Lecture 29 - Rheumatoid Arthritis - Treatment Flashcards Preview

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Flashcards in Lecture 29 - Rheumatoid Arthritis - Treatment Deck (44):
1

What are the phases of clinical trials?

What is being tested in each phase?

What is the cohort size in each phase?

Phase I
• Testing of new intervation for the first time
• Small group (20-80)
• Evaluation of safety

Phase II
• Evaluating efficacy
• Larger group (several hundred)

Phase III
• Comparison of new intervention with current gold standard of treatment
• Large groups (several hundred to several thousand)

Phase IV
• Post marketing surveillance
• Monitoring of efficacy and adverse effects over long period of time

2

What is SPIRIT 2013?

Standard Protocol Items: Recommendations for Interventional Trials 2013

Outline the principle elements of optimal clinical trial design
• Ethical
• Randomisation
• Blinding
• Placebo / control
• Adequate power (sample size)

3

What are the principles of RA treatment?

1. Therapeutic 'Window of opportunity'
• Early treatment leads to better outcomes in the long run
• First 3 months after onset
• Start aggressively with DMARDs

2. Intensity is key
• High doses lead to better outcomes
• No adverse effects
• Cost savings

3. Combination therapy
• Tri-therapy has best outcomes

4. Treat to target
• ACR20
• Remission (<2.6 on DAS28)

4

What is the window of opportunity?

What can be the effects of treatment at this time?

Definition: first three months after symptom onset

Treatment:
• DMARDs (Disease-modifying antirheumaatic drugs)

Treatment in this phase may:
• Hamper disease progression
• Reduced burden of disease
• Reduced biologic DMARD requirement (disease-modifying anti rheumatic drugs)

5

What is 'Treat-to-target'

Treatment is not aimless

Treatment aims for disease remission or low disease activity

e.g. DAS28-CRP criteria:
• Remission: <2.6
• Low disease activity: 2.6-3.2

6

Characterise treatment regimens for RA now and in the past

In the past: 'go slow, go low'

Now:
• Intensive
• Combination DMARDs
• Escalating therapy
• Frequent changes

7

What is the most important factor in the treatment of RA?

Approach is the most important factor (i.e. intensive)

More important the the agent of therapy

8

What is the evidence for intensive therapeutic regimens?

'TICORA: Tight Intensive Control of RA'

Two groups:
1. Intensive group
• Monthly treatment
• Escalation of treatment

2. Routine group

Observations in intensive group:
• Decrease in disease activity score
• Less radiographic joint erosions
• No increase in adverse effects (despite immunosuppression)
• Cost savings

9

What are the various pharmacological agents for RA treatment?

1. Analgesics
• Various opiates: paracetamol

2. NSAIDS
• Aspirin

3. Glucocorticoids
• Prednisolone

4. DMARDs
• Synthetic disease-modifying anti rheumatic drugs

5. Biological DMARDs (bDMARDs)

10

What is the effect of 'disease modifying' drugs?

Specifically, in RA?

Alter the natural course of disease

In RA:
• Prevents damage to the joints

11

What are some synthetic DMARDs?

Methotrexate
Sulfasalazine
Antimalarial drugs
Leflunomide

12

Which is the initial DMARD of choice in the majority of RA cases?

Methotrexate

13

Describe the features of methotrexate

• Mechanisms of action

Been around since the 80's
First port of call

• Highly effective at preventing progressive damage to joint
• Improves quality of life of patients
• Well tolerated

'Anchor drug': used in most combinations of treatment

M.O.A:
• Not fully known
• Anti-folate agent
• Blocks purine synthesis
• Purines needed to make nucleotides

14

What is the evidence for combination DMARDs in RA?

1996
Studies of Triple therapies

Observations:
• Far greater efficacy that mono-therapy and dual-therapy
• No serious safety issues

15

What are biologic DMARDs?

In which patients are they used?

List some examples

Target a particular inflammatory protein that contributes to rheumatoid arthritis

Reserved for patients that are not responding to synthetic DMARDs

Currently 4 approved

Examples:
• TNF inhibitors
• IL-1 antagonists
• CTLA4 decoy receptor (T cell co-stimulator)
• B cell depleting agents

• IL-6 antagonists

16

List some TNF inhibitors

• Infliximab
• Etanercept
• Certolizumab pegol
• Golimumab
• Adalimumab

17

Describe the mechanism of action of biologic DMARDs

Interfere with inflammatory proteins that contribute to the disease process in RA

1. TNF inhibition
• mAbs directly neutralise TNF
e.g. Infliximab, Adalimumab, Golimumab, Certolizumab, Etanercept

2. IL-1 inhibition
• Competitive inhibition
• IL-1 inhibitor binds to the IL-1R to block action of IL-1
e.g. Anakinra

3. IL-6 inhibition
• Competitive inhibition
• Binds IL-6R
e.g. Tocilizumab

4. CTLA4
• mAb binds CD80 or CD86
• APC can not co-stimulate T cells (Signal 2)
• Anergy of T cells
e.g. Abatacept

5. B cell depletion
• mAb binds to CD20
• B cells marked and the immune system comes in and removes them
e.g. Rituximab

18

What is Tocilizumab?

mAb
Binds IL-6R
Blocks action of IL-6

19

Describe the mechanism of action of Abatacept

• mAb binds CD80 or CD86
• APC can not co-stimulate T cells (Signal 2)
• Anergy of T cells

20

What is the PBS?

Pharmaceutical benefits scheme

Government subsidy of medications
• 90% of drugs on the market covered

Began in 1948

21

What are the PBS criteria for bDMARD eligibility in RA?

i. Failed six months intensive DMARD
• Two agents for minimum of three months each

ii. Active disease:
• Erythrocyte sedimentation rate (ESR) greater than 25 mm/hour
• CRP more than 15mg/L

iii. Active joint count
• >20 active joints (swollen and tender)
• > 4 major joints involved (elbows, wrists, knee, ankle, shoulder, hip)

22

What is the first line bDMARD?

TNF inhibitors (TNFi)

However, some people will not be able to take these drugs, so they are given others as the first line

23

How long is the Window of Opportunity?

3 months

24

Dogma: Earlier treatment of RA leads to...

better prognosis in the long run

25

What are the targets of treatment?

• Remission
• Low disease activity

26

What is the anchor drug of DMARD combination therapy?

Methotrexate

27

What is the name of the RA patient?

William Barling

28

When was Bill first diagnosed?

1969
i.e. he has had RA for 45 years

29

What were Bill's initial symptoms

Pains in the neck

Went to the doctor

Had some tablets, and it cleared up for a while

After a few weeks, it got much worse:
• Hand deformities
• Trouble walking

Went back to the doctor

Blood tests confirmed RA

30

What was the impact on day-to-day activities?

Needed help with
• Dressing
• Shoe laces
• Combing hair

31

Which treatment did he receive?

Gold injections
• 6 years

Thereafter, he got rashes and came off the injections

Penomine tablet

Methotrexate
• 'it was alright'
• Controlled RA for 10-15 years

Then another flare up

Humira
• no good
• 14 months

Enbrel injections
• Very good
• Can close his hands

Taken off methotrexate
• Arthritis came back, so he went back on it

32

What is the economic burden for RA treatment?

Health card
$254 / year
Covers most drugs

Enbrel injections are very expensive, but it is covered by the PBS

33

Did Bill experience any side effects of treatment?

Only rashes with Gold injections

34

Does Bill know when he needs to get another injection?

No

Some patients do though

35

What recreational activities can Bill participate in?

Walks his dogs every morning for about an hour

36

What can be observed in Bill's hands?

Some deformities

He had to have an operation on one of his fingers because he couldn't close it

After the operation he can close it very well

37

Why is surgery sometimes needed for deformities?

Once the deformities form, treatment isn't able to remove them.

Surgery is required

38

What is seen in Bill's feet?

Valgus deformity

Big toe on the left foot pointing outwards

39

Describe triple-therapy

Methotrexate
Sulfasalazine
Hydroxychloroquine

This was a study in the 90's that compared triple therapy with methotrexate on its own and SSZ/HCQ

Using these medications in combination is far more efficacious than using just two, or methotrexate on its own

40

Which is more efficacious:
• MTX/HCQ/SSZ
• MTX
• HCQ/SSZ

Triple therapy

41

Describe the mechanism of action of the following:
• Methotrexate
• Sulfasalazine
• Antimalarial drugs
• Leflunomide

Methotrexate: anti-metabolite

Sulfasalazine: anti-inflammatory and antimicrobial

Antimalarial drugs: interference with antigen processing

Leflunomide: anti-metabolite

42

What are some of the adverse effects encountered with DMARDs?

• Hepatotoxicity
• Myelotoxicity
• Fibrosing alveolitis
• Hypersensitivity reactions
• Retinopathy
• Hypertension

43

Compare the structure of the following:
• Abatacept
• Adalimumab
• Anakinra
• Certolizumab pegol
• Etanercept
• Golimumab
• Infliximab
• Rituximab
• Tocilizumab

Abatacept:
• Recombinant CTLA4 extracellular domain on IgG1 frame

Adalimumab:
• Human monoclonal IgG1

Anakinra:
• Recombinant IL-R antagonist

Certolizumab pegol:
• Humanised Fab that has been pegylated

Etanercept:
• Recombinant TNF receptor (p75) on human IgG1 frame

Golimumab:
• Human monoclonal

Infliximab:
• Chimaeric monoclonal IgG1

Rituximab:
• Chimaeric monoclonal IgG1

Tocilizumab:
• Humanised monoclonal

44

Which biologic has the worst efficacy?

Anakinra
It has now been taken off the PBS