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BIOM30002 - M2M > Lecture 29 - Rheumatoid Arthritis - Treatment > Flashcards

Lecture 29 - Rheumatoid Arthritis - Treatment Flashcards

1
Q

What are the phases of clinical trials?

What is being tested in each phase?

What is the cohort size in each phase?

A

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

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2
Q

What is SPIRIT 2013?

A

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)
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3
Q

What are the principles of RA treatment?

A
  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)
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4
Q

What is the window of opportunity?

What can be the effects of treatment at this time?

A

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)

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5
Q

What is ‘Treat-to-target’

A

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

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6
Q

Characterise treatment regimens for RA now and in the past

A

In the past: ‘go slow, go low’

Now: 
 • Intensive
 • Combination DMARDs
 • Escalating therapy 
 • Frequent changes
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7
Q

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

A

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

More important the the agent of therapy

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8
Q

What is the evidence for intensive therapeutic regimens?

A

‘TICORA: Tight Intensive Control of RA’

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

  1. Routine group
Observations in intensive group:
 • Decrease in disease activity score
 • Less radiographic joint erosions
 • No increase in adverse effects (despite immunosuppression)
 • Cost savings
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9
Q

What are the various pharmacological agents for RA treatment?

A
  1. Analgesics
    • Various opiates: paracetamol
  2. NSAIDS
    • Aspirin
  3. Glucocorticoids
    • Prednisolone
  4. DMARDs
    • Synthetic disease-modifying anti rheumatic drugs
  5. Biological DMARDs (bDMARDs)
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10
Q

What is the effect of ‘disease modifying’ drugs?

Specifically, in RA?

A

Alter the natural course of disease

In RA:
• Prevents damage to the joints

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11
Q

What are some synthetic DMARDs?

A

Methotrexate
Sulfasalazine
Antimalarial drugs
Leflunomide

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12
Q

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

A

Methotrexate

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13
Q

Describe the features of methotrexate

• Mechanisms of action

A

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
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14
Q

What is the evidence for combination DMARDs in RA?

A

1996
Studies of Triple therapies

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

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15
Q

What are biologic DMARDs?

In which patients are they used?

List some examples

A

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

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16
Q

List some TNF inhibitors

A
  • Infliximab
  • Etanercept
  • Certolizumab pegol
  • Golimumab
  • Adalimumab
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17
Q

Describe the mechanism of action of biologic DMARDs

A

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
  1. B cell depletion
    • mAb binds to CD20
    • B cells marked and the immune system comes in and removes them
    e.g. Rituximab
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18
Q

What is Tocilizumab?

A

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

19
Q

Describe the mechanism of action of Abatacept

A
  • mAb binds CD80 or CD86
  • APC can not co-stimulate T cells (Signal 2)
  • Anergy of T cells
20
Q

What is the PBS?

A

Pharmaceutical benefits scheme

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

Began in 1948

21
Q

What are the PBS criteria for bDMARD eligibility in RA?

A

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
Q

What is the first line bDMARD?

A

TNF inhibitors (TNFi)

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

23
Q

How long is the Window of Opportunity?

A

3 months

24
Q

Dogma: Earlier treatment of RA leads to…

A

better prognosis in the long run

25
Q

What are the targets of treatment?

A
  • Remission

* Low disease activity

26
Q

What is the anchor drug of DMARD combination therapy?

A

Methotrexate

27
Q

What is the name of the RA patient?

A

William Barling

28
Q

When was Bill first diagnosed?

A

1969

i.e. he has had RA for 45 years

29
Q

What were Bill’s initial symptoms

A

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
Q

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

A

Needed help with
• Dressing
• Shoe laces
• Combing hair

31
Q

Which treatment did he receive?

A

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
Q

What is the economic burden for RA treatment?

A

Health card
$254 / year
Covers most drugs

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

33
Q

Did Bill experience any side effects of treatment?

A

Only rashes with Gold injections

34
Q

Does Bill know when he needs to get another injection?

A

No

Some patients do though

35
Q

What recreational activities can Bill participate in?

A

Walks his dogs every morning for about an hour

36
Q

What can be observed in Bill’s hands?

A

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
Q

Why is surgery sometimes needed for deformities?

A

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

Surgery is required

38
Q

What is seen in Bill’s feet?

A

Valgus deformity

Big toe on the left foot pointing outwards

39
Q

Describe triple-therapy

A

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
Q

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

A

Triple therapy

41
Q 
Describe the mechanism of action of the following:
 • Methotrexate
 • Sulfasalazine
 • Antimalarial drugs
 • Leflunomide
A

Methotrexate: anti-metabolite

Sulfasalazine: anti-inflammatory and antimicrobial

Antimalarial drugs: interference with antigen processing

Leflunomide: anti-metabolite

42
Q

What are some of the adverse effects encountered with DMARDs?

A
  • Hepatotoxicity
  • Myelotoxicity
  • Fibrosing alveolitis
  • Hypersensitivity reactions
  • Retinopathy
  • Hypertension
43
Q 
Compare the structure of the following:
 • Abatacept
 • Adalimumab
 • Anakinra
 • Certolizumab pegol
 • Etanercept
 • Golimumab
 • Infliximab
 • Rituximab
 • Tocilizumab
A

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
Q

Which biologic has the worst efficacy?

A

Anakinra

It has now been taken off the PBS

BIOM30002 - M2M (36 decks)

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