Lecture 28 - RA Treatment Flashcards
Phase I clinical trials
1)
2)
1) Test intervention for the first time in humans
2) Small group (20-80) to evaluate safety
Phase II clinical trials
1)
2)
3)
1) Determine efficacy
2) Further test safety
3) Larger group of people (several hundred)
Phase III clinical trials
1)
2)
1) Compare drug to current gold standard therapy
2) Large group (several hundred to thousands)
Phase IV clinical trials
1)
2)
1) Post-marketing surveillance
2) Monitor efficacy and adverse events over a long period of time
SPIRIT 2013
Standard Protocol Items: Recommendations of Interventional Trials
For optimal clinical trial design
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
Therapeutic window of opportunity
First three months after symptoms onset
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
bDMARD
Biologic disease-modifying antirheumatic drug
Important insight in RA therapy
Approach is more important than agent
Approach is more important than agent
Intensive, multidrug therapy has a greater effect on outcomes than does the use of a specific drug
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)
Therapeutic approach in RA
1)
2)
3)
1) Treat early
2) Treat to target
3) Intensive therapy
TICORA
Tight intensive control of RA
Do adverse events increase with more intense RA treatments?
No
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)
Way around the ethical issue of giving some RA patients a placebo in clinical trials
Compare current treatment with new drug
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
Initial DMARD of choice for most patients
Methotrexate
Anchor drug
Central component of many multi-drug therapies
EG: Methotrexate
Methotrexate mode of action
Not fully known
Maybe a metabolite inhibitor?
Common RA triple therapy
Methotrexate, sulfasalazine, hydroxychloroquine
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
When are bDMARDs used?
When a patient fails to respond to DMARDs
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)
Proportion of licensed bDMARDs that are TNF inhibitors
Currently 9 licensed bDMARDs, 5 of which are anti-TNF
Anti-TNF bDMARDs 1) 2) 3) 4) 5)
1) Adalimumab
2) Certolizumab pegol
3) Etanercept
4) Golimumab
5) Infliximab
Adalimumab
TNF blockade
Abatacept
T cell costimulation blocker (CTLA4 ligand)
Anakinra
Recombinant IL-1 receptor antagonist
Tocilizumab
IL-6 receptor blockade
How does Anakinra work?
It acts as a competitive inhibitor of IL-1 (it binds IL-1R)
Drug that binds IL-1R
Anakinra
Drug that binds to IL-6R
Tocilizumab
Drug that binds to CD80/CD86
Abatacept
When do B cells express CD20?
Between pro-B and memory B stages.
Not expressed on plasma cells
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
Major joints
Elbow, wrist, knee, shoulder, hip
