pathophysiology Flashcards
inflammation: recognise the role of prostaglandins and inflammatory molecules (including cytokines, gamma-interferon, interleukins and TNF-alpha) in mediating inflammation, recall the scientific basis for the use of TNF-alpha inhibitors and prostaglandin blockade in rheumatic disease
what cell can produce different cytokines, and what are their effect
T cells and macrophages, causing macrophage, B and T cell activation
what is the dominant pro-inflammatory cytokine in rheumatoid synvoium and is therefore inhibited in treatment
TNF-a
8 actions of TNF-a in synovium
proinflammatory cytokine release, PGE2 production, osteoclast activation, chondrocyte activation, angiogenesis, leukocyte accumulation, endothelial cell activation, chemokine release, hepcidin induction
what cytokines will take over from TNF-a if TNF-a inhibited, and therefore also have a clinically available blockade
IL-1, IL-6
what else can be done in addition to cytokine blockade when treating rheumatoid arthritis
deplete B cells by parenteral (i.v.) administration of antibody against B cell surface antigen CD20
what other cytokine is important in bone destruction in rheumatoid arthritis
RANKL
what cells produce RANKL in rheumatoid arthritis, and function
produced by T cells and synovial fibroblasts, acting to stimulate osteoclast formation by binding to RANK on osteoclast precursors
what is a monoclonal antibody against RANKL, and what is it used to treat
denosumab, used for treatment in osteoporosis, bone metastases, multiple myeloma and giant cell tumours
what is a key feature of systemic lupus erythematosus, and is therefore targeted
B cell hyper-reactivity
2 biological treatments of systemic lupus erythematosus
rituximab, belimumab
how does rituximab help treat systemic lupus erythematosus
chimeric anti-CD20 antigen antibody used to deplete B cells
how does belimumab help treat systemic lupus erythematosus
recombinant fully human IgG1 monoclonal antibody against B cell survival factor (BLYS); inhibits this, resulting in impaired B cell survival and reduced B cell numbers
what do other biological therapies for systemic lupus erythematosus
antigens, B cell survival factors, B cell receptors, IL, complement
what are prostaglandins
lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells
what are prostaglandins synthesised from
essential fatty acids
what does phospholipase A2 generate from diacylglycerol in cell membranes, and what drug inhibits it
arachidonic acid, with glucocorticoids inhibiting phospholipase A2
2 pathways arachidonic acid enters and what they form
cyclooxygenase (COX) pathway to form prostaglandins (anti-inflammatory), lipooxygenase pathway to form leukotrienes (pro-inflammatory)
what do NSAIDs inhibit
cyclooxygenase pathway (COX)
4 benefits of NSAIDs inhibiting COX
analgesia, anti-pyretic, anti-inflammatory, anti-platelet (thromboxane A2)
5 unwanted effects of NSAIDs inhibiting COX
asthma exacerbation, gastro-intestinal ulcers, thrombosis, liver and renal problems
2 isoforms of COX
COX-1 (constitutive) and COX-2 (inducible)
