Rheumatoid Arthritis

Question 1

What is the prevalence of RA?

Answer 1

2-3x more common in women
late age onset
0.5-1% globally
Ireland has highest incidence rate of RA in EU

Question 2

What are 4 things that can cause RA?

Answer 2

Genetic susceptibility eg MHC region genes
Epigenetic alterations eg DNA methylation
Immune microenvironment eg macrophages
Metabolic disorders Glucose

Question 3

What is the difference between B and T cells?

Answer 3

B cells make antibodies
T cells sends signal to T cells (innate immune system)

Question 4

What do myeloid stem cells differentiate into?

Answer 4

RBCs
Platelets
granulocytes

Question 5

What do lymphoid stem cells differentiate into?

Answer 5

Effector/adaptor immune cells (B, T and natural killer cells)

Question 6

What autoantibodies are being released in synovial fluid?

Answer 6

80% of cases
Rheumtoid factor
Anticitrullinated protein antibodies (ACPAs)

Question 7

Where do ACPAs come from?

Answer 7

Peptidylarginine deiminases (PADs)

Question 8

What are ACPAs predicative to?

Answer 8

Bone erosion
CVD

Question 9

How are PADs released from Neutrophils?

Answer 9

During NET if PAD levels are high

Question 10

What is the MoA of PADs?

Answer 10

Citrullination of extracellular proteins, structural proteins

Question 11

What are 3 cytokines that drive inflammation in RA?

Answer 11

IL-1
IL-6
TNF-alpha

Question 12

What do T cells signal osteoclasts through?

Answer 12

Osteoprotegerin ligands

Question 13

What do FLS become?

Answer 13

APC and secrete cytokines & MMPs

Question 14

Where do the main cytokines for RA come from?

Answer 14

Macrophages

Question 15

What are 2 ways of neutralization of cytokines?

Answer 15

Soluble receptor
Monoclonal antibody

Question 16

What are 2 ways for receptor blockade?

Answer 16

Anatagonist
Mabs

Question 17

Whar are 3 ways to treat RA?

Answer 17

Neutralization of cytokines (infliximab)
Receptor blockade (Recombinant IL-1)
Activation of anti-inflammatory pathways (IL-4/10)

Question 18

What are the 4 signalling pathways in FLS?

Answer 18

Triggered by cytokine binding
Transcriptional regulation
Phosphorylation of downstream proteins
Crosstalk between pathways

Question 19

How high is the genetic link for seropositive (ACPA positive)?

Answer 19

53-68%

Question 20

How much does the hypermethylation signal of CpG promoter regions in FLS increase to?

Answer 20

> 84%

Question 21

What region is the most attributable to genetic factors?

Answer 21

MHC (20%)

Question 22

What can target methylation of promoter regions?

Answer 22

DNMT inhibitors

Question 23

What pathway do RA Pts use instead of glycolysis?

Answer 23

PPP - Redox imabalnce -> low aspartate -> ER expansion -> T cell turned into TNF-a super producer

Question 24

What are 3 RA therapeutics?

Answer 24

NSAIDs eg. ibuprofen
GCs eg glucocorticoids
DMARDs

Question 25

What are three types of DMARDs?

Answer 25

conventional synthetic biological targeted synthetic

Question 26

Whats an example of csDMARDs?

Answer 26

Methotrexate

Question 27

What are 6 characteristics of methotrexate?

Answer 27

Very effective rapid adenosine is naturally anti-inflammatory high intolerance anti-cancer combination therapy

Question 28

What are 2 downfalls of methotrexate?

Answer 28

Increase susceptibility to other infections Narrow therapeutic range

Question 29

What are 2 characteristics of the TNF-a hypothesis?

Answer 29

Produced by macrophage first responders Increase level of other cytokines (IL-1_

Question 30

What 3 things does IL-1 increase?

Answer 30

Anti-inflammatory cytokines bone and cartilage destruction Pro-inflammatory cytokines

Question 31

What were 3 downfalls of early anti-TNFa trials?

Answer 31

Hamster IgG suppressed systemic inflammation Caused local inflammation in transgenic lines other s/es

Question 32

What are the 3 main TNF-a inhibitors?

Answer 32

Infliximab Adalimumab Etanercept (soluble receptor)

Question 33

What are 5 characteristics of Adalimumab?

Answer 33

Specific for TNF-a Binds soluble & transmembrane SC EOW fully human produced from CHO

Question 34

What are 4 characteristics of Etanercept?

Answer 34

Soluble fusion protein Human TNF receptor p75 & Fc human IgG1 Dimeric

Question 35

What are 3 other bDMARDs?

Answer 35

Anti-TNFa - infliximab IL-6 antibodies - Tocilizumab Target B cells directly - Rituximab

Question 36

What are characteristics of Tofacitinib (tsDMARDs)?

Answer 36

Pan-JAK inhibitor Prevents cytokine transcription S/e - herpes

Question 37

What are characteristics of 5-AZA-CdR?

Answer 37

DNA methylation inhibitor reduces chemokine/cytokine release allevaites inflammation