Inflammatory Bowel Disease

Question 1

colitis

Answer 1

a digestive disease that involves inflammation of the colon, or large intestine

could be acute or chronic

Question 2

some of the most common forms of IBD

Answer 2

Chron’s disease
Ulcerative colitis
Intermediate colitis

Question 3

intermediate colitis

Answer 3

types of colitis which do not present with enough of the criterion for CD or UC to enable them to be
classified.

Question 4

some common/similar features of Chron’s and Ulcerative colitis

Answer 4

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

Question 5

key differences between UC and Chron’s

Answer 5

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.

Question 6

chron’s disease

Answer 6

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

Question 7

main symptoms of chron’s

Answer 7

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

Question 8

pathophysiology of Chron’s

pathophysiology the disordered physiological processes associated with disease or injury

Answer 8

• 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

Question 9

transmural inflammation in CD

Answer 9

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

Question 10

local complications of CD

Answer 10

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

Question 11

the cause of chron’s disease is unknown, true or false

Answer 11

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

Question 12

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

Answer 12

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

Question 13

how do we investigate chron’s

Answer 13

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

Question 14

which test helps different between IBS and IBD and how does it do this

Answer 14

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)

Question 15

the aims of treatment in chron’s

Answer 15

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

Question 16

management of CD according to NICE

Answer 16

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

Question 17

describe how drug therapy is used in the “step-up” method to treat CD, and the different drugs involved in each step

Answer 17

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

Question 18

can corticosteroids be used as maintenance therapy in CD

Answer 18

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

Question 19

How is PLA2 inhibition induced.

Answer 19

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.

Question 20

check nice guidelines on the use of these drugs

how thioropurines help in CD treatment and other important information to know about thioropurines

Answer 20

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

Question 21

all thioropurines are pro drugs, true or false

Answer 21

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).

Question 22

what enzyme’s levels need to be assesed before using thioropurines, and why

Answer 22

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

Question 23

what is NF-κB (nuclear factor-κB) and describe it’s activity(or functions)

Answer 23

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

Question 24

Annexin A1 and it’s functions

it is aka

Answer 24

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

Question 25

effects of corticosteroids on NF-κB and Annexin A1

Answer 25

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

Question 26

Methotrexate cannot be used in UC, true or false

Answer 26

true

Methotrexate is an antimetabolite

Question 27

major drawbacks in the use of methotrexate to treat CD

Answer 27

it is teratogenic
hepatic fibrosis
Risk of nephrotoxicity at high doses.

Teratogenic means relating to, or causing, developmental malformations in a fetus or embryo

Question 28

describe the mechanism of action of methotrexate

Answer 28

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

Question 29

biologics like infliximab..etc are aka ?

Answer 29

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.

Question 30

what is the maintenance period for biologics

Answer 30

every 8 weeks

Question 31

some adverse effects of biologics

Answer 31

Infusion reactions and injection site reactions
▪Delayed hypersensitivity reactions
▪Infections-TB
▪Lymphoma-Hepatosplenic T cell lymphoma
▪Demyelinating illness
▪Congestive Heart failure

Question 32

how does infliximab work

Answer 32

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:

Question 33

is CD there is consistently raised TNFa, true or false

Answer 33

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

Question 34

can humans develop antibodies against infliximab, give a reason for your answer

Answer 34

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

Question 37

how is immunogenicity of infliximab reduced

when immune system acts against infliximab

Answer 37

with immunosuppresive therapy

Question 38

important points to know on adalimumab

Answer 38

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

Question 39

state some important facts or information to know about ulcerative

Answer 39

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

Question 40

toxic megacolon

symptoms associated with this

Answer 40

megacolon a condition where the colon abnormally dilates, which can lead to a number of complication

fever,
▪prostration,
▪severe pain,
▪dehydration
▪tachycardia

Question 41

some signs and symptoms of UC

Answer 41

Bloody diarrhoea
▪Rectal bleeding
▪Faecal urgency
▪Nocturnal defecation
▪Abdominal pain – left lower quadrant
▪Weight loss

Question 42

first line treatments for maintaining remission UC (where there is Proctitis and proctosigmoiditis) in descending order

Answer 42

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

Question 43

why are oral aminosalicylates less effective than topical ones

Answer 43

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.

Question 44

step 1 therapy(first line treatment) for **acute severe UC in patients admitted to the hospital **

this is to induce remission

Answer 44

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

Question 45

step 2 therapy for **acute severe UC in patients admitted to the hospital **

Answer 45

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.

Question 46

state some classes of drugs used in the management of UC

Answer 46

aminosalicylates,
▪corticosteroids
▪immunosuppressants and/or
▪biologics

Question 47

mechanism of action of ciclosporin

Answer 47

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.

Question 48

examples of aminosalicylates

Answer 48

sulfasalazine

mesalazine

balsalazide

olsalazine

general action is to work on the gut to reduce inflammation

Question 49

first line treatment for mild to moderate UC

Answer 49

offer a topical aminosalicylate as first-line treatment.