeks
what are the problems with anti-TNF-a antibodies?
- evidence that up to 50% of responders lose response within 3yrs
- loss of response is due to production of anti-drug antibodies and increased drug clearance
what are the adverse effects associated with anti-TNF-a?
- increase in incidence of TB
- risk of reactivating dormant TB
- increased risk of septicaemia
- worsening heart failure
- risk of demyelinating disease (MS)
- increased risk of malignancy
- can be immunogenic