IBD 2 Flashcards by Rachael Christie

Give some example some examples of TNF-alpha monoclonal antibodies

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

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What do TNF-alpha monoclonal antibodies do?

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

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

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

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When should TNF-alpha antibodies not be used?

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

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What are the risks of using TNF-alpha antibodies?

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

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What is immunogenicity?

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

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Describe immunogenicity of infliximab

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

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What is the immunogenicity of certolizumab?

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

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What is the immunogenicity of adalimumab?

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

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Which form of monoclonal antibody achieves clinical remission?

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

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Is the Fc domain of a monoclonal antibody important?

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

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Which monoclonal antibody does not have an Fc domain?

Certolizumab

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When are monoclonal antibodies used?

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

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What is the treatment plan for monoclonal antibodies

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

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What do matrix metaloproteases do?

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

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How much should serum infliximab levels be to maintain remission?

2 micrograms per mil or higher

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How can the response of monoclonal antibodies be enhanced?

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

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What are the down sides to co administration of immunomodulators?

Possible risks of
Increased infection
Neurological disorders
Cancer

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What guidance is given when taking immunomodulators with monoclonal antibodies?

Discontinue the modulator if remission has lasted longer than a year

Name the other cytokine based therapies used to tackle IBD

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

What are recombinant human TNF alpha soluble receptors?

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

Describe soluble TNF alpha receptors

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

What do TNF alpha soluble receptors do?

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

What is the success of the TNF alpha soluble receptors?

Disappointing clinical trial results
More success seen in treating rheumatoid arthritis

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

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

What are the differences between TNF l and TNF ll?

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

What is interleukin IL-10?

A human recombinant anti inflammatory cytokine

What does IL-10 do?

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

What antibodies have been developed for pro inflammatory cytokines?

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

How do antibodies for pro inflammatory cytokines help?

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

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

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

What was the down side associated with natalizumab?

An increased risk of opportunistic infections

What receptors do natalizumab target?

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

What is progressive multi focal leukoencephalopathy?

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

What does vedolizamab target?

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)

What is a different adhesion molecule / integrin based therapy?

Antisense oligonucleotides to adhesion molecules (ICAM-1)

What novel therapies are being developed for IBD?

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

What do PDE4 inhibitors do?

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

What do TRPV4 channel inhibitors do?

Possibly inhibit pro inflammatory signalling pathways

What is granulocyte macrophage colony stimulating factor?

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

How does recombinant human epidermal growth factor help in IBD?

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

Name the JAK kinase inhibitor and how it works

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

Why is intestinal flora so important?

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

What are the results surrounding the effects of probiotics?

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

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

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

What are the surgical interventions for Crohn’s?

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

What surgical intervention is there for ulcerative colitis?

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