Rheumatology/Osteoporosis/Weightlessness

Question 1

What are potential problems with inflammation?

Answer 1

Bystander Damage

Too intense of a response

Question 2

Why doesn’t everyone get auto-immune diseases?

Answer 2

Tolerance (controlled unresponsiveness to self)

Immune system has regulatory checks

Question 3

What is the 2 hit mechanism of autoimmune disease?

Answer 3

Genetic susceptibility-> susceptible genes resulting in failure of self-tolerance
Infection/inflammation

Question 4

How do RA patients present?

Answer 4

Pain, swelling (metacarpal-phalangeal joints, seen when trying to form fist), stiffness
Pain is common in morning and due to inactivity

Question 5

What sex is more likely to develop autoimmune disease?

Answer 5

Women, 2-3x more

Potentially due to fact that women live with foreign material (during pregnancy)

Question 6

What is palmer deviation?

Answer 6

Movement of phalangeal bones laterally/medially.

Way the tendons will pull the bones if RA becomes very severe

Question 7

What other morbidities may occur alongside RA?

Answer 7

Sarcopenia (extreme loss of muscle mass)
Metabolism abnormailities (store fat in liver)
Vessel inflammation (can cause CVD, increase in myocardial infarction)
Fatigue
Depression

Question 8

Why do people get RA?

Answer 8

Born with risk factors

Environmental exposures later in life

Question 9

What are the phases of RA?

Answer 9

Phase A- Genetic Risk factors
B- Environmental Risk factors 
C- autoimmunity, but no symptoms (tells us maybe RA starts outside the joints and moves there later)
D- symptoms
E- Undifferentiated arthritis 
F- Established RA

Question 10

What are genetic risk factors? Fix this question.

Answer 10

Genome wide association studies show evidence of immune function contribution displaying it is adaptive
Epigenetic abnormalities (methylation)

Question 11

What is the strongest risk factor for RA?

Answer 11

Smoking.
HLA-DRB1 alleles (the shared epitope, can have 1, or double shared-epitope, more equals larger risk)
If you have the gene and smoke, there is an exponential risk at developing RA.

Question 12

How does microbiome relate to RA?

Answer 12

Prevotella copri bacteria is enriched in early RA

This is where our immune system becomes educated about the environment and learns to tolerate things.

Question 13

What are 2 important molecules involved in systemic autoimmunity leading to RA?

Answer 13

CCP antibodies (binds to post translational modifications of proteins. CCP is cyclic citrullinate peptide, where citrulline replaces arginine) 
Rheumatoid factor (antibody directed against an self-antibody (FC fragment of IgG or IgM))

Question 14

Why does RA go to the joints?

Answer 14

We don’t know.
We have systemic response, and then we get immune cells that invade joints.
There are defects in CD4 T cells where differentiation of naïve CD4 to Th effector cells happens, and this ‘starts a war’ in the joints.

Question 15

How do cells within joints change as a result of RA?

Answer 15

Fibroblast-like synoviocytes start releasing inflammatory cytokines
Osteoclasts release MMP
DC presentation to:
T cells -> release cytokines
B cells -> release autoantibodies
Both contribute to worsening inflammation

Question 16

What are some treatments in RA?

Answer 16

NSAIDs
Corticosteroids- don’t prevent damage though, used short term
Disease-modifying antirheumatic drugs (DMARDs)- There are conventional synthetics which reduce reactivity of leukocytes helping decrease cytokines, and Biologics ones (monoclonals) which can bind receptors for particular cytokines (typically TNF)

Question 17

What are some popular Disease Modifying Anti-Rheumatic Drugs?

Answer 17

Methotrexate
Sulphasalizine
Leflunomide
Hydroxychloroquine
Many also have an immune dampening effect.

Question 18

What are biologic agent DMARDs?

Answer 18

Drugs, like monoclonal abs, receptors, or peptides, that are developed rationally by targeting processes important in the disease pathogenesis, i.e. cytokines, t cells, and B cells
They have to be injected

Question 19

In relation to B cells, what drug can be used to treat RA?

Answer 19

CD20 receptor on B cells can be blocked by Anti-C20 monoclonal antibody (rituximab), depleting mature B cell levels and therefore reducing levels of Auto-Ab

Question 20

How can we treat RA by targeting cytokines?

Answer 20

Can interfere with pro-inflammatory cytokines
Anti-6 receptors (TNF, or IL-6)
IL6 and cytokine storm is important

Question 21

Why is inhibiting JAK kinases not going to work in comparison to blocking cytokines when treating rheumatoid arthritis?

Answer 21

JAK 1-3 and TYK2 receptors sit on surface with the tyrosine kinase receptors.
If you block them though, you block all pathways, so you can get a lot of off target effects.

Question 22

How does the immune and nervous system relate in terms of developing RA?

Answer 22

Mice who have had their vagus nerves cut cannot produce TNFa and therefore don’t develop RA.

Question 23

How does TNFa related to RA?

Answer 23

TNF is pro-inflammatory involved largely in bacterial infection (not viral, this is interferons).
Blocking TNFa also reduces further inflammatory cytokines, like IL1.

Question 24

Is RA and its treatments associated with increased risk of infection?

Answer 24

Yes

Question 25

Is RA and its treatments associated with increased risk of malignancy?

Answer 25

Yes

Question 26

How much bone density is lost by age 80, and when does most bone loss occur?

Answer 26

25-40% | Most loss occurs first 5 years following menopause

Question 27

What is a fragility fracture?

Answer 27

Fractures resulting from mechanical force that would not ordinarily result in fracture Said force equivalent to falling from a standing height or less

Question 28

What fragility fracture is most and least common?

Answer 28

Spinal vertebrae, hip (proximal femur), then wrist (distal radius) is least

Question 29

What causes the most hospital admissions in people over 75?

Answer 29

Fracture of femur (significantly greater) | Then lumbar/pelvic fracture

Question 30

What people are at highest risk for fragility fracture and are invited for screening?

Answer 30

Those who have fragility fractures after 50 years of age Also carry out fracture-risk assessments (online) to determine people's risk which will determine risk (if major risk, they should be invited for DXA)

Question 31

How can you maximize peak bone mass?

Answer 31

``` Regular weight bearing exercise Healthy diet Sufficient Vitamin D Avoid smoking Responsible alcohol consumption ```

Question 32

What are the 2 main forms of pharmaceutical treatment for osteoporosis?

Answer 32

Antiresorptive- inhibit osteoclasts, but don't promote building muscle (bisphosphonates, denosumab) Anabolic- stimulate bone formation via osteoblast (Teriparatide- injection stimulates osteoblasts)

Question 33

How much muscle bulk is lost during aging and when?

Answer 33

From 30 years onwards, 3-8% atrophy of muscle fibers per decade is lost General muscle fibre loss (5% 24-50, then 25% over next 25 years)

Question 34

Can you prevent muscle aging?

Answer 34

Yes, by doing weight bearing exercise

Question 35

What is sarcopenia?

Answer 35

Progressive and generalized skeletal muscle disorder associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality.

Question 36

What is the primary parameter in defining sarcopenia?

Answer 36

Low muscle STRENGTH, not necessarily muscle loss

Question 37

What declines are more drastic in terms of muscle with aging?

Answer 37

More of a decline in muscle strength | Decline of muscle mass is not as drastic

Question 38

What are the two types of sarcopenia?

Answer 38

Primary- age related, no cause for sarcopenia | Secondary- activity, disease, or nutritional related declines

Question 39

How do you screen for sarcopenia?

Answer 39

Sarc-F screening tool- if they score positive on tool, you look for further investigations

Question 40

How do you diagnose sarcopenia?

Answer 40

Muscle function is tested first- look for muscle weakness (grip strength, chair-stand strength, gait speed) Muscle mass- can use CT/MRI cross sectioning and calculate muscle bulk. Can use DXA scanners. Bioimpedance analysis- scale and height used to calculate body composition but not reproducible

Question 41

What are the steps of diagnosis of sarcopenia according to the European Algorithm?

Answer 41

Suspicion -> Grip strength test -> DXA Scan (will confirm) -> Performance measurements (Gait speed, TUG) -> severity is confirmed

Question 42

What impacts does sarcopenia have on a person?

Answer 42

Increased hospitalization Increased mortality Increased frailty

Question 43

What is the treatment for sarcopenia?

Answer 43

``` Exercise- resistant and aerobic Nutrition attention (increased protein) Vitamin D supplementation for those deficient ```

Question 44

What are consequences of musculoskeletal aging?

Answer 44

Altered gait and balance leading to falls Increased injury (fracture) Chronic pain (50% in community, 80% in long-term care) Isolation Loss of independence

Question 45

What changes are seen in both hormone and cell activity in relation to bone ageing

Answer 45

Reduction of oestrogen following menopause causes loss of inhibition of resorption leading to increased osteoclast activity -> increased remodelling Reduction in secretion of and sensitivity to Growth Factors and IGF-B (needed for osteoblast differentiation) Reduction in osteoblast proliferation and differentiation Reduced ability of osteoblasts to sense/respond to mechanical force

Question 46

Does osteoporosis cause pain?

Answer 46

No, it is painless. Its complications cause pain

Question 47

How does the body respond to weightlessness?

Answer 47

It begins to excrete more calcium and phosphate, as the body 'thinks' it is not needed. Muscle fibre loss/weakness occurs

Question 48

What is the turnover rate of bone in young people vs elderly?

Answer 48

20% turnover in young | 2% in elderly

Question 49

When is peak muscle typically reached?

Answer 49

28-29 years.

Question 50

What changes cause bone and muscle mass loss?

Answer 50

Linked to endocrines and rates of activity

Question 51

What type of force does gravity create and what resists this?

Answer 51

Compressive Hydroxyapatite resists this force, although collagen aids in the flexibility needed when undergoing compressive force (they reinforce it by allowing for flexion)

Question 52

What drives bone remodelling?

Answer 52

Loading forces

Question 53

What hormones/factors help regulate bone remodelling?

Answer 53

PTH- increases osteoclast activity via ^RANKL expression (also inhibit PO4 reabsorption in kidney) Vit D- Increases Ca and PO4 absorption from gut and recovery from renal filtrate Calcitonin- Lowers plasma Ca by reducing osteoclast activity FGF23- Reduces PO4 and calcium reabsorption from kidneys Oestrogen- Inhibits bone resorption

Question 54

How does air quality relate to rickets?

Answer 54

Too much fog will reduce sunlight, which will reduce Vitamin D activation.

Question 55

What are the physiological consequences of prolonged space flight?

Answer 55

Fluid shifts, fluid and electrolyte loss (change in urine composition) Negative energy balance (not eating enough calories) Both points above result in: -Bone Loss -Skeletal and (some) cardiac muscle atrophy Less radiation exposure These changes are similar to aging

Question 56

What percentage of muscle loss is seen in the lower limbs when in free-fall conditions?

Answer 56

6-8% in thigh | 4-6% in calf

Question 57

How can we prevent bone loss when in space?

Answer 57

Alendronate- form of bisphosphonates which slows bone turnover by being absorbed onto hydroxyapatite crystals Maintain formation with heavy resistance exercise Maintain nutrients- vit d supplementation (and other minerals/vitamins like Vitamin K which has role in stabilizing bone)

Question 58

What are physiological impacts observed in astronauts returning to earth?

Answer 58

Hypotension (reduced blood volume) Weakness (sarcopenia) Bone demineralization (osteopenia)