Crohns and ulcerative colitis

Question 1

Are there only two categories of IBD?

Answer 1

not necessarily, UC and CD are the main ones (polygenic) and like subcategories within them- and overlap between them.
But you also have early onset monogenic IBD.

Question 2

what are typical presentations of CD?

Answer 2

persistent abdominal pain
non-bloody diarrhea
weight loss
perianal disease (fistulas and fissures)

Question 3

what are typical presentations of UC?

Answer 3

short-lived cramps and abdominal pain
urgency to relieve themselves due to rectal inflammation.
blood and mucus in stools are seen in 96% of flares.

Question 4

what sites of the Tract does CD affect?

Answer 4

anywhere from mouth to anus-

Often patchy inflammation of ileum, colon and ileo-colon area.

Question 5

What sites of the tract does UC affect?

Answer 5

Large portion of the colon (large bowel).

Question 6

How does inflammation and crypt presentation differ in CD and UC?

Answer 6

CD: inflammation can be deep and transmural
UC: inflammation is mucosal
CD: crypt is intact, but granulomas may be present.
U: crypts are distorted.

Question 7

What complications can you see in CD and UC?

Answer 7

CD: ulcers, rashes and may overlap with ankylosing spondylitis.

UC: link with primary sclerosing cholangitis (PSC) and increased risk of bowel cancer.

Question 8

what does PSC cause in UC?

Answer 8

affects the bile ducts, and leads to inflammation and strictures, increased risk of bowel cancer.

Question 9

what is the age of onset like in both UC and CD?

Answer 9

younger preponderance (in UC may be due to protectiveness of smoking?)

Question 10

What risks does smoking carry for UC and CD?

Answer 10

smoking increases risk of CD but decreases UC risk and progression.

Question 11

What is most well-established therapy for monogenic and polygenic IBD?

Answer 11

HSCT can be for monogenic IBD

anti-TNFa (infliximab and adalimumab) for polygenic

Question 12

What is the genetic concordance like for CD and UC patients in monozygotic twins?

Answer 12

CD: 40-45%

Uc-15-20%

Question 13

What risk alleles affecting autophagy are thoguht to increase susceptibility to IBD in polygenic IBD?

Answer 13

NOD2 risk alleles, as well as ATG16C1 (and IRGM)

Question 14

why might NOD2 risk alleles increase susceptibility to IBD?

Answer 14

NOD2 normally detects intracellular peptidoglycan and stimulates xenophagy, so increased microbial load in these patients if this is defective

(monogenic disease-causing IBD that affects autophagy is Nieman pick type C- although mainly has neurological defects)

Question 15

There is alot of overlap in genetic risk alleles for UC and CD, which notable allele predisposes to both and each individually?

Answer 15

Those involved in the Th17 pathway: Il-23R (Il-12p40 and STAT3 (activation enhances Th17 survial)) predisposes to both.

NOD2 alleles only associated withCD.

HLA risk alleles only associated with UC.

Question 16

What can affect microflora at young age, what can predispose children to later IBD?

Answer 16

Colonisation by skin or vaginal flora.

Multiple courses of antibiotics when young can alter the microbiome and increase IBD risk.

Question 17

4 Indications that microbiome is important for disease and IBD?

Answer 17

Germ-free mice don’t develop the disease in mouse models for type 1 diabetes, EAE and IBD.

you can transfer colitis with the transfer of the microbiome from a mouse with colitis.

antibiotics can ameliorate disease.
Faecal stream diversion is effective.

Question 18

what complications can arise because CD has a transmural inflammation?

Answer 18

Can cause ulcers, perforation and leakage in the peritoneum.

Fistulas.

Question 19

2 aims of treatment?

Answer 19

To improve quality of life

Control inflammation which can increase risk of bowel cancer and CD progression.

Question 20

what progression in CD can be seen if inflammation isn’t controlled?

Answer 20

fibrosis and narrowing of bowel leading to strictures and fistulas and surgery- repeats.

Question 21

Although not a risk of strictures in UC what risk is there if inflammation not controlled?

Answer 21

risk of bowel cancer higher.

risk of sclerosing cholangitis (fibrosis and naroorwing of biliary ducts).

Question 22

How can you maximise the benefit from inflixmab and adalimumab?

Answer 22

With earlier use of therapies- improved remission.

Reduce risk of antibodies against biologics with co-administration of immunodulators.

Question 23

what is an anti-IL-6 monoclonal used in COVID treatment?

Answer 23

tocilizumab.

Question 24

What drug is currently used to disrupt the IL-17 axis in IBD?

Answer 24

ustekinumab which non specifically targets p40 subunit of IL-23R and Il12R.

Question 25

What is the benefit of ustekinumab vs infliximab?

Answer 25

no anti biologic antibodies generated, dose stays more constant over time and no need for extra immunomodulatory drug.

Question 26

what broad JAK inhibitor has been tried in IBD which affects multiple cytokine pathways?

Answer 26

tofacitinib- targets JAKs to prevent STAT posphorylation in IL2,4 7,9 15 adn 21 (all with the common y chain?

Question 27

what is the non-specific anti-trafficking agent licensed in America (not UK) for IBD, and also for MS?

Answer 27

Natalizumab, anti- a4B1/7 integrin (leukocyte trafficking to gut and brain).

Question 28

What receptor does a4B1 integrins on leukocytes bind to on endothelial cells?

Answer 28

Binds to VCAM-1 on endothelial cells.

Question 29

What do a4b7 integrins on leukocytes bind to on endothelial cells specific for gut migration?

Answer 29

Binds to MAdCAM1 on gut endothelial cells

Question 30

What does the integrin aEB7 on leukocytes bind to?

Answer 30

E-cadherin on epithelial cells.

Question 31

What drug instead of natalizumab binds specifically to a4B7?

Answer 31

vedolizumab binds to a4B7 integrins to prevent leukocyte adhesion to gut-specific MAdCAM1.

Question 32

What fatal disease does natalizumab increase the risk of?

Answer 32

PML caused by john cunningham virus.

Question 33

what future drugs may target the p19 subunit of Il23 specifically? Indications may be effective?

Answer 33

risankizumab and mirikizumab.

Has proved more effective for psoriasis.

Question 34

What neglected Th17 cytokine is there and drug for it?

Answer 34

oncostatin M- anti OS-M drugs.

Question 35

Why aren’t anti-Il17 drugs used?

Answer 35

Although effective in Ankolysing s. and psoriasis, caused a worsening of disease and CD development in AS.

Question 36

Two other future drugs that are anti-trafficking?

Answer 36

Etrolizumab (anti integrin for gut)

anti SIP1 Etrasimod, prevents recirculation of lymphocytes from local lymph nodes.