Systems- Musculoskeletal Flashcards Preview

1st year Medicine > Systems- Musculoskeletal > Flashcards

Flashcards in Systems- Musculoskeletal Deck (16):
1

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

2

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

3

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

4

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

5

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)

6

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

7

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

8

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

9

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

10

Chemokines causing joint destruction in RA

IL-8 attracts neutrophils
IL-16 attracts eosinophils
Both release inflammatory mediators, vicious cycle of damage

11

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

12

LRP5

Drives osteoblast differentiation pathway, so new bone formation leads to high bone mass

13

Sclerostin

A brake to bone formation, so in high strain it is switched off

14

Antiresorptive treatment of osteoporosis

Bisphosphonates
Denosumab
Suppress bone turnover

15

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

16

Osteoarthritic bone releases these factors to cause articular cartilage degradation

TGF B
PGE2
IL6
IGF 1