Lecture 29 - Rheumatoid Arthritis - Treatment Flashcards
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
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)
What are the principles of RA treatment?
- Therapeutic ‘Window of opportunity’
• Early treatment leads to better outcomes in the long run
• First 3 months after onset
• Start aggressively with DMARDs - Intensity is key
• High doses lead to better outcomes
• No adverse effects
• Cost savings - Combination therapy
• Tri-therapy has best outcomes - Treat to target
• ACR20
• Remission (<2.6 on DAS28)
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)
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
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
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
What is the evidence for intensive therapeutic regimens?
‘TICORA: Tight Intensive Control of RA’
Two groups:
1. Intensive group
• Monthly treatment
• Escalation of treatment
- Routine group
Observations in intensive group: • Decrease in disease activity score • Less radiographic joint erosions • No increase in adverse effects (despite immunosuppression) • Cost savings
What are the various pharmacological agents for RA treatment?
- Analgesics
• Various opiates: paracetamol - NSAIDS
• Aspirin - Glucocorticoids
• Prednisolone - DMARDs
• Synthetic disease-modifying anti rheumatic drugs - Biological DMARDs (bDMARDs)
What is the effect of ‘disease modifying’ drugs?
Specifically, in RA?
Alter the natural course of disease
In RA:
• Prevents damage to the joints
What are some synthetic DMARDs?
Methotrexate
Sulfasalazine
Antimalarial drugs
Leflunomide
Which is the initial DMARD of choice in the majority of RA cases?
Methotrexate
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
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
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
List some TNF inhibitors
- Infliximab
- Etanercept
- Certolizumab pegol
- Golimumab
- Adalimumab
Describe the mechanism of action of biologic DMARDs
Interfere with inflammatory proteins that contribute to the disease process in RA
- TNF inhibition
• mAbs directly neutralise TNF
e.g. Infliximab, Adalimumab, Golimumab, Certolizumab, Etanercept - IL-1 inhibition
• Competitive inhibition
• IL-1 inhibitor binds to the IL-1R to block action of IL-1
e.g. Anakinra - 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
- B cell depletion
• mAb binds to CD20
• B cells marked and the immune system comes in and removes them
e.g. Rituximab
What is Tocilizumab?
mAb
Binds IL-6R
Blocks action of IL-6
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
What is the PBS?
Pharmaceutical benefits scheme
Government subsidy of medications
• 90% of drugs on the market covered
Began in 1948
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)
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
How long is the Window of Opportunity?
3 months
Dogma: Earlier treatment of RA leads to…
better prognosis in the long run
