IBD 2 Flashcards
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)
What do TNF-alpha monoclonal antibodies do?
Induce T cell apoptosis
Attenuate proliferation and activation
Promote mucosal repair
Induce and maintain remission
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
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
What are the risks of using TNF-alpha antibodies?
Risk of immunogenicity
Infusion reactions (rash, fever, joint pain)
Decreased response over time (especially infliximab)
What is immunogenicity?
The ability of a foreign substance to provoke an immune response in the body
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
What is the immunogenicity of certolizumab?
It is 80% human complexed to polyethylene glycol
It has a decreased immunogenicity to infliximab
(Precise)
What is the immunogenicity of adalimumab?
It is fully human but antibodies can still develop due to genetic variation in human IgG1
(Classic)
Which form of monoclonal antibody achieves clinical remission?
IgG1 monoclonal antibodies
As the reduce systemic inflammation (CRP level) and mucosal healing
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
Which monoclonal antibody does not have an Fc domain?
Certolizumab
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
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
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
How much should serum infliximab levels be to maintain remission?
2 micrograms per mil or higher
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
What are the down sides to co administration of immunomodulators?
Possible risks of
Increased infection
Neurological disorders
Cancer
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
