Treatment of Rheumatoid Arthritis Flashcards
What is the therapeutic ‘window of opportunity’?
Definition: first three months after symptom onset
- Early phase of disease when intervention may
- hamper disease progression (chronicity reduced)
- reduced burden of disease
- reduce biologic disease-modifying antirheumatic drug (bDMARD) requirement
Recall the types of therapeutic approach in RA.
Recall the pharmacological agents for RA treatment.
What are DMARDs?
Disease-modifying antirheumatic drugs (DMARDs) is a category of drugs defined by their use in rheumatoid arthritis to slow down disease progression.
The term is often used in contrast to nonsteroidal anti-inflammatory drug (which refers to agents that treat the inflammation but not the underlying cause) and steroids (which blunt the immune response but are insufficient to slow down the progression of the disease).
Recall some of the csDMARDs.
When is DMARD going to be started on RA patients?
- Following the diagnosis of RA
- DMARDs started as early as possible
- Methotrexate
- initial DMARD choice in majority of patients
- anchor drug
- mechanism of action –not fully known
- DMARDs can be used in
- Monotherapy, or
- Combination (performs better)
Recall the evidence for intensive therapeutic regimens in RA.
Recall the evidence for combination DMARDs in RA.
Recall some of the bDMARDs.
When are bDMARDs administered? Recall the classes of bDMARDs.
Recall the following diagram matching each bDMARD with its effector function.
Recall the current PBS criteria for bDMARD eligibility in RA.
Recall the four phases of clinical trials.
Recall the features of optimal clinical trial design.
- Ethical
- Randomisation
- Placebo/Control
- Blinding
- Adequate power (sample size)
Recall the histology of the synovial tissue response to anti-TNF.
- Improvement in symptoms
- Reduced signs of inflammation
- No alarming adverse events (AE)
Mention the five anti-TNF used for RA treatment.
- Infliximab (IFX)
- Etanercept (ETA)
- Adalimumab (ADA)
- Certolizumab pegol (CERT)
- Golimumab (GOL)
Recall IFX.
Infliximab(IFX)
- chimeric (mouse/human)
- human immunoglobulin G1 (IgG1) constant region
- mouse variable region
Recall ETA.
Etanercept(ETA)
- fusion protein
- two p75 TNF-alpha receptors
- human IgG1 constant region
Recall ADA.
Adalimumab(ADA)
- fullyhumanmonoclonal antibody
- human IgG1 constant & variable region
Recall CERT.
Certolizumab pegol(CERT)
- humanized monoclonal antibody
- antigen-binding fragment (Fab’)
- polyethylene glycol (PEG)
Recall GOL.
- Golimumab(GOL)
- human IgG1 kappa monoclonal antibody
Recall the reason for non-responders to TNF inhibitors
Recall the safety issue with TNF-inhibitors.
What is anakinra?
Anti-IL1 - non-TNFi bDMARDs for RA
What is tocilizumab?
Non-TNFi bDMARDs for RA –Anti-IL-6
What is Abatacept?
Non-TNFi bDMARDs for RA – CTLA4-blockade
What is rituximab?
Non-TNFi bDMARDs for RA – Anti-CD20
Recall the target site of rituximab action.
Recall the 60-40-20 rule.
“60–40–20” rule, with about 60% of patients reaching ACR20, 40% reaching ACR50, and 20% reaching ACR70.
Recall the efficacy of bDMARD vs placebo.
Recall the ‘Head-to-Head’ bDMARD Trials between ABA and ADA.
Recall the ‘Head-to-Head’ bDMARD Trials between TCZ (IV) vs ADA (SC).
Recall the ‘Head-to-Head’ bDMARD Trials between RTX (IV) vs ADA/ETA
Recall the ‘head-to-head’ bDMARD trials between CERT vs ADA.
Recall the ‘head-to-head’ bDMARD trials between Sarilumab vs ADA.
Describe JAK and its role.
- Non-receptor tyrosine kinases comprising 4 family members:
- JAK 1, JAK 2, JAK 3, Tyk2
- JAK 1 and 2: role in growth, neurodevelopment, hematopoiesis, host defense
- JAK3 and Tyk 2: engaged in immune response
- JAK 1, JAK 2, JAK 3, Tyk2
- Activated JAK plays role in intracellular signal transduction critical for:
- immune cell activation
- proinflammatory cytokine production
- cytokine signalling involved in RA pathophysiology
Recall the mechanism of JAK pathway activation and effect.
- Cytokine binding to paired JAK receptors:
- Autophosphorylation
- Phosphorylation of tyrosine residues
- Phosphorylation with activation of signal transducer and activator of transcription (STAT) molecules
- Results in
- increase in JAK activity
- Further cytokine recruitment
- Changes in gene expression through JAK-STAT pathway
Describe the mechanism of tofacitinib function in RA.
- Novel oralJanus Kinase (JAK) inhibitor
- Preferentially inhibits JAK 1& 3
- (lesser extent): JAK 2 & tyrosine kinase
- By limiting T cell & other leukocyte recruitment, net effect of JAK inhibition is:
- decrease in synovial inflammation
- reduced structural damage in RA
Recall the efficacy of tofacitinib.
Recall the safety of tofacitinib.
Describe baricitinib.
- Efficacy
- ACR20 response –baricitinib(70%) vs. ADA (61%) vs. Pbo(40%)
- Radiographic inhibition (mTSS0.41 vs. 0.33 vs. 0.90 respectively)
- Adverse Events
- Baricitinib & ADA: more infections cf. Pbo
- Baricitinib:
- decreased neutrophil counts •
- increased creatinine & low-density lipoprotein (LDL) cholesterol
- Summary:
- In RA MTX-IR, baricitinib is a/w signif clinical improvements as compared w ADA and Pbo
Describe upadacitinib.
- Selective inhibitor of JAK1
- 2 x Phase III RCT: baricitinib15mg or 30mg/day vs. Pbo. BG stable csDMARD
- IR csDMARDs(MTX, arava, SSZ)
- • Study outcomes: week 12
- ACR20 response
- DAS28-CRP =< 3.2
- Conclusion:
- Upadacitinib 15mg & 30mg/day (+/-csDMARDs) are both effective for improving clinical signs and symptoms of RA
Recall the effect of TFNi on the occurrence of serious infections and malignancies in RA.
