Inflammatory Bowel Disease Flashcards
colitis
a digestive disease that involves inflammation of the colon, or large intestine
could be acute or chronic
some of the most common forms of IBD
Chron’s disease
Ulcerative colitis
Intermediate colitis
intermediate colitis
types of colitis which do not present with enough of the criterion for CD or UC to enable them to be
classified.
some common/similar features of Chron’s and Ulcerative colitis
Abdominal pain and cramping
Diarrhea (often chronic and sometimes bloody)
Urgency to defecate
Weight loss and malnutrition due to poor absorption
Fatigue and fever during flare-ups
key differences between UC and Chron’s
fistulas in CD but not in UC
sinuses in CD but not in UC
Location: Crohn’s can affect any part of the GI tract from mouth to anus, while ulcerative colitis is limited to the colon and rectum.
Pattern of Inflammation: Crohn’s often presents with “skip lesions” (patchy areas of inflammation) and can affect deeper layers of the bowel wall. Ulcerative colitis is usually continuous and affects only the innermost lining of the colon
Fistulas are an abnormal passageway, or tunnel, in the body.
chron’s disease
a long-term condition where the gut becomes inflamed. it’s a relapsing disease. severity and incidents of complications increase over time
affects both genders equally, occurs between 20-40 and a small peak between 50-60
main symptoms of chron’s
diarrhoea, stomach aches and cramps, rectal bleeding, Unintended weight loss, systemic illness…etc
with CD some patients mignt not experience any GI symptoms at all
pathophysiology of Chron’s
pathophysiology the disordered physiological processes associated with disease or injury
- It can affect any part of the gastrointestinal tract
from the mouth to the anus.
▪ Characterised by patchy transmural
inflammation.
▪ The chronic inflammatory process leads of
thickening of the bowel wall and can cause a
narrowed lumen.
▪ In early CD there are prominent lymphoid
follicles followed by aphthoid ulceration.
▪ Later this progresses to larger deep fissuring
ulcers separated by normal looking mucosa
Skip lesions are a characteristic feature of Crohn’s disease that appear as inflamed tissue patches surrounded by non-inflamed tissue
transmural inflammation in CD
Transmural inflammation is a characteristic feature of Crohn’s disease (CD), an inflammatory bowel disease (IBD) that can affect the entire gastrointestinal tract. Transmural means existing or occurring across the entire wall of an organ or blood vessel. In CD, this inflammation can extend through to the serosa, resulting in sinus tracts or fistula formation
local complications of CD
Fistula formation
Perforation
Abscesses
Strictures and Bowel Obstruction
A stricture is a narrowing of a passageway in the body, such as the intestines, esophagus, heart valves, or trachea
the cause of chron’s disease is unknown, true or false
true
however pathogenic mechanisms(eg genetic predisposition, environmental factors and the subsequent reaction of the host immune system) have been proposed to explain why they occur
complications that affect areas outside the GI tract
what are some extra-intestinal complications of Chron’s disease
note these are spread all around the body. so there are complications that affect the joints, the eyes, the liver etc…state at least one complication for each area of the body mentioned
Sclerosing Cholangitis(causes unknown)
Pyoderma gangrenosum
Erythema nodosum
osteopenia
osteoporosis
Ankylosing spondylitis
Episcleritis
Uveitis
Sclerosing cholangitis is a chronic liver disease characterized by inflammation, scarring (fibrosis), and narrowing of the bile ducts, which transport bile from the liver to the gallbladder and small intestine
Pyoderma gangrenosum occurs in ~2% of CD patients, starting as a small pustule, then developing into a painful, enlarging ulcer, most commonly on the leg
Erythema nodosum- Hot, red tender nodules appear on the arms and legs and subside after a few days
how do we investigate chron’s
taking patient’s Full history
Physical examinations
stool sample
Faecal Calprotectin testing
endoscopy
radiology
note that physical examination is not just about touching the patient, it could be about what you see, smell…etc
which test helps different between IBS and IBD and how does it do this
faecal Calprotectin test
it does this by measuring the level of calciprotectin in a stool sample
Calprotectin is a protein released by white blood cells in inflamed areas of the bowel. Elevated levels of calprotectin indicate inflammation, while normal levels indicate no inflammation.
There is no inflammation in irritable bowel syndrome(IBS)
the aims of treatment in chron’s
Relieve symptoms and improve quality of life
Induce and maintain remission
Promote mucosal healing
Prevent complications
remission either the reduction or disappearance of the signs and symptoms of a disease. The term may also be used to refer to the period during which this reduction occurs. A remission may be considered a partial remission or a complete remission
management of CD according to NICE
Drug therapy
Smoking cessation
Attention to nutrition
Surgery in cases where needed
note that CD has no cure. The goal of treatment is to induce remission by controlling symptoms and maintain remission to prevent relapse.
In drug therapy, the “step-up” or “top down” methods can be adopted depending on the patient and their symptoms. Standard care however is the step-up method
describe how drug therapy is used in the “step-up” method to treat CD, and the different drugs involved in each step
for acute flare-ups in the GI tract, mild-moderate symptoms, monotherapy with glucoticosteroids recommended. Aminosalicylates also used at this stage but only if corticosteroids cannot be used
if 2 or more exacerbations in a 12 month period or cannot
taper steroid dose, use immunomodulators like azathioprine or mercaptopurine (or methotrexate)
for Severe active Crohn’s, unresponsive to or if unable to take conventional therapy- use biologics like infliximab or adalimumab
can corticosteroids be used as maintenance therapy in CD
No, corticosteroids are not effective for maintaining remission of Crohn’s disease (CD) and should be avoided for long-term use, due to their side effects
note that they are effective for inducing remission but not as maintenance therapy
How is PLA2 inhibition induced.
Corticosteroids (e.g., glucocorticoids) bind to glucocorticoid receptors (GR) in the cytoplasm of the target cell. These receptors are part of the steroid hormone receptor family.
Upon binding, the receptor-ligand complex undergoes a conformational change, allowing it to translocate into the nucleus.
corticosteroid-receptor complex acts as a transcription factor by binding to specific DNA sequences known as glucocorticoid response elements (GREs) in the promoter regions of target genes.
This binding stimulates the transcription of anti-inflammatory genes. Specifically, the gene encoding Lipocortin-1 (also known as Annexin A1) is activated.
The DNA is transcribed into mRNA, which is then exported to the cytoplasm and translated into the Lipocortin protein.
Lipocortin acts as an inhibitor of phospholipase A2 (PLA2), the enzyme responsible for releasing arachidonic acid from membrane phospholipids.
Since arachidonic acid is the precursor for pro-inflammatory mediators like prostaglandins and leukotrienes, inhibiting PLA2 reduces inflammation.
check nice guidelines on the use of these drugs
how thioropurines help in CD treatment and other important information to know about thioropurines
Immunosuppressants used for induction of remission
Maintenance of remission after medically or surgically induced
remission
they have a slow onset(3 - 4 months)
Review after 4 years before considering stopping
dose should not be reduced to achieve remission
examples are;
Azathioprine: A prodrug for mercaptopurine
Mercaptopurine,Thioguanine
all thioropurines are pro drugs, true or false
true, so they are all metabolised to their active forms
Azathioprine is converted to 6-mercaptopurine (6-MP).
6-MP is further metabolized to active metabolites like 6-thioguanine nucleotides (6-TGNs).
what enzyme’s levels need to be assesed before using thioropurines, and why
thiopurine methyltransferase (TPMT) levels, if deficient or very low, do not use
to determine a patient’s risk of side effects and to ensure they can metabolize the drugs
note that the dose can be adjusted based on a patient’s TPMT levels
what is NF-κB (nuclear factor-κB) and describe it’s activity(or functions)
NF-κB is a key transcription factor involved in the expression of many pro-inflammatory genes
increased chemokine release
Increased adhesion molecule expression on endothelium
Increased anti-apoptotic factor production
Synthesis of inflammatory mediators
Transcription factors (TFs) are proteins that regulate gene activity by binding to DNA and controlling when and how genes are expressed
Annexin A1 and it’s functions
it is aka
it is a calcium-dependent protein that binds to cell membranes. it’s functions include;
Anti-inflammtion by promoting neutrophil detachment from adhesion molecules
and by Shedding adhesion molecules from endothelium, which makes it impossible for immune cells to attach to them
lipocortin-1
note that for immune cells to attach to endothelial cells, adhesion molecules need to be expressed on the endothelial cells, a mechanism that is aided by NF-κB
effects of corticosteroids on NF-κB and Annexin A1
they repress NF-kB, therefore preventing;
increased chemokine release
Increased adhesion molecule expression on endothelium
Increased antiapoptotic factor production
Synthesis of inflammatory mediators
they also upregulate AnnexinA1 function, thereby** promoting neutrophil detachment from adhesion molecules** and Shedding adhesion molecules from endothelium, reducing inflammation
Methotrexate cannot be used in UC, true or false
true
Methotrexate is an antimetabolite
major drawbacks in the use of methotrexate to treat CD
it is teratogenic
hepatic fibrosis
Risk of nephrotoxicity at high doses.
Teratogenic means relating to, or causing, developmental malformations in a fetus or embryo
describe the mechanism of action of methotrexate
Methotrexate is an antimetabolite.
▪A structural analog of tetrahydrofolate (FH4),
▪Inhibits dihydrofolate reductase (DFR1)
▪Prevents conversion of FH2 to FH4, blocking replenishment of the cellular
pools of FH4
▪FH4 is required for the synthesis of thymine and the purine bases used to
produce precursors of DNA
▪Thus FH4 is required for cell division
▪Blockage of thymine and purine base synthesis by folate deficiency, or drugs that interfere with folate metabolism, produces a decreased rate of cell division and growth
biologics like infliximab..etc are aka ?
anti-TNFs
anti-tumor necrosis factor drugs, are a type of biological therapy that treat inflammatory conditions by blocking the action of tumor necrosis factor (TNF)
TNF is a pro-inflammatory cytokine that drives inflammatory responses by inducing the expression of inflammatory genes and cell death. TNF is involved in many chronic inflammatory diseases, including rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease.
what is the maintenance period for biologics
every 8 weeks
some adverse effects of biologics
Infusion reactions and injection site reactions
▪Delayed hypersensitivity reactions
▪Infections-TB
▪Lymphoma-Hepatosplenic T cell lymphoma
▪Demyelinating illness
▪Congestive Heart failure
how does infliximab work
Infiximab is a chimeric MAb which neutralises TNFα comprised of:
mouse V region (25 %)
human C region of IgG1 (75 %)
Binds to and neutralises both soluble and membrane bound TNFα and blocks its interaction with the cell surface TNF-R’s(tnf receptors )
tnfa is a chemical messenger that triggers inflammation and plays a role in many inflammatory and autoimmune diseases:
is CD there is consistently raised TNFa, true or false
true, because there is a lot of inflammation in CD and TnFa mediates that
note that faecal concentrations of TNFa reflects disease severity, so the higher the concentrations, the more severe the disease
can humans develop antibodies against infliximab, give a reason for your answer
yes, certain patients develop antibodies against infliximab, and these antibodies are especially detectable after the fifth infliximab infusion.
this is because infliximab is made with human and mouse proteins, so the immune system tries to act against foreign activity in the patient’s body
how is immunogenicity of infliximab reduced
when immune system acts against infliximab
with immunosuppresive therapy
important points to know on adalimumab
efficient as second line therapy for patients with loss of response or intolenrance to infliximab
the first fully human monoclonal immunoglobulin directed against TNF-α,
▪binds with high affinity and specificity to membrane and soluble TNF.
▪administered subcutaneously
effective for inducing and maintaining remission in moderate to severe active chron’s disease
has lower immunogenicity than infliximab and theres
lower rates of adverse effects
read about the mechanisms of the other biologics on the slides please
state some important facts or information to know about ulcerative
it has a gradual onset
can begin at any stage in life, but peaks around 15-30yrs
presents with superficial inflammation of the colon, bloody diarrhoea, constipation and very rarely as toxic megacolon
has negligible risk of cancer in 1st 10years, but risk increases thereafter
responds well to total colectomy if drug therapy fails
megacolon a condition where the colon abnormally dilates, which can lead to a number of complication
toxic megacolon
symptoms associated with this
megacolon a condition where the colon abnormally dilates, which can lead to a number of complication
fever,
▪prostration,
▪severe pain,
▪dehydration
▪tachycardia
some signs and symptoms of UC
Bloody diarrhoea
▪Rectal bleeding
▪Faecal urgency
▪Nocturnal defecation
▪Abdominal pain – left lower quadrant
▪Weight loss
first line treatments for maintaining remission UC (where there is Proctitis and proctosigmoiditis) in descending order
a topical aminosalicylate alone (daily or intermittent) or
an oral aminosalicylate plus a topical aminosalicylate (daily or intermittent) or
an oral aminosalicylate alone, explaining that this may not be as effective as combined treatment or an intermittent topical aminosalicylate alone
why are oral aminosalicylates less effective than topical ones
Topical aminosalicylates are delivered directly to the affected area, particularly in the colon or rectum, where inflammation is most prominent. Oral aminosalicylates, on the other hand, need to be absorbed and then travel through the entire digestive tract before reaching the inflamed regions, which means they may not reach higher concentrations where they are needed most, especially in the rectum and distal colon.
step 1 therapy(first line treatment) for **acute severe UC in patients admitted to the hospital **
this is to induce remission
offer intravenous corticosteroids to induce remission and
assess the likelihood that the person will need surgery
remember to also take into account patient’s preference when giving treatment
step 2 therapy for **acute severe UC in patients admitted to the hospital **
Consider adding intravenous ciclosporin to intravenous corticosteroids or consider surgery for people:
who have little or no improvement within 72 hours of starting intravenous corticosteroids or
whose symptoms worsen at any time despite corticosteroid treatment.
state some classes of drugs used in the management of UC
aminosalicylates,
▪corticosteroids
▪immunosuppressants and/or
▪biologics
mechanism of action of ciclosporin
Ciclosporin binds to an intracellular protein, cyclophilin.
▪The ciclosporin-cyclophilin complex binds to calcineurin,enzyme vital to the transcription of several T-cell cytokines, including interleukin (IL)-2.
▪Inhibition of cytokine transcription results in specific and reversible inhibition of immunocompetent T-cell activation
T cells fail to make IL-2 or IFN.
Ciclosporin also makes the cells unable to express IL-2 receptors.
▪the T-helper (CD4) cell is the main target.
examples of aminosalicylates
sulfasalazine
mesalazine
balsalazide
olsalazine
general action is to work on the gut to reduce inflammation
first line treatment for mild to moderate UC
offer a topical aminosalicylate as first-line treatment.
