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Biotherapeutics > Rheumatoid Arthritis > Flashcards

Rheumatoid Arthritis Flashcards

1
Q

What is the prevalence of RA?

A

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

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2
Q

What are 4 things that can cause RA?

A

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

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3
Q

What is the difference between B and T cells?

A

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

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4
Q

What do myeloid stem cells differentiate into?

A

RBCs
Platelets
granulocytes

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5
Q

What do lymphoid stem cells differentiate into?

A

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

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6
Q

What autoantibodies are being released in synovial fluid?

A

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

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7
Q

Where do ACPAs come from?

A

Peptidylarginine deiminases (PADs)

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8
Q

What are ACPAs predicative to?

A

Bone erosion
CVD

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9
Q

How are PADs released from Neutrophils?

A

During NET if PAD levels are high

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10
Q

What is the MoA of PADs?

A

Citrullination of extracellular proteins, structural proteins

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11
Q

What are 3 cytokines that drive inflammation in RA?

A

IL-1
IL-6
TNF-alpha

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12
Q

What do T cells signal osteoclasts through?

A

Osteoprotegerin ligands

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13
Q

What do FLS become?

A

APC and secrete cytokines & MMPs

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14
Q

Where do the main cytokines for RA come from?

A

Macrophages

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15
Q

What are 2 ways of neutralization of cytokines?

A

Soluble receptor
Monoclonal antibody

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16
Q

What are 2 ways for receptor blockade?

A

Anatagonist
Mabs

17
Q

Whar are 3 ways to treat RA?

A

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

18
Q

What are the 4 signalling pathways in FLS?

A

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

19
Q

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

A

53-68%

20
Q

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

A

> 84%

21
Q

What region is the most attributable to genetic factors?

A

MHC (20%)

22
Q

What can target methylation of promoter regions?

A

DNMT inhibitors

23
Q

What pathway do RA Pts use instead of glycolysis?

A

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

24
Q

What are 3 RA therapeutics?

A

NSAIDs eg. ibuprofen
GCs eg glucocorticoids
DMARDs

25
Q

What are three types of DMARDs?

A

conventional synthetic
biological
targeted synthetic

26
Q

Whats an example of csDMARDs?

A

Methotrexate

27
Q

What are 6 characteristics of methotrexate?

A

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

28
Q

What are 2 downfalls of methotrexate?

A

Increase susceptibility to other infections
Narrow therapeutic range

29
Q

What are 2 characteristics of the TNF-a hypothesis?

A

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

30
Q

What 3 things does IL-1 increase?

A

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

31
Q

What were 3 downfalls of early anti-TNFa trials?

A

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

32
Q

What are the 3 main TNF-a inhibitors?

A

Infliximab
Adalimumab
Etanercept (soluble receptor)

33
Q

What are 5 characteristics of Adalimumab?

A

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

34
Q

What are 4 characteristics of Etanercept?

A

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

35
Q

What are 3 other bDMARDs?

A

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

36
Q

What are characteristics of Tofacitinib (tsDMARDs)?

A

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

37
Q

What are characteristics of 5-AZA-CdR?

A

DNA methylation inhibitor
reduces chemokine/cytokine release
allevaites inflammation

38
Q
A

Biotherapeutics (9 decks)

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