Lecture 29 - TNF Treatment Flashcards Preview

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Flashcards in Lecture 29 - TNF Treatment Deck (39):
1

Cells that synthesise TNFa
1)
2)

1) Activated macrophages
2) T cells

2

TNF receptors
1)
2)

1) TNFR1 (p55)
2) TNFR2 (p75)

3

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

4

IL-1ra

IL-1 receptor antagonist

5

sTNF-R

Soluble TNF receptor

6

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

7

Is the efficacy of anti-TNF treatments dose-dependent?

Yes. Efficacy increases with dose

8

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

9

Histology of RA synovium before and after anti-TNF therapy

Before - CD68+ macrophage infiltrate
After - No CD68+ macrophages

10

Infliximab
1)
2)
3)
4)

1) Chimeric human/mouse
2) Human IgG1 constant region
3) Mouse variable region
4) Anti-TNFa

11

Etanercept
1)
2)
3)

1) Fusion protein
2) Two p75 TNFa receptors
3) Receptors bound to a human IgG1 constant region

12

Adalimumab
1)
2)

1) Fully humanised monoclonal antibody
2) Human IgG1 constant and variable regions

13

Certolizumab pegol
1)
2)
3)

1) Humanised monoclonal antibody
2) Antigen binding fragment (Fab')
3) Fab' bound to polyethylene glycol (PEG)

14

Golimumab

Human IgG1 kappa monoclonal antibody

15

Anti-TNF RA treatments
1)
2)
3)
4)
5)

1) Infliximab
2) Etanercept
3) Adalimumab
4) Certolizumab pegol
5) Golimumab

16

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

17

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

18

Etanercept administration

Weekly injection

19

PEGylation

Makes Fab' fragment last longer in plasma
Only have to administer once avery 28 days

20

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

21

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

22

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)

23

Primary failure of a drug

Patient condition doesn't improve. Drug has no effect

24

Implications of a primary failure of a TNFa inhibitor

TNFa not causative agent of RA in patient

25

Secondary failure of a drug

Drug loses efficacy over time

26

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

27

Drug survival

How long a patient uses a drug for

28

Best to worst drug survival between Etanercept, Adalimumab and Infliximab

1) Etanercept
2) Adalimumab
3) Infliximab

29

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)

30

Tofacitinimib

Janus Kinase (JAK) inhibitor
Small-molecule inhibitor treatment for RA

31

Abatacept vs Adalimumab trial
1)
2)

1) Comparable efficacy at 12 months
2) Adalimumab has more injection-site adverse reactions

32

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

33

On whom was the Tocilizumab vs Adalimumab test carried out on?

Methotrexate inadequate responders (MTX-IR)

34

What does Tofacitinib preferentially inhibit?

Janus Kinase (JAK) 1 and 3

35

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

36

Where does Tofacitinib act?

Intracellularly, blocking JAK 1 and 3

37

JAK inhibitor RA treatment

Tofacitinib

38

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

39

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)