Lecture 29 - TNF Treatment

Question 1

Cells that synthesise TNFa
1)
2)

Answer 1

1) Activated macrophages

2) T cells

Question 2

TNF receptors
1)
2)

Answer 2

1) TNFR1 (p55)

2) TNFR2 (p75)

Question 3

TNF cytokine-dependent cascade in RA
1) a, b, c
2) a, b, c
3)

Answer 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

Question 4

IL-1ra

Answer 4

IL-1 receptor antagonist

Question 5

sTNF-R

Answer 5

Soluble TNF receptor

Question 6

How was the role of TNF in RA synovial inflammation proven?
1)
2)

Answer 6

1) Addition of anti-TNF antibody reduced joint inflammation, protected joint structures in model (hamster) systems
2) hTNF.Tg mice have erosive polyarthritis

Question 7

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

Answer 7

Yes. Efficacy increases with dose

Question 8

First human clinical study of anti-TNF antibodies
1)
2)
3)
4)

Answer 8

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

Question 9

Histology of RA synovium before and after anti-TNF therapy

Answer 9

Before - CD68+ macrophage infiltrate

After - No CD68+ macrophages

Question 10

Infliximab
1)
2)
3)
4)

Answer 10

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

Question 11

Etanercept
1)
2)
3)

Answer 11

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

Question 12

Adalimumab
1)
2)

Answer 12

1) Fully humanised monoclonal antibody

2) Human IgG1 constant and variable regions

Question 13

Certolizumab pegol
1)
2)
3)

Answer 13

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

Question 14

Golimumab

Answer 14

Human IgG1 kappa monoclonal antibody

Question 15

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

Answer 15

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

Question 16

American college of rheumatology 20% improvement criteria

1) a, b
2) a, b, c, d, e

Answer 16

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

Question 17

60-40-20 rule

Answer 17

Only 60% of patients meet ACR20 improvement criteria.
Of this 60%, only 40% reach ACR50.
Of this 40%, only 20% reach ACR70

Question 18

Etanercept administration

Answer 18

Weekly injection

Question 19

PEGylation

Answer 19

Makes Fab’ fragment last longer in plasma

Only have to administer once avery 28 days

Question 20

Odds ratio
1)
2)
3)

Answer 20

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

Question 21

Anakinra performance in comparing ACR50 of Anakinra vs placebo

Answer 21

Anakinra error bars cross odds ratio=1.

This means that some patients had worse symptoms after taking Anakinra

Question 22

In comparing ACR50 responses of DMARDs and bDMARDs, which drugs were as effective or more effective than Methotrexate?

Answer 22

1) Tocilizumab (as effective)
2) Adalimumab (as effective)
3) Certolizumab pegol (more effective)

Question 23

Primary failure of a drug

Answer 23

Patient condition doesn’t improve. Drug has no effect

Question 24

Implications of a primary failure of a TNFa inhibitor

Answer 24

TNFa not causative agent of RA in patient

Question 25

Secondary failure of a drug

Answer 25

Drug loses efficacy over time

Question 26

Implications of a secondary failure of a TNFa inhibitor

Answer 26

Neutralising antibodies. | These are either human anti-chimaeric antibodies (against infliximab), or human anti-human antibodies

Question 27

Drug survival

Answer 27

How long a patient uses a drug for

Question 28

Best to worst drug survival between Etanercept, Adalimumab and Infliximab

Answer 28

1) Etanercept 2) Adalimumab 3) Infliximab

Question 29

``` Dangers of anti-TNFa drugs 1) 2) 3) 4) 5) 6) 7) ```

Answer 29

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)

Question 30

Tofacitinimib

Answer 30

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

Question 31

Abatacept vs Adalimumab trial 1) 2)

Answer 31

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

Question 32

Tocilizumab vs Adalimumab monotherapy 1) 2) a, b, c

Answer 32

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

Question 33

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

Answer 33

Methotrexate inadequate responders (MTX-IR)

Question 34

What does Tofacitinib preferentially inhibit?

Answer 34

Janus Kinase (JAK) 1 and 3

Question 35

Janus Kinase role | 1) a, b, c,

Answer 35

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

Question 36

Where does Tofacitinib act?

Answer 36

Intracellularly, blocking JAK 1 and 3

Question 37

JAK inhibitor RA treatment

Answer 37

Tofacitinib

Question 38

``` Tofacitinib phase III trial results 1) 2) 3) 4) 5) ```

Answer 38

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

Question 39

``` Tofacitinib adverse reactions 1) 2) 3) 4) 5) ```

Answer 39

1) Headaches 2) URT, urinary tract infections 3) Elevated LDL and HDL cholesterol levels 4) Neutropaenia 5) Opportunistic infections (EG: TB)