Lecture 28 - RA Treatment Flashcards Preview

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Flashcards in Lecture 28 - RA Treatment Deck (38):
1

Phase I clinical trials
1)
2)

1) Test intervention for the first time in humans
2) Small group (20-80) to evaluate safety

2

Phase II clinical trials
1)
2)
3)

1) Determine efficacy
2) Further test safety
3) Larger group of people (several hundred)

3

Phase III clinical trials
1)
2)

1) Compare drug to current gold standard therapy
2) Large group (several hundred to thousands)

4

Phase IV clinical trials
1)
2)

1) Post-marketing surveillance
2) Monitor efficacy and adverse events over a long period of time

5

SPIRIT 2013

Standard Protocol Items: Recommendations of Interventional Trials

For optimal clinical trial design

6

Tenants of Standard Protocol Items: Recommendations of Interventional Trials
1)
2)
3)
4)
5)

1) Ethical
2) Double-blind
3) Randomisation
4) PLacebo/control
5) Adequate size/power

7

Therapeutic window of opportunity

First three months after symptoms onset

8

Why try to treat in the first three months after symptoms onset?
1)
2)
3)

1) Hamper disease progression
2) Hamper disease burden
3) Reduce need for biologic disease-modifying antirheumatic drugs

9

bDMARD

Biologic disease-modifying antirheumatic drug

10

Important insight in RA therapy

Approach is more important than agent

11

Approach is more important than agent

Intensive, multidrug therapy has a greater effect on outcomes than does the use of a specific drug

12

Treat-to-target
1)
2)
a)
b)

1) Aim for remission or low disease activity
2) By DAS28 criteria
a) Low disease [2.6,3.2]
b) Remission (below 2)

13

Therapeutic approach in RA
1)
2)
3)

1) Treat early
2) Treat to target
3) Intensive therapy

14

TICORA

Tight intensive control of RA

15

Do adverse events increase with more intense RA treatments?

No

16

Pharmacological agents use to treat RA
1)
2)
3)
4)
5)

1) Analgesics
2) NSAIDS
3) Glucocorticoids
4) Synthetic disease-modifying antirheumatic drugs (DMARDs)
5) Biologic disease-modifying antirheumatic drugs (bDMARDs)

17

Way around the ethical issue of giving some RA patients a placebo in clinical trials

Compare current treatment with new drug

18

Disease-modifying antirheumatic drugs
1)
2)
3)
4)
5)
6)
7)
8)

1) Methotrexate
2) Sulphasalazine
3) Antimalarial drugs
4) Leflunomide
5) Gold salts
6) Auranofin (oral gold salt)
7) Ciclosporin A
8) Azathioprine

19

Initial DMARD of choice for most patients

Methotrexate

20

Anchor drug

Central component of many multi-drug therapies
EG: Methotrexate

21

Methotrexate mode of action

Not fully known
Maybe a metabolite inhibitor?

22

Common RA triple therapy

Methotrexate, sulfasalazine, hydroxychloroquine

23

Results of a study comparing different DMARD therapies
1)
2)
3)

1) Most effective was methotrexate, sulfasalazine, hydroxychloroquine combination
2) Second-most effective was sulfasalazine and hydroxychloroquine combination
3) Least effective was methotrexate

24

When are bDMARDs used?

When a patient fails to respond to DMARDs

25

Classes of bDMARDs
1)
2)
3)
4)
5)

1) TNF inhibitors
2) IL-1 antagonists
3) IL-6 receptor antagonists
4) Cytotoxic T lymphocyte antigen 4 (CTLA4) ligand (co-stimulation modifier)
5) B-cell depleting agents (anti-CD20)

26

Proportion of licensed bDMARDs that are TNF inhibitors

Currently 9 licensed bDMARDs, 5 of which are anti-TNF

27

Anti-TNF bDMARDs
1)
2)
3)
4)
5)

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

28

Adalimumab

TNF blockade

29

Abatacept

T cell costimulation blocker (CTLA4 ligand)

30

Anakinra

Recombinant IL-1 receptor antagonist

31

Tocilizumab

IL-6 receptor blockade

32

How does Anakinra work?

It acts as a competitive inhibitor of IL-1 (it binds IL-1R)

33

Drug that binds IL-1R

Anakinra

34

Drug that binds to IL-6R

Tocilizumab

35

Drug that binds to CD80/CD86

Abatacept

36

When do B cells express CD20?

Between pro-B and memory B stages.
Not expressed on plasma cells

37

PBS criteria for bDMARD therapy in Australia
1)
2)
3)

1) Failed six months of intensive DMARD (two agents, for minimum of three months each)
2) Erythrocyte sedimentation rate over 25mm/hour or C-reactive protein over 15mg/L
3) Over 20 active swollen joints or over 4 major large joints swollen

38

Major joints

Elbow, wrist, knee, shoulder, hip