Lecture 29 - TNF Treatment Flashcards
Cells that synthesise TNFa
1)
2)
1) Activated macrophages
2) T cells
TNF receptors
1)
2)
1) TNFR1 (p55)
2) TNFR2 (p75)
TNF cytokine-dependent cascade in RA
1) a, b, c
2) a, b, c
3)
1) Anti-inflammatory
a) IL-1ra
b) IL-10
c) sTNF-R
2) Pro-inflammatory
a) IL-6
b) IL-8
c) GM-CSF
3) TNFa stimulates IL-1 release, which also stimulates the anti- and pro-inflammatory pathways
IL-1ra
IL-1 receptor antagonist
sTNF-R
Soluble TNF receptor
How was the role of TNF in RA synovial inflammation proven?
1)
2)
1) Addition of anti-TNF antibody reduced joint inflammation, protected joint structures in model (hamster) systems
2) hTNF.Tg mice have erosive polyarthritis
Is the efficacy of anti-TNF treatments dose-dependent?
Yes. Efficacy increases with dose
First human clinical study of anti-TNF antibodies 1) 2) 3) 4)
1) 1992, in Charing Cross Hospital
2) Open, non-placebo controlled design
3) 20 long-standing patients, all refractory to other treatment
4) Reduced inflammation, no adverse events
Histology of RA synovium before and after anti-TNF therapy
Before - CD68+ macrophage infiltrate
After - No CD68+ macrophages
Infliximab 1) 2) 3) 4)
1) Chimeric human/mouse
2) Human IgG1 constant region
3) Mouse variable region
4) Anti-TNFa
Etanercept
1)
2)
3)
1) Fusion protein
2) Two p75 TNFa receptors
3) Receptors bound to a human IgG1 constant region
Adalimumab
1)
2)
1) Fully humanised monoclonal antibody
2) Human IgG1 constant and variable regions
Certolizumab pegol
1)
2)
3)
1) Humanised monoclonal antibody
2) Antigen binding fragment (Fab’)
3) Fab’ bound to polyethylene glycol (PEG)
Golimumab
Human IgG1 kappa monoclonal antibody
Anti-TNF RA treatments 1) 2) 3) 4) 5)
1) Infliximab
2) Etanercept
3) Adalimumab
4) Certolizumab pegol
5) Golimumab
American college of rheumatology 20% improvement criteria
1) a, b
2) a, b, c, d, e
1) At least 20% improvement in:
a) Swollen joint counts
b) Tender joint counts
2) Three of the following five variables:
a) Patient-assessed global disease activity
b) Evaluator-assessed global disease activity
c) Patient pain assessment
d) Functional disability
e) Acute phase response
60-40-20 rule
Only 60% of patients meet ACR20 improvement criteria.
Of this 60%, only 40% reach ACR50.
Of this 40%, only 20% reach ACR70
Etanercept administration
Weekly injection
PEGylation
Makes Fab’ fragment last longer in plasma
Only have to administer once avery 28 days
Odds ratio
1)
2)
3)
1) Measure of association between an exposure and an outcome
2) If above one, means that an outcome is more likely after exposure.
3) If below one, means that an outcome is less likely after exposure
Anakinra performance in comparing ACR50 of Anakinra vs placebo
Anakinra error bars cross odds ratio=1.
This means that some patients had worse symptoms after taking Anakinra
In comparing ACR50 responses of DMARDs and bDMARDs, which drugs were as effective or more effective than Methotrexate?
1) Tocilizumab (as effective)
2) Adalimumab (as effective)
3) Certolizumab pegol (more effective)
Primary failure of a drug
Patient condition doesn’t improve. Drug has no effect
Implications of a primary failure of a TNFa inhibitor
TNFa not causative agent of RA in patient
Secondary failure of a drug
Drug loses efficacy over time
Implications of a secondary failure of a TNFa inhibitor
Neutralising antibodies.
These are either human anti-chimaeric antibodies (against infliximab), or human anti-human antibodies
Drug survival
How long a patient uses a drug for
Best to worst drug survival between Etanercept, Adalimumab and Infliximab
1) Etanercept
2) Adalimumab
3) Infliximab
Dangers of anti-TNFa drugs 1) 2) 3) 4) 5) 6) 7)
1) Administration (infusion, injection site reactions)
2) Neutropaenia
3) URT/soft-tissue infections
4) Demyelinating disease
5) Exacerbates risk of heart disease in NYHA 3 and 4 patients
6) Non-melanoma, lymphoma malignancies
7) Induction of autoimmunity (psoriasis, systemic lupus erythematosus)
Tofacitinimib
Janus Kinase (JAK) inhibitor Small-molecule inhibitor treatment for RA
Abatacept vs Adalimumab trial
1)
2)
1) Comparable efficacy at 12 months
2) Adalimumab has more injection-site adverse reactions
Tocilizumab vs Adalimumab monotherapy
1)
2) a, b, c
1) Tocilizumab superior in reducing DAS28 at 6 month mark
2) Tocilizumab had more adverse reactions
a) Increase cytopaenia (decrease neutrophils, platelets)
b) Increase LDL-cholesterol
c) Increase alanine transaminase
On whom was the Tocilizumab vs Adalimumab test carried out on?
Methotrexate inadequate responders (MTX-IR)
What does Tofacitinib preferentially inhibit?
Janus Kinase (JAK) 1 and 3
Janus Kinase role
1) a, b, c,
1) Intracellular signal transduction critical for:
a) Immune cell activation
b) Proinflammatory cytokine production necessary for lymphocyte activation
c) Cytokine signalling involved in RA pathology
Where does Tofacitinib act?
Intracellularly, blocking JAK 1 and 3
JAK inhibitor RA treatment
Tofacitinib
Tofacitinib phase III trial results 1) 2) 3) 4) 5)
1) Superior to placebo
2) Effective in treating methotrexate inadequate-responders
3) Safe in combination with methotrexate
4) Comparable efficacy to Adalimumab
5) Treatment alternative to TNFa inadequate responder patients
Tofacitinib adverse reactions 1) 2) 3) 4) 5)
1) Headaches
2) URT, urinary tract infections
3) Elevated LDL and HDL cholesterol levels
4) Neutropaenia
5) Opportunistic infections (EG: TB)
