Systems- Musculoskeletal Flashcards
Sulphasalazine
DMARD
Reduces absorption of antigens from colon that may promote joint inflammation
Reduces synthesis of inflammatory mediators
Side effects- GI
- reversible decrease in sperm count
- blood dyscrasias, anaphylaxis
Methotrexate
DMARD Inhibits enzymes involved in purine metabolism, so adenosine accumulated, T cell activation inhibited, adhesion molecules expression by T cell suppressed Side effects - blood dycrasias (due to bone marrow suppression) - liver cirrhosis - diarrhoea - ulcerative stomatitis - peptic ulceration
Gold (aurothiomalate, auranifin)
DMARD Binds to tissue proteins and accumulates widely, including in synovium of inflamed joint Unsure of mechanism Side effects - blood disorders (aplastic anaemia, agranulocytosis) - skin rashes - diarrhoea - glomerulonephritis
Steroids
Therapy for RA
Immunosuppressive, act on cell-mediated immune responses
Reduced transcription of pro inflammatory genes IL2, TNFa, IFy
Blocks eicosanoid production
Many side effects, hard to ensure benefits outweigh negatives
Biologics
To treat RA
Expensive and new
Monoclonal antibodies that remove some pathways, dampening the immune response
Eg Inflicimab works on TNFa pathway
Injection needed every 2-4 weeks
Effects wear off eventually, though huge improvement initially
Only prescribed if- failed 2 standard DMARDs including methotrexate after 6 months
-not pregnant, breastfeeding, intolerant, severe infection, malignant (don’t want to suppress immune system)
Gastrulation
3 layers of inner cell mass of a blastocyst:
Ectoderm will form nervous system and skin
Mesoderm will form blood, heart and muscle
Endoderm will form pancreas, liver, but and lungs
Outer cells are profoblast cells, will form placenta etc
Role of B cells in RA
MAKING ANTIBODIES
-Rheumatoid Factor is autoantibody to own Fc fragment, 70-80% RA patients have
-Anti-CCP is antibody to cyclic citrullinated peptides, 90% RA patients have. Citrullinated peptides bind to HLA genes via QKRAA
-Antibodies to nuclear proteins (eg histone)
-Antibodies to heat shock proteins (HSPs)
These form immune complexes by interracting with one another, their deposition causes acute inflammation
SECRETE CYTOKINES
IL6, IL10, TNFa
MAINTAIN T CELL ACTIVATION
Role of T cells in RA
Unsure of how, but must be critical role as…
- T cell directed treatments effective in RA
- Cyclosporin is beneficial
- Many T cells in pannus
- RA resolution in AIDs and pregnancy
Cytokines and inflammatory mediators causing joint destruction in RA
TNFa
-> stimulates macrophages to produce matrix metalloproteases and free radicals
-> induces production of pro inflammatory cytokines IL-1 and IL-6
-> stimulates cells in joint to breakdown matrix
-> activates endothelial cells so more recruitment
IL-1B
y-INF
IL-6
Chemokines causing joint destruction in RA
IL-8 attracts neutrophils
IL-16 attracts eosinophils
Both release inflammatory mediators, vicious cycle of damage
Enzymes causing joint destruction in RA
Classes of proteases produced by fibroblasts, degrade cartilage in RA
CYSTEINE PROTEASES
Cathepsin M and B destroy proteoglycan and collagen in cartilage
Cathepsin K resorbs bone
ASPARTATE PROTEASES
SERINE PROTEASES
METALLOPROTEASES
-Collagenase (MMP-1, MMP-8, MMP-13) destroys collagen II in articular cartilage
-Stromelysin (MMP-3, MMP-10, MMP-11) degrades proteoglycan in articular cartilage
-Gelatinase (MMP-1, MMP-9) degrades product of MMP-1 further
LRP5
Drives osteoblast differentiation pathway, so new bone formation leads to high bone mass
Sclerostin
A brake to bone formation, so in high strain it is switched off
Antiresorptive treatment of osteoporosis
Bisphosphonates
Denosumab
Suppress bone turnover
Anabolic treatment of osteoporosis
Parathyroid hormone (PTH) Long term stimulates bone resorption to maintain calcium levels in the body Short term (one off injection) stimulates bone formation by enhancing osteoblast activity
