lecture 29 Flashcards
Learning objectives?
- principles of clinical trial design
- principles of RA treatment
- window of opportunity
- treat early
- disease modifying anti-rheumatic drugs (DMARDs)
- combination therapy
- biological DMARD (bDMARD) classes
- pharmaceutical benefits scheme (PBS) restrictions
- patient experience of RA - interview
What are the four phases of clinical trials?
phase I
- test new intervention for the first time
- small group (e.g. 20 - 80) of people to evaluate safety
- includes healthy controls and some diseased
phase II
- determine efficacy, further evaluate safety
- larger group of people (e.g. several hundred)
phase III
- compare intervention to current gold standard of treatment
- large groups of trial patients (e.g. several hundred to several thousands)
phase IV
- post marketing surveillance
- monitor efficacy and adverse effects over longer periods of time
What is SPIRIT?
- Standard Protocol Items: Recommendations for Interventional Trials
- published 2013
- clinical trial design
- foundation of good practice when running clinical trials
What are key components of clinical trial design?
- ethical
- randomisation
- placebo/control (ethical?)
- blinding (masking) (reduces risk of bias)
- adequate power (sample size)
What are treatment principles of RA?
- delay in treatment initiation after diagnosis –> more joint damage
- therapeutic ‘window of opportunity’
- definition: first three months after symptom onset
- early phase of disease when intervention may:
- hamper disease progression (chronicty reduced)
- reduced burden of disease
- reduce biologic disease-modiyfying antirheumatic drug (bDMARD) requirement
treat early
- prompt initiation of treatment following diagnosis
- early use of disease-modifying antirheumatic drugs (DMARDs)
- early recognition and referral to a rheumatologist
treat-to-target - aim for remission or low disease activity -- by DAS28-CRP criteria >> low disease: ≥2.6 and ≤3.2 >> remission: < 2.6
intensive therapeutic regimens
- no longer ‘start slo, go slow’
- combination DMARDs
- escalating therapy and frequent changes
approach is more important than the agent
What is more important: approach or agent?
approach
What is evidence for intensive therapeutic regimens in RA?
- the tight intensive control of RA (TICORA)
- compared routine vs intensive care
intensive group:
- less radiographic joint erosions
- no increase in adverse events
- cost savings (short-term)
What are pharmacological agents for RA treatment?
i. analgesics (paracetomol)
ii. non-steroidal anti-inflammatory drugs (NSAIDs)
iii. glucocorticoids e.g. prednisolone (PNL) (steroids)
iv. synthetic disease-modifying antirheumatic drugs (DMARDs)
v. biological DMARDs (bDMARDs)
What are DMARDs?
- drugs that alter the course of the disease
- currently seven/eight agents:
1. methotrexate
2. sulfasalazine
3. antimalarial drugs
4. leflunomide
5a. gold salts (parenteral)
5b. auranofin (oral gold salt)
6. ciclosporin A: renal transplant medication
7. azathioprine : transplant medication
top four most widely used agents in practise currently
all work via different mechanisms
- DMARDs started as early as possibly following diagnosis
What is methotrexate?
- DMARD
- initial DMARD choice in majority of patients
- anchor drug (always used when combinations are there)
- mechanism of action - not fully known - antifolate agent, blocks purine synthesis (DNA/RNA), accumulation of ademozine?
- well tolerated
- improves quality of life
How can DMARDs be used?
i. monotherapy, or
ii. combination (performs better)
What is evidence for combination DMARDs in RA?
- triple therapy: MTX/HCQ/SSZ > MTX or HCQ/SSZ
- COBRA: MTX/SSZ/PNL > SSZ
- FINRACO: MTX/SSZ/HCS/PNL > SSZ
- BeSt: escalate or switch
- ATTRACT: infliximab/MTX > MTX
- PREMIER: adalimumab (ADA)/MTX > ADA vs. MTX
triple therapy significantly more effective than either double or monotherapy
What are bDMARDs?
- reserved for patients who fail to respond to conventional DMARDs (in aus)
- currently five classes available:
i. TNF-alpha inhibitors
ii. IL-1 antagonists
iii. IL-6 receptor antagonists
iv. cytotoxic T-lymphocyte antigen 4 (CLA4) ligand (co-stimulation modifier) (decoy receptor)
v. B-cell depleting agents (anti-CD20)
currently 9 agents that are licensed for treatment of RA
- abatacept (t-cell)
- adalimumab (TNF) (subcutaneous injections)
- anakinra (IL-1)
- certolizumab pegol (TNF)
- etanercept (TNF) (sbi)
- golimumab (TNF)
- infliximab (TNF) (infusion)
- rituximab (b-cells)
- tocilizumab (il-6)
How do bDMARDs work?
TNF inhibitors
- surrounded by mAbs
- prevent it from binding receptor molecules
- prevent it causing inflammation
IL-1
- competitive inhibition
- binds receptor but doesn’t initiate downstream signalling
IL-6
- similar
CTLA4
- blocks co-signal required for T cell activation
rituximab
- cd20 on b cells (not plasma cells)
What is PBS?
- pharmaceutical benefits scheme
- began in 1948 in Australia
- government subsidises the cost of medications for (most) medical conditions
current PBS criteria for bDMARD eligibility in RA
i. failed six months intensive DMARD
- two agents minimum of three months each
ii. erythrocyte sedimentation rate (ESR) >25mm/hour, AND/OR C-reactive protein (CRP) > 15mg/L
iii. active joint count
- ≥ 20 active (swollen and tender) joints, OR
- ≥ 4 major (large) joints - elbows, wrists, knee, ankle, shoulder and/or hip
- first line - TNF inhibitors (TNFi)
- except patients with history of heart failure, demyelinating conditions such as MS, or patients who have known malignancy
