IBD 2

Question 1

Give some example some examples of TNF-alpha monoclonal antibodies

Answer 1

Infliximab (mouse-human chimeric, I.v)
Certolizumab pegol (80% human complexed to polyethylene glycol, s.c)
Adalimumab and golimumab (fully human, s.c)

Question 2

What do TNF-alpha monoclonal antibodies do?

Answer 2

Induce T cell apoptosis
Attenuate proliferation and activation
Promote mucosal repair
Induce and maintain remission

Question 3

What are the side effects of TNF-alpha monoclonal antibodies?

Answer 3

Nausea
Abdominal pain
Headache
Risk of T cell lymphoma (not truly greater that other IBD treatments?)
Possible reactivation of latent tuberculosis and viral infections

Question 4

When should TNF-alpha antibodies not be used?

Answer 4

I’m heart failure
Someone who has an autoimmune condition infection prescreening is recommended, with prophylaxis and vaccines

Question 5

What are the risks of using TNF-alpha antibodies?

Answer 5

Risk of immunogenicity
Infusion reactions (rash, fever, joint pain)
Decreased response over time (especially infliximab)

Question 6

What is immunogenicity?

Answer 6

The ability of a foreign substance to provoke an immune response in the body

Question 7

Describe immunogenicity of infliximab

Answer 7

Mouse part (25%) recognises human TNF-alpha but antibodies develop to this part of the antibody
Human part (75%) reduces immunogenicity

Question 8

What is the immunogenicity of certolizumab?

Answer 8

It is 80% human complexed to polyethylene glycol
It has a decreased immunogenicity to infliximab
(Precise)

Question 9

What is the immunogenicity of adalimumab?

Answer 9

It is fully human but antibodies can still develop due to genetic variation in human IgG1
(Classic)

Question 10

Which form of monoclonal antibody achieves clinical remission?

Answer 10

IgG1 monoclonal antibodies
As the reduce systemic inflammation (CRP level) and mucosal healing

Question 11

Is the Fc domain of a monoclonal antibody important?

Answer 11

Antibodies lacking this domain have reduced side effects but are also less clinically effective
It may be necessary for induction of wound healing macrophages

Question 12

Which monoclonal antibody does not have an Fc domain?

Answer 12

Certolizumab

Question 13

When are monoclonal antibodies used?

Answer 13

Initially they were only used as a last resort when conventional therapies didn’t work
Now they are used in the beginning stages of the disease to reduce the disease progression and limit its effects on the body

Question 14

What is the treatment plan for monoclonal antibodies

Answer 14

Normally 12 months treatment (or until treatment fails)
Reassessed for maintained response before returning to the treatment

Question 15

What do matrix metaloproteases do?

Answer 15

Causes cleavage of the antibody and potential loss of the acc binding site in inflamed tissues
Could explain reduced efficacy over time

Question 16

How much should serum infliximab levels be to maintain remission?

Answer 16

2 micrograms per mil or higher

Question 17

How can the response of monoclonal antibodies be enhanced?

Answer 17

With the Co administration of an immunomodulator to prevent antibodies forming to the monoclonal antibody treatment

Question 18

What are the down sides to co administration of immunomodulators?

Answer 18

Possible risks of
Increased infection
Neurological disorders
Cancer

Question 19

What guidance is given when taking immunomodulators with monoclonal antibodies?

Answer 19

Discontinue the modulator if remission has lasted longer than a year

Question 20

Name the other cytokine based therapies used to tackle IBD

Answer 20

Recombinant human TNF alpha soluble receptors
Anti inflammatory cytokines
Pro inflammatory cytokines

Question 21

What are recombinant human TNF alpha soluble receptors?

Answer 21

Cytokines based therapy
Fusion of the protein part of extracellular part of human type ll TNF receptor and human IgG1Fc fragment
Fusion protein lacks hinge and less flexible than antibody

Question 22

Describe soluble TNF alpha receptors

Answer 22

Prevent apoptosis in infiltrating cells and promote ventricular rupture and remodelling after myocardial infarction

Question 23

What do TNF alpha soluble receptors do?

Answer 23

To mop up any extracellular TNF alpha and stop it binding to a functional receptor to mediate a physiological response

Question 24

What is the success of the TNF alpha soluble receptors?

Answer 24

Disappointing clinical trial results
More success seen in treating rheumatoid arthritis

Question 25

Why have clinical results of TNF alpha soluble receptors been disappointing?

Answer 25

There are two TNF alpha receptors (l and ll)
The strategy was intended to target receptor ll
The soluble receptors will more readily bind to the soluble form of TNF alpha which usually binds to the type l receptor while the soluble receptors are based on the type ll receptors for membrane bound TNF alpha

Question 26

What are the differences between TNF l and TNF ll?

Answer 26

1 - mainly for soluble TNF alpha
Activates caspase 8, pro apoptotic pathways
Activates NFKB transcription, innate immunity, anti apoptotic pathways
2 - mainly for membrane bound TNF alpha
Only activates the NFKB and anti apoptotic pathways

Question 27

What is interleukin IL-10?

Answer 27

A human recombinant anti inflammatory cytokine

Question 28

What does IL-10 do?

Answer 28

Promotes protective T helper 3 cells and T regulatory 1 cells
Disappointing to date
Trying to optimise dose and drug delivery

Question 29

What antibodies have been developed for pro inflammatory cytokines?

Answer 29

Anti IL-2, IL-12, IL-18, IL-23
Interferon gamma antibodies

Question 30

How do antibodies for pro inflammatory cytokines help?

Answer 30

Influence T cell differentiation, T helper 1&2 signalling pathways
Primary results are promising

Question 31

What drugs target the adhesion molecules of the endothelium and the integrins of T lymphocytes?

Answer 31

Alpha 4 integrin (natalizumab)
Alpha 4 beta 7 integrin (vedolizamab)

Question 32

What was the down side associated with natalizumab?

Answer 32

An increased risk of opportunistic infections

Question 33

What receptors do natalizumab target?

Answer 33

Alpha 4 beta 1 as well as alpha 4 beta 7
A4B1 - influences trafficking of leukocytes through the BBB and alters the ratio of CD4+ and CD8+ cells in cerebrospinal fluid
Risk of progressive multi focal leukoencephalopathy

Question 34

What is progressive multi focal leukoencephalopathy?

Answer 34

An opportunistic brain infection due to reactivation of latent John Cunningham polyomavirus

Question 35

What does vedolizamab target?

Answer 35

It is more selective and will only target alpha 4 beta 7 integrins meaning it only influence leukocyte trafficking in the intestine and not across the BBB
This integrin specifically interacts with mucosal addression cell adhesion molecule 1 (MadCam-1)

Question 36

What is a different adhesion molecule / integrin based therapy?

Answer 36

Antisense oligonucleotides to adhesion molecules (ICAM-1)

Question 37

What novel therapies are being developed for IBD?

Answer 37

PDE4 inhibitors
TRPV4 channel inhibitors
Granulocyte macrophage colony stimulating factor
Recombinant human epidermal growth factor
JAK kinase inhibitors
Chemokine receptor CCR9 inhibitors

Question 38

What do PDE4 inhibitors do?

Answer 38

Cilomilast and roflumilast
Increase cAMP levels
Reduce pro inflammatory and tissue destructive effects of leukocytes

Question 39

What do TRPV4 channel inhibitors do?

Answer 39

Possibly inhibit pro inflammatory signalling pathways

Question 40

What is granulocyte macrophage colony stimulating factor?

Answer 40

A growth factor that has been found to augment innate immune defence mechanisms

Question 41

How does recombinant human epidermal growth factor help in IBD?

Answer 41

Preserves
epithelial barrier function
Innate immunity
Influences T lymphocyte migration
Promotes healing

Question 42

Name the JAK kinase inhibitor and how it works

Answer 42

Tofactinib
It is a small molecule inhibitor not an antibody therefore there is no risk of immunogenicity
It reduces signalling by multiple cytokine receptors

Question 43

Why is intestinal flora so important?

Answer 43

It is involved in
The fine tuning of immune responses
Epithelium signalling
Neuromuscular activity
Nutrient production
Metabolism of dietary carcinogens and prodrugs

Question 44

What are the results surrounding the effects of probiotics?

Answer 44

There is both positive and negative results from clinical trials surrounding the use of probiotics
However the bacteria can be genetically engineered to deliver therapeutic molecules locally to the intestinal mucosa

Question 45

What are the miscellaneous stats Evie’s for treating IBD?

Answer 45

Dietary manipulation or supplementation
Benefits of a low FODMAP diet?
Omega 3 fatty acids contained in fish and oils
Restrict NSAIDs and Coxibs
Use care with opioids to avoid toxic megacolon

Question 46

What are the surgical interventions for Crohn’s?

Answer 46

Bowel resection for intestinal obstruction
Drainage of abscesses
Temporary ileostomy to rest bowel, reduce inflammation, increases effectiveness of medical therapy

Question 47

What surgical intervention is there for ulcerative colitis?

Answer 47

Colectomy
This is the resection of the large intestine
Can be partial or full (the entire large intestine is removed)
Proctocolectomy means’s the rectum is included