What is the 'Triple Therapy' for RA?
A treatment with 3 csDMARDS
Methotrexate, Sulfasalazine and Hydroxychloroquine
What are Matrix Metalloproteinases (MMPs)?
Enzymes that break down collagen
Active at neutral pHs, and require Zn2+
Activated by the removal of propeptides by other proteases
Can be inhibited by Tissue Inhibitors of Metallo-Proteinases (TIMPs)
What are the main 'risk' genes for RA?
Genes in the MHC region
Explain the Reactive Oxygen Species pathway
What is LAD-1?
An adhesion deficincy
Leukocytes do not adhere to extracellular material or endothelium
Leukocytes deficient in the B2 integrin
What is Rheumatoid Arthritis?
The persistant joint inflammation (of synovium) of at least 3 joint areas
Early morning stiffness of at least 30 min duration
1% of people in the UK have RA
What are Anti-Citrullinated Protein Antibodies (ACPA)?
These are highly specific for RA
Can be found in the body up to 14yrs before the onset of RA symptoms
Can predict erosive and progressive disease
What is the main active ingrediant in Sulfasalazine?
What is Leflunomide?
A new DMARD
Inhibits dihydro-oroate dehydrogenase --> used in the ynthesis of pyrimidines
Explain Prostanoid receptors
PGE2 (prostaglandins)--> EP1 - 4 Act on very specific GPCRs on target cells
PGI2 (prostacyclin) --> IP
Thromboxane receptor = TP
PGD2 --> DP1 + 2
What are the effect of RONS?
Activation of inflammatory gene transcription
Amino acid modifications
DNA damage --> cell apoptosis
What is the EP3 receptor?
A prostaglandin receptor
Activates leukocytes and mast cells
Promotes oedema formation
What are Chemokines?
Produced in responce to bacteria, TNF and IL-1
Act on GPCRs
CXC --> Neutrophil attractants
What are eicosanoids?
Oxidation products of 20carbon long fatty acids
Primerily from Arachidonic Acid
Main type is prostaglandins
What are chemotaxins?
Molecules that attract and activate leukocytes (increasing integrin avidity and affinity)
Selective = Chemokines
Explain how low dose aspirin is beneficial......and how therefore taking a COX-2 selective NSAID can have adverse effects
Aspirin is selective to COX-1, and so prevents (pro-thrombotic) thromboxane from platelets, which will decrease the chances of clotting)
This is effective as platelets cannot remake proteins as they have no nucleus, so this effect occurs for a period of time. Also the endothelial produced PGI2 is unaffected
However, when a COX-2 inhibitor is used, PGI2 production stops, and so clotting becomes much more common, as the pro-thrombotic thromboxane is still present (as COX-1 isn't inhibited)
What are the key indications of poor outcome in RA?
Genetics --> eg, the HLA-DRB1 genotype present
Lab Results --> RF or ACPA presence.....high CRP level
Clinical Assessment --> Many active joints and poor scores
Low educational / social-economical circumstances
What is Rheumatoid Factor?
Antibodies that bind to the Fc domain of IgG
What are the 2 neuropeptides that can positively feedback on histamine release and oedema formation?
NKA (Neurokinin A)
Explain which each of the 3 selectins are
L - Expressed on inactivated leukocytes
This causes leukocyte activation, which increases avidity (stickability)
There is rapid shredding of the selectin by proteolytic cleavage (shedase)
P - Expressed on platelets and endothelium
Start in granules, and are rapidly translocated to the cell surface upon activation
E - Endothelial expression is induced by cytokines or LPS
Required 'de novo' synthesis --> made on demand --> so takes time (hours)
Their expression is inhibited by glucocorticoids
What is Rituximab?
A B cell depleting monoclonal anti-CD20 antibody
What are the 5 cardinal signs of inflammation?
Loss of Function
What is the enzyme that primarily controls steroid biosynthesis?
Produces mevalonic acid
What are the 3 things that plasma proteases are used to create, in reference to inflammation
Kinins (Bradykinin) --> Increases permeability/vasodialtion and pain
Complement --> Activates leukocytes, mast cell degranulation, and bacterial lysis and opsonisation
Clotting Cascade --> Amplifies the kinin and complement pathways
Also causes thrombosis and platelet activation
What are Leukotrienes (LTs)? And what are their actions?
A classic eiconisoid
Present in inflammation
What is a selectin?
A lectin-like adhesion molecule
So bind to carbohydrate molecules weakly
Important in the tethering of leukocytes to the endothelium
What is leukocyte adhesion deficiency II (LAD-II)?
Patients have defective fucose (a CHO) metabolism
So leukocytes do not express the correct ligands for selectins..... which causes a reduced 'rolling' response (for E/P selectins only)
So less white blood cells where the inflammation has taken place
Reccurent infections without pus
What are integrins?
Heterodimeric proteins that re expressed on the surface of leukocytes
Important for 'Firm Adhesion'
When leukocytes are activates, a conformational change of the integrin occurs, increasing avidity (stickiness) and affinity
What is Angioedema?
Deep cutaneous and mucosal swelling
Can be induced from ACE inhibitors
Driven mainly from mast cell degranulation (release of histamine) --> due to the activation of plasma proteases
How does Oedema (swelling) occur?
H1 receptor binding of histamine causes endothelial-derived Nitric Oxide to be released, causing arteriolar dialation
The endothelium then contracts, which makes venules leaky --> increasing permeability