Rheumatology/Osteoporosis/Weightlessness Flashcards
What are potential problems with inflammation?
Bystander Damage
Too intense of a response
Why doesn’t everyone get auto-immune diseases?
Tolerance (controlled unresponsiveness to self)
Immune system has regulatory checks
What is the 2 hit mechanism of autoimmune disease?
Genetic susceptibility-> susceptible genes resulting in failure of self-tolerance
Infection/inflammation
How do RA patients present?
Pain, swelling (metacarpal-phalangeal joints, seen when trying to form fist), stiffness
Pain is common in morning and due to inactivity
What sex is more likely to develop autoimmune disease?
Women, 2-3x more
Potentially due to fact that women live with foreign material (during pregnancy)
What is palmer deviation?
Movement of phalangeal bones laterally/medially.
Way the tendons will pull the bones if RA becomes very severe
What other morbidities may occur alongside RA?
Sarcopenia (extreme loss of muscle mass)
Metabolism abnormailities (store fat in liver)
Vessel inflammation (can cause CVD, increase in myocardial infarction)
Fatigue
Depression
Why do people get RA?
Born with risk factors
Environmental exposures later in life
What are the phases of RA?
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
What are genetic risk factors? Fix this question.
Genome wide association studies show evidence of immune function contribution displaying it is adaptive Epigenetic abnormalities (methylation)
What is the strongest risk factor for RA?
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.
How does microbiome relate to RA?
Prevotella copri bacteria is enriched in early RA
This is where our immune system becomes educated about the environment and learns to tolerate things.
What are 2 important molecules involved in systemic autoimmunity leading to RA?
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))
Why does RA go to the joints?
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.
How do cells within joints change as a result of RA?
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
What are some treatments in RA?
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)
What are some popular Disease Modifying Anti-Rheumatic Drugs?
Methotrexate Sulphasalizine Leflunomide Hydroxychloroquine Many also have an immune dampening effect.
What are biologic agent DMARDs?
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
In relation to B cells, what drug can be used to treat RA?
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
How can we treat RA by targeting cytokines?
Can interfere with pro-inflammatory cytokines
Anti-6 receptors (TNF, or IL-6)
IL6 and cytokine storm is important
Why is inhibiting JAK kinases not going to work in comparison to blocking cytokines when treating rheumatoid arthritis?
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.
How does the immune and nervous system relate in terms of developing RA?
Mice who have had their vagus nerves cut cannot produce TNFa and therefore don’t develop RA.
How does TNFa related to RA?
TNF is pro-inflammatory involved largely in bacterial infection (not viral, this is interferons).
Blocking TNFa also reduces further inflammatory cytokines, like IL1.
Is RA and its treatments associated with increased risk of infection?
Yes
Is RA and its treatments associated with increased risk of malignancy?
Yes
How much bone density is lost by age 80, and when does most bone loss occur?
25-40%
Most loss occurs first 5 years following menopause
What is a fragility fracture?
Fractures resulting from mechanical force that would not ordinarily result in fracture
Said force equivalent to falling from a standing height or less
What fragility fracture is most and least common?
Spinal vertebrae, hip (proximal femur), then wrist (distal radius) is least
What causes the most hospital admissions in people over 75?
Fracture of femur (significantly greater)
Then lumbar/pelvic fracture
What people are at highest risk for fragility fracture and are invited for screening?
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)
How can you maximize peak bone mass?
Regular weight bearing exercise Healthy diet Sufficient Vitamin D Avoid smoking Responsible alcohol consumption
What are the 2 main forms of pharmaceutical treatment for osteoporosis?
Antiresorptive- inhibit osteoclasts, but don’t promote building muscle (bisphosphonates, denosumab)
Anabolic- stimulate bone formation via osteoblast (Teriparatide- injection stimulates osteoblasts)
How much muscle bulk is lost during aging and when?
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)
Can you prevent muscle aging?
Yes, by doing weight bearing exercise
What is sarcopenia?
Progressive and generalized skeletal muscle disorder associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality.
What is the primary parameter in defining sarcopenia?
Low muscle STRENGTH, not necessarily muscle loss
What declines are more drastic in terms of muscle with aging?
More of a decline in muscle strength
Decline of muscle mass is not as drastic
What are the two types of sarcopenia?
Primary- age related, no cause for sarcopenia
Secondary- activity, disease, or nutritional related declines
How do you screen for sarcopenia?
Sarc-F screening tool- if they score positive on tool, you look for further investigations
How do you diagnose sarcopenia?
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
What are the steps of diagnosis of sarcopenia according to the European Algorithm?
Suspicion -> Grip strength test -> DXA Scan (will confirm) -> Performance measurements (Gait speed, TUG) -> severity is confirmed
What impacts does sarcopenia have on a person?
Increased hospitalization
Increased mortality
Increased frailty
What is the treatment for sarcopenia?
Exercise- resistant and aerobic Nutrition attention (increased protein) Vitamin D supplementation for those deficient
What are consequences of musculoskeletal aging?
Altered gait and balance leading to falls
Increased injury (fracture)
Chronic pain (50% in community, 80% in long-term care)
Isolation
Loss of independence
What changes are seen in both hormone and cell activity in relation to bone ageing
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
Does osteoporosis cause pain?
No, it is painless. Its complications cause pain
How does the body respond to weightlessness?
It begins to excrete more calcium and phosphate, as the body ‘thinks’ it is not needed.
Muscle fibre loss/weakness occurs
What is the turnover rate of bone in young people vs elderly?
20% turnover in young
2% in elderly
When is peak muscle typically reached?
28-29 years.
What changes cause bone and muscle mass loss?
Linked to endocrines and rates of activity
What type of force does gravity create and what resists this?
Compressive
Hydroxyapatite resists this force, although collagen aids in the flexibility needed when undergoing compressive force (they reinforce it by allowing for flexion)
What drives bone remodelling?
Loading forces
What hormones/factors help regulate bone remodelling?
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
How does air quality relate to rickets?
Too much fog will reduce sunlight, which will reduce Vitamin D activation.
What are the physiological consequences of prolonged space flight?
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
What percentage of muscle loss is seen in the lower limbs when in free-fall conditions?
6-8% in thigh
4-6% in calf
How can we prevent bone loss when in space?
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)
What are physiological impacts observed in astronauts returning to earth?
Hypotension (reduced blood volume)
Weakness (sarcopenia)
Bone demineralization (osteopenia)
