Treatment of Rheumatoid Arthritis

Question 1

What is the therapeutic ‘window of opportunity’?

Answer 1

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

Question 2

Recall the types of therapeutic approach in RA.

Answer 2

Question 3

Recall the pharmacological agents for RA treatment.

Answer 3

Question 4

What are DMARDs?

Answer 4

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).

Question 5

Recall some of the csDMARDs.

Answer 5

Question 6

When is DMARD going to be started on RA patients?

Answer 6

• 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)

Question 7

Recall the evidence for intensive therapeutic regimens in RA.

Answer 7

Question 8

Recall the evidence for combination DMARDs in RA.

Answer 8

Question 9

Recall some of the bDMARDs.

Answer 9

Question 10

When are bDMARDs administered? Recall the classes of bDMARDs.

Answer 10

Question 11

Recall the following diagram matching each bDMARD with its effector function.

Answer 11

Question 12

Recall the current PBS criteria for bDMARD eligibility in RA.

Answer 12

Question 13

Recall the four phases of clinical trials.

Answer 13

Question 14

Recall the features of optimal clinical trial design.

Answer 14

• Ethical
• Randomisation
• Placebo/Control
• Blinding
• Adequate power (sample size)

Question 15

Recall the histology of the synovial tissue response to anti-TNF.

Answer 15

• Improvement in symptoms
• Reduced signs of inflammation
• No alarming adverse events (AE)

Question 16

Mention the five anti-TNF used for RA treatment.

Answer 16

• Infliximab (IFX)
• Etanercept (ETA)
• Adalimumab (ADA)
• Certolizumab pegol (CERT)
• Golimumab (GOL)

Question 17

Recall IFX.

Answer 17

Infliximab(IFX)

• chimeric (mouse/human)
• human immunoglobulin G1 (IgG1) constant region
• mouse variable region

Question 18

Recall ETA.

Answer 18

Etanercept(ETA)

• fusion protein
• two p75 TNF-alpha receptors
• human IgG1 constant region

Question 19

Recall ADA.

Answer 19

Adalimumab(ADA)

• fullyhumanmonoclonal antibody
• human IgG1 constant & variable region

Question 20

Recall CERT.

Answer 20

Certolizumab pegol(CERT)

• humanized monoclonal antibody
• antigen-binding fragment (Fab’)
• polyethylene glycol (PEG)

Question 21

Recall GOL.

Answer 21

• Golimumab(GOL)
  
  • human IgG1 kappa monoclonal antibody

Question 22

Recall the reason for non-responders to TNF inhibitors

Answer 22

Question 23

Recall the safety issue with TNF-inhibitors.

Answer 23

Question 24

What is anakinra?

Answer 24

Anti-IL1 - non-TNFi bDMARDs for RA

Question 25

What is tocilizumab?

Answer 25

Non-TNFi bDMARDs for RA –Anti-IL-6

Question 26

What is Abatacept?

Answer 26

Non-TNFi bDMARDs for RA – CTLA4-blockade

Question 27

What is rituximab?

Answer 27

Non-TNFi bDMARDs for RA – Anti-CD20

Question 28

Recall the target site of rituximab action.

Answer 28

Question 29

Recall the 60-40-20 rule.

Answer 29

“60–40–20” rule, with about 60% of patients reaching ACR20, 40% reaching ACR50, and 20% reaching ACR70.

Question 30

Recall the efficacy of bDMARD vs placebo.

Answer 30

Question 31

Recall the ‘Head-to-Head’ bDMARD Trials between ABA and ADA.

Answer 31

Question 32

Recall the ‘Head-to-Head’ bDMARD Trials between TCZ (IV) vs ADA (SC).

Answer 32

Question 33

Recall the ‘Head-to-Head’ bDMARD Trials between RTX (IV) vs ADA/ETA

Answer 33

Question 34

Recall the ‘head-to-head’ bDMARD trials between CERT vs ADA.

Answer 34

Question 35

Recall the ‘head-to-head’ bDMARD trials between Sarilumab vs ADA.

Answer 35

Question 36

Describe JAK and its role.

Answer 36

• 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
• Activated JAK plays role in intracellular signal transduction critical for:
  
  • immune cell activation
  • proinflammatory cytokine production
  • cytokine signalling involved in RA pathophysiology

Question 37

Recall the mechanism of JAK pathway activation and effect.

Answer 37

• 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

Question 38

Describe the mechanism of tofacitinib function in RA.

Answer 38

• 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

Question 39

Recall the efficacy of tofacitinib.

Answer 39

Question 40

Recall the safety of tofacitinib.

Answer 40

Question 41

Describe baricitinib.

Answer 41

• 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

Question 42

Describe upadacitinib.

Answer 42

• 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

Question 43

Recall the effect of TFNi on the occurrence of serious infections and malignancies in RA.

Answer 43