IBD Pathophysiology

Question 1

Describe the epidemiology of Crohn’s disease: Prevalence, geography, sex, age

Answer 1

Prevalence: 26-200/100k (Rising)
Higher prevalence in Northern lattitudes
Even F:M ratio
Dx between 15-30 with another peak in 50-60s

Question 2

Describe the epidemiology of Ulcerative Colitis: geography, prevalence, age of onset, sex

Answer 2

North-south gradient
Rates of UC are stable
Age of onset similar
Even incidence between sexes

Question 3

Describe the function of NOD2. What is its significance

Answer 3

NOD2 recognizes bacterial MDP and binds peptidoglycans. It then up regulates NF-kB and MAPK signaling to modulate inflammation

Question 4

What is evidence for the role of microbiome in IBD? (4)

Answer 4

IBD does not occur in germ-free environment
Some pts with CD develop Ab to enteric flora proteins
Most common locations of CD are ileum/colon, where bacteria levels are highest
Abx appear to have potential benefit for some

Question 5

Which immune cell types are involved in IBD?

Answer 5

There is dysregulation of both Th1 and Th2- mediated response

Question 6

Which environmental factors are related to IBD? (4)

Answer 6

High SES
Dietary factors
Smoking: increases risk of CD; protective in UC
Stress

Question 7

What are goals of therapy in IBD?

Answer 7

Improvement in QOL, induce remission, avoid surgery, mucosal healing

Question 8

Which forms of IBD are “curable”?

Answer 8

UC can be cured with colectomy. Crohn’s is not curable

Question 9

What factors warrant more aggressive early therapy? (5)

Answer 9

Tobacco use (for Crohn’s)
Perianal or penetrating disease
Requirement for steroids
Age

Question 10

What are recommended therapies for mild disease? (4)

Answer 10

Short course of glucocorticoids for initial induction of remission
5-ASAs for UC
Budesonide for CD
Topical steroids for distal disease

Question 11

What are recommend therapies for moderate to severe disease?

Answer 11

Immunomodulators: thiopurine antimetabolites and methotrexate
Biologics: anti-TNF, anti-alpha4, anti-cell signaling molecules

Question 12

What are different preparations of melamine that have been developed? (4)

Answer 12

pH dependent systems
Diazo-bonded systems with bacterial release
Osalazine (double 5-ASAs)
Belsalazide (inert carrier)

Question 13

What is MOA of ASAs?

Answer 13

Anti-inflammatory==>inhibition of T cell proliferation, antigen presentation, leukocyte adhesion, decreased TNF production

Question 14

What is use for ASAs? What are AEs? (2)

Answer 14

Beneficial in UC, not in Crohn’s.

AEs: Paradoxical diarrhea, interstitial nephritis

Question 15

What is clinical use for glucocorticoids in IBD?

Answer 15

Mainstay in induction of remission, but not useful in maintenance of remission

Question 16

What are AE associated with glucocorticoid use? (long list)

Answer 16

Neuropsychiatric, Cushingoid, myopathy, glucose intolerance, infection, wound healing, hirsutism, bon effects, hypertension

Question 17

What is budesonide? What are the reasons for its use?

Answer 17

Novel steroid compound with ileal or colonic release formulations.

High degree of first-pass lessens system side effects
Standard initial therapy

Question 18

What is MOA of immunomodulators?

Answer 18

Both azathioprine and 6MP inhibit DNA synthesis

Question 19

What is role of TPMT polymorphism in azathioprine/6MP?

Answer 19

1/300 have a reduced TPMT activity==>shunts AZA/6MP to an active metabolite 6-TGN, which markedly increases side effects

Question 20

Describe the use and efficacy for thiopurines

Answer 20

Induction and maintenance of remission of CD

Reduces steroid utilization

Question 21

What are AE of thiopurines? (5)

Answer 21

Leukopenia/marrow suppression
Pancreatitis
Drug-induced hepatitis 
Infection
Malignancy

Question 22

What is mechanism of methotrexate?

Described its efficacy

Answer 22

Folate antagonist that carriers anti-inflammatory properties

It’s effective in induction/maintenance of remission in Crohn’s; being evaluated for UC

Question 23

What are AE of methotrexate? (6)

Answer 23

Nausea
Hepatic fibrosis
Teratogenic
Marrow suppression
Infection
Pneumonitis

Question 24

What is mechanism of anti-TNF therapy?

Answer 24

Bind soluble/cell-bound TNF-a and inhibit.
Induce apoptosis of T cells and lymphocytes in lamina propria
Alter cyotkine secretion in serum

Question 25

What is approved use for anti-TNF therapy?

Answer 25

Induction and maintenance of remission in Crohn’s and UC

Question 26

What are AE for anti-TNF therapy? (4)

Answer 26

Transfusion reactions or delayed hypersensitivity reactons
Drug-induced lupus
Infection
Malignancy

Question 27

What is the use for anti-alpha4 inhibitors?

Answer 27

Natalizumab– benefit for MS also induction and maintenance of remission in Crohn’s

Question 28

What is major risk of natalizumab? How is it managed?

Answer 28

Increased risk of progressive multifocal leukoencephalopathy.

Screen for JC virus

Question 29

What is advantage of vedolizumab?

Answer 29

No PML risk

Approved for use in both CD/UC