Question 1

Learning objectives?

Accepted Answer

- 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

Question 2

What are the four phases of clinical trials?

Accepted Answer

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

Question 3

What is SPIRIT?

Accepted Answer

- Standard Protocol Items: Recommendations for Interventional Trials - published 2013 - clinical trial design - foundation of good practice when running clinical trials

Question 4

What are key components of clinical trial design?

Accepted Answer

- ethical - randomisation - placebo/control (ethical?) - blinding (masking) (reduces risk of bias) - adequate power (sample size)

Question 5

What are treatment principles of RA?

Accepted Answer

- 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

Question 6

What is more important: approach or agent?

Accepted Answer

approach

Question 7

What is evidence for intensive therapeutic regimens in RA?

Accepted Answer

- 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)

Question 8

What are pharmacological agents for RA treatment?

Accepted Answer

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)

Question 9

What are DMARDs?

Accepted Answer

- 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

Question 10

What is methotrexate?

Accepted Answer

- 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

Question 11

How can DMARDs be used?

Accepted Answer

i. monotherapy, or ii. combination (performs better)

Question 12

What is evidence for combination DMARDs in RA?

Accepted Answer

- 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

Question 13

What are bDMARDs?

Accepted Answer

- 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)

Question 14

How do bDMARDs work?

Accepted Answer

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)

Question 15

What is PBS?

Accepted Answer

- 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

lecture 29 Flashcards

(26 cards)