IBD pathogenesis and treatment Flashcards
what is the definition of IBD
chronic relapsing and remitting inflammatory disorders of unknown aetiology
what are two types of IBD
crohns and ulcerative colitis
what is the difference between crohns disease and UC
crohns can affect any part of the GIT although most cases start in the terminal ileum
UC is restricted to the colon and the rectum
what is IBD caused by
failure to maintain oral tolerance
what is the genetic predisposition of IBD
increased susceptibility associate with mutations in genes NOD2 (CD)
also with polymorphisms in IL23-R (CD and UC)
positive family history is the largest independent risk factor for IBD
what is NOD2 and IL23-R
nucleotide binding oligomerisation domain containing 2 - activates NF kB in response to bacterial LPS
IL-23 produced by DC nd functions as a regulator of chronic inflammation
what are the symptoms of UC
diarrhoea with blood and mucus, weight loss, abdominal pain, nocturnal symptoms
what are the clinical signs of UC
tender abdomen
tachycardia
pyrexial
extra intestinal manifestations
describe the pathogenesis of crohns
cam affect any part of GI but most commonly affect the ileum and colon
typically discontinuous, transmural and with granulomas
what is the current concept and association with why we have IBD
results from a lack of abrogation of oral tolerance to commensal bacterial Ag’s
CD associated with Th1 response
UC associated with Th2 response
what is the medical treatment of mild proctitis
5 ASA/steroid
topical
what is the medical management of left sided UC
5 ASA steroid
topical
what is the medical management of pan colitis
5 ASA - systemic
how do you treatment moderate UC
5ASA steroid topical
systemic steroid
immunomodulator
surgery
how do you treat severe UC
parenteral steroids
ciclosporin
surgery
what are the complications of crohns disease which require surgery
abscess, fistula, perforation stricture cancer
what is sulphasalazine
sulphapyridine diazo bounded with 5 ASA showed to improve symptoms of UC
azo bond prevents proximal absorption and colonic bacteria splits the molecule
how does azathioprine work
Aza - 6-MP - 6-thioguanine
6-thioguanine - thioinosinic acid & thioguanylic acid (conj. with ribose)
Incorporated into DNA (halt replication)
Inhibit purine biosynthesis (via GPAT)
Phosphorylated to triphosphate forms -block Rac1 - increased apoptosis (of mononuclear cells)
what is the mechanism of action of methotrexate
inhibits folate metabolism
cytotoxic effects via DHFR inhibition
anti-inflammatory effects via inhibition of other enzymes
leads to IL-1 receptor blockade
increased IL-2 production
decreased IL-6 and 8 production
impaired neutrophil chemotaxis
what do these drugs do in IBD
natalizumab
vedolizumab
vercimon
blocks a4b1 - but receptor found elsewhere in the body and be a problem
blocks a4b7 which is more specific to he gut
withdrawn after phase 3 trials but stopped adhesion for inflammation
when do we need to operate on patients with IBD
emergency such as bowel obstruction/perforation, abscess, severe bleeding
elective (planned) - cancer, patient choice
what are the pros and cons of laparoscopic surgery
pros - less pain after surgery, smaller scars, faster recovery, reduced risk of infection
cons - not available in all surgeries and may not be appropriate if already had abdominal surgery
name other potential forms of therapy for IBD
inhibitors of inductive cytokines cytokines to induce Treg cells genetically engineered probiotics attenuated helminths faecal transplantation manipulation of flora
what are the benefits of probiotic therapy / vaccination
targeted delivery to site
protection against disease and infection
easy administration
cheap
systemic and mucosal responses are stimulated
increased compliance
how do you treat murine IBD
lactoccoucus lactis secreting IL-10
this however is non-commensal bacteria and cannot be regulated
describe how helminths are used treat crohns disease
limited infection in humans
80% response with ingestion of ova
