Rheumatoid Arthritis Flashcards
What is the prevalence of RA?
2-3x more common in women
late age onset
0.5-1% globally
Ireland has highest incidence rate of RA in EU
What are 4 things that can cause RA?
Genetic susceptibility eg MHC region genes
Epigenetic alterations eg DNA methylation
Immune microenvironment eg macrophages
Metabolic disorders Glucose
What is the difference between B and T cells?
B cells make antibodies
T cells sends signal to T cells (innate immune system)
What do myeloid stem cells differentiate into?
RBCs
Platelets
granulocytes
What do lymphoid stem cells differentiate into?
Effector/adaptor immune cells (B, T and natural killer cells)
What autoantibodies are being released in synovial fluid?
80% of cases
Rheumtoid factor
Anticitrullinated protein antibodies (ACPAs)
Where do ACPAs come from?
Peptidylarginine deiminases (PADs)
What are ACPAs predicative to?
Bone erosion
CVD
How are PADs released from Neutrophils?
During NET if PAD levels are high
What is the MoA of PADs?
Citrullination of extracellular proteins, structural proteins
What are 3 cytokines that drive inflammation in RA?
IL-1
IL-6
TNF-alpha
What do T cells signal osteoclasts through?
Osteoprotegerin ligands
What do FLS become?
APC and secrete cytokines & MMPs
Where do the main cytokines for RA come from?
Macrophages
What are 2 ways of neutralization of cytokines?
Soluble receptor
Monoclonal antibody
What are 2 ways for receptor blockade?
Anatagonist
Mabs
Whar are 3 ways to treat RA?
Neutralization of cytokines (infliximab)
Receptor blockade (Recombinant IL-1)
Activation of anti-inflammatory pathways (IL-4/10)
What are the 4 signalling pathways in FLS?
Triggered by cytokine binding
Transcriptional regulation
Phosphorylation of downstream proteins
Crosstalk between pathways
How high is the genetic link for seropositive (ACPA positive)?
53-68%
How much does the hypermethylation signal of CpG promoter regions in FLS increase to?
> 84%
What region is the most attributable to genetic factors?
MHC (20%)
What can target methylation of promoter regions?
DNMT inhibitors
What pathway do RA Pts use instead of glycolysis?
PPP - Redox imabalnce -> low aspartate -> ER expansion -> T cell turned into TNF-a super producer
What are 3 RA therapeutics?
NSAIDs eg. ibuprofen
GCs eg glucocorticoids
DMARDs
What are three types of DMARDs?
conventional synthetic
biological
targeted synthetic
Whats an example of csDMARDs?
Methotrexate
What are 6 characteristics of methotrexate?
Very effective
rapid
adenosine is naturally anti-inflammatory
high intolerance
anti-cancer
combination therapy
What are 2 downfalls of methotrexate?
Increase susceptibility to other infections
Narrow therapeutic range
What are 2 characteristics of the TNF-a hypothesis?
Produced by macrophage first responders
Increase level of other cytokines (IL-1_
What 3 things does IL-1 increase?
Anti-inflammatory cytokines
bone and cartilage destruction
Pro-inflammatory cytokines
What were 3 downfalls of early anti-TNFa trials?
Hamster IgG suppressed systemic inflammation
Caused local inflammation in transgenic lines
other s/es
What are the 3 main TNF-a inhibitors?
Infliximab
Adalimumab
Etanercept (soluble receptor)
What are 5 characteristics of Adalimumab?
Specific for TNF-a
Binds soluble & transmembrane
SC EOW
fully human
produced from CHO
What are 4 characteristics of Etanercept?
Soluble fusion protein
Human TNF receptor p75 & Fc human IgG1
Dimeric
What are 3 other bDMARDs?
Anti-TNFa - infliximab
IL-6 antibodies - Tocilizumab
Target B cells directly - Rituximab
What are characteristics of Tofacitinib (tsDMARDs)?
Pan-JAK inhibitor
Prevents cytokine transcription
S/e - herpes
What are characteristics of 5-AZA-CdR?
DNA methylation inhibitor
reduces chemokine/cytokine release
allevaites inflammation
