LOCO1 Flashcards
Pharmacological managementfor OA
COME BACK
- Start with oral analgesics &/ or topical NSAIDs
- Where paracetamol or topical NSAIDs are ineffective then substitute with oral NSAID/COX-2 inhibitor
- Intra-articular injections; Corticosteroid injections
State 6 surgical interventions for OA [6]
Arthroscopic lavage
Arthroscopic lavage plus debridement
Microfracture
Mosiacplasty (osteochondral transplant)
Chondrocyte grafts
Joint replacement
Explain the MoA of chondrocyte grafting
Take chondrocytes from other areas of the body (e.g. costochondral joint)
Grow chondrocytes in culture
Place in graft and get more hyaline cartilage
OA treatment
Explain MoA of mosaicplasty (osteochondral grafting) [1]
Take undamaged cartilage from less weight bearing regions plus the underlying bone and move to OA region
OA treatment
Adalimumab targets which cytokine? [1]
TNF inhibition
Gout is a disorder of metabolising which substance? [1]
What does this mean has deposition in soft tissue? [1]
Uric acid metabolism disordered: causes monosodium urate crystals get deposited in soft tissues
Describe the pathophysiology of gout
Sudden increase in the number of crystals and the body isn’t able to respond by coating crystals with serum proteins
Uncoated crystals in the joint that triggers an attack.
Naked urate crystals are then believed to interact with intracellular and surface receptors of local dendritic cells and macrophages, serving as a danger signal to activate the innate immune system
This interaction may be enhanced by immunoglobulin G (IgG) binding.
(Triggering of these receptors, including Toll-like receptors, NALP3 inflammasomes, and the triggering receptors expressed on myeloid cells (TREMs) by MSU) results in the production of interleukin (IL)–1, which in turn initiates the production of a cascade of pro-inflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumour necrosis factor (TNF)–alpha
Neutrophil phagocytosis leads to another burst of inflammatory mediator production
Describe the role of neutrophils in gout pathogenesis
- Sudden increase in MSU uncoated crystals cause neutrophils to enter synovial fluid
- Neutrophils phagocytose MSU crystals, and macrophages that detect crystals release IL-1
- .The structure of MSU crystals cause neutrophil to be pierced, lyse and die
- Contents of neutrophil released: proteins, etc which bring more white blood cells in, and production of pro-inflammatory cytokines
- Acid released from neutrophils lowers pH, makes crystals precipitate even more: attack will start of pain, etc
- This inflammation from neutrophil phagocytosis is also aided by massive release of IL-1 from original macrophages that come into contact with crystal, which initiates a cascade of release of other cytokines like TNF-alpha, IL-6, IL-8, etc.
Explain the three mechanisms of gout development [3]
Purine overproduction:
* This occurs when there is increased cell turnover or lysis of cells leading to release of purines and breakdown to uric acid.
* Causes include myelo- or lymphoproliferative disorders, psoriasis and use of chemotherapy agents.
Increase purine intake:
* There are several foods and beverages that are rich in purines and increase the risk of developing gout.
* These include seafood (i.e. anchovies, sardines), red meat, alcohol and fructose-rich beverages.
Decreased uric acid secretion:
* Uric acid is predominantly renal excreted so anything that affects the kidneys can increase the risk of developing gout.
* Causes include diuretics (i.e. furosemide), acute kidney injury, chronic kidney disease, ACE inhibitors and diabetes mellitus
State two drug classes that could cause decreased uric acid secretion [2]
Name a disease that could cause high turnover of cells and therefore increased purine production [1]
Diuretics: Loop and Thiazide like
psoriasis
How would you treat acute gout / gout attack? [4]
NSAIDs:
* Start with highest dose for 2-3 days & taper down over 2 weeks
Colchicine:
* 2nd line (narrow therapeutic window and risk of toxicity)
Corticosteroids
* For those that can’t use NSAID or colchicine
IL1 biologicals
* Rilonacept, canakinumab, anakinra
* Reduces length of attack and reoccurrences
* Used for patients who have severe and frequent flares
Which IL1 biologicals can be used to treat acute gout? [3]
Rilonacept, canakinumab, anakinra
Describe how you treat chronic gout [5]
Allopurinol:
* Blocks xanthine oxidase, which is responsible from converting xanthine (which comes from purines in the diet) to urate
Febuxostat:
* non-purine selective inhibitor of xanthine oxidase
uricosuric:
* increases uric acid excretion
Probenecid:
* increases the secretion of uric acid
* fewer side effects than allopurinol.
Rasburicase:
* Catalyses conversion of uric acid to allantoin
Describe the pathogenesis of pseudogout [2]
Deposition of calcium pyrophosphate in and around joints onto the surface of the articular cartilage and the fibrocartilage:
- Release of calcium pyrophosphate crystals into the joint space
- followed by neutrophils, macrophages etc phagocytosing the crystals: cytokine release and inflammation.
- The crystals are not as shiny or sharp/needle like, meaning they don’t cause NETosis and the attack is much milder, with a slower onset.
This sign is suggestive of
Osteoarthritis
Gout
Pseudogout
Rheumatoid arthritis
Osteoporosis
Rheumatoid arthritis: Bakers cyst
Teriparatide is a treatment for
Osteoarthritis
Gout
Pseudogout
Rheumatoid arthritis
Osteoporosis
Osteoporosis
Teriparatide is a recombinant PTH:
PTH upregulates RANKL - signals osteoblast to differentiate when have low Ca2+: work indirectly on osteoclasts to boost bone making potential
Intermittent exposure to PTH activates osteoblasts more than osteoclasts
Recombinant PTH used to treat OP is called? [1]
Teriparatide
Name drug A used to treat osteoporosis [1]
Denosumab
Name drug A used to treat osteoporosis [1]
Teriparatide
Osteoporosis treatment
Describe the MoA of Teriparatide [2]
Teriparatide is a recombinant PTH:
- PTH upregulates RANKL - signals osteoblast to differentiate when have low Ca2+: work indirectly on osteoclasts to boost bone making potential
- Intermittent exposure to PTH activates osteoblasts more than osteoclasts
Osteoporosis treatment
Describe the MoA of Denosumab [2]
PTH normally inhibits OPG.
Denosumab is a an osteoprotegrin artificial antibody & acts as a monoclonal antibody to RANK:
Denosumab: human monoclonal antibody that inhibits RANKL and helps regulate turnover in healthy bone. Denosumab binds with high specificity and affinity to the cytokine RANKL, inhibiting its action; as a result, osteoclast recruitment, maturation and action are inhibited, and bone resorption slows
Descibe pathophysiology of Pagets disease [2]
Describe the three phases of Pagets disease [3]
(Theory) osteoclasts: may be infected with a virus that alters them AND genetics
Phases:
1. increased rate of bone resorption:
* large number of giant osteoclasts
2. Compensatory phase / proliferative:
* increased bone formation & accelerated depostion in disorganised manner
3. Burnt out phase: sclerotic:
* Hyper-vascular bone marrow; Bone hypercellularity may diminish leaving dense “Pagetic bone”
How do serum results for Ca, PO4, ALP, PTH and 1,25(OH)D2 present for osteomalacia? [1]
Explain each result
Low Ca
Low PO4
ALP high
PTH high
Vit D low
- Main cause of osteomalacia: low vitamin d
- Low PO4 and Ca due to phosphate being excreted in order to keep any calcium possible via renal regulation).
- ALP high because produced in osteoblasts
- PTH high due to low Ca2+
How do serum results for Ca, PO4, ALP, PTH and 1,25(OH)D2 present for Pagets disease? [5]
Explain your answer [1]
Ca: normal
PO4: normal
ALP: raised
PTH normal
Vit D: normal
ALP raised due to characterised by high burn turnover
How do serum results for Ca, PO4, ALP, PTH and 1,25(OH)D2 present for renal failure [5]
Explain your answer [1]
failure leads to vitamin D deficiency, as 1,25(OH)2 D3 is made in the kidney.
This results in high PO4, low calcium and normal/high alkaline phosphatase
How would you confirm Osteosarcoma from a biopsy? [1
Giant cells confirm the diagnosis of an osteosarcoma arising out of Paget’s disease.
How do you treat Pagets disease? [5]
- Bisphosphonates work directly on osteoclasts to slow bone resorption. Can be given orally for 2-6 months, or IV single infusion-3 infusions. Bisphosphonates can almost cure Paget’s disease if you catch it early, and stop the osteoclast hyperactivity, as this will prevent sclerotic bone from forming.
- Calcium and vitamin D supplements
- Pain management
- Surgery
- Calcitonin used to be used more often, but now less than bisphosphonates
What is sclerostosis caused by? [1]
How do patients with sclerotosis present? [2] Explain your answer [1]
Absence, abnormal or reduced produced of sclerostin
Sclerostin produced by healthy osteocytes and inhibtis osteoblasts to prevent XS bone formation
Condition results in resistance to fractures and XS height
Which nerve is at risk here? [1]
median
A patient is found to have the following results: low serum calcium, low serum phosphate, raised ALP and raised PTH. Which condition are these findings most consistent with?
Paget’s disease
Chronic kidney disease
Primary hyperparathyroidism
Osteoporosis
Osteomalacia
Osteomalacia
Colchicine - inhibits microtubule polymerization by binding to tubulin, interfering with mitosis. Also inhibits neutrophil motility and activity
State three eye complications of RA [3]
Why is the eye commonly a problem? [1]
RA effects type 2 collagen; get lots of type 2 collagen in they eye
Keratoconjunctivitis sicca
Scleritis & episcleritis
Scleromalacia perforans: intraocular contents prolaspes out of the sclera
Describe three neuromuscular complications of RA [3]
Muscle wasting
Carpal tunnel syndrome
Atlanto-axial subluxation: odointal peg impinges on the spinal cord
State three connective tissue diseases
Systemic lupus erythematosus:
Scleroderma / Systemic sclerosis: progressive atrophy of soft tissue
Dermatomyositis: high level of creatine kinase; muscle weakness - get lots of rashes. proximal weakness
Gottron sign is an indication of which disease? [1]
Dermatomyositis
State an autoimmune disease that can cause AVN block [1]
Ankylosing spondylitis
What is the name for this sign of dermatomyositis? [1]
Gottron sign: red, thickened, scaly skin over the knuckles
This rash is likely to be sign of:
Scleroderma
Ankylosing spondylitis
Dermatomyositis
SLE
Dermatomyositis: purple rash around eye lids and face
Describe the difference in pathology of calcinosis between scleroderma and dermatomyositis [1]
systemic sclerosis: vascular hypoxia
dermatomyositis: release of calcium from mitochondria in muscle cells damaged by myopathy
Inflammation of the middle layer of the eye is a complication of:
Scleroderma
Ankylosing spondylitis
Dermatomyositis
SLE
Ankylosing spondylitis: anterior uveitis
Describe the pathophysiology of Scleroderma [1]
Autoimmune inflammatory and fibrotic connective tissue disease: immune mediated damage to vascular stuctures and excessive synthesis and depostion of extracellular martrix like collagen.
Cause chronic fibrosis, scarring and damage to organs
Cause of condition unknown
Describe a phenomenon associated with scleroderma [1]
Raynaud phenomenon: skin colour changes that occur in the fingers and toes from vasospasm.
What are skin features of dermatoymyositis? [5]
Gottron lesions (scaly erythematous patches) on the knuckles, elbows and knees
Photosensitive erythematous rash on the back, shoulders and neck
Purple rash on the face and eyelids
Periorbital oedema (swelling around the eyes)
Subcutaneous calcinosis (calcium deposits in the subcutaneous tissue)
Describe extra-articular manifestations of AS [3]
Anterior uveitis: inflammation of the middle layer of the eye. Typically causes unilateral eye pain and redness
Aortitis: can lead to aortic regurg
Atrioventricular block
Articular features of reactive arthritis? [3]
Extra-articular associations of reactive arthritis? [3]
Articular features:
* Peripheral arthritis
* Axial arthritis: inflammatory back pain
* Enthesitis and/or dactylitis
Extra-articular associations
* Bilateral conjunctivitis (non-infective)
* Anterior uveitis
* Circinate balanitis is dermatitis of the head of the penis
* Triad: arthritis, urethritis and, conjunctivitis
Which disease is depicted?
Systemic lupus erythematosus
Dermatomyositis
Scleroderma
Tendinitis
Scleroderma: Perioral skin tightening with decreased oral opening: gives rise to a ‘pursed-string’ appearance
This lady presents with puffy eyes. What disease is she most likely to have?
Systemic lupus erythematosus
Dermatomyositis
Scleroderma
Tendinitis
Dermatomyositis: Periorbital oedema (swelling around the eyes)
A 54-year-old woman, who is known to have systemic sclerosis, complains that her hands change colour in the cold. This is associated with severe pain. She asks if there is any medication you can prescribe.
Which of the following is a suitable first line option?
Amlodipine
Atenolol
Amitriptyline
Bisoprolol
Nifedipine
Nifedipine is a pharmacological option for Raynaud’s phenomenon
Explain the peripheral mechanism of inflammation during tissue injury [4]
Release of inflammatory mediators (K+ H+ bradykinin, histamine, 5HT, nitric oxide): make membranes more unstable
Activation of arachidonic acid pathway: production of leukotrienes and prostanoids
Activation of peripheral nociception (pain enhanced in inflammation)
Modulation of primary afferents to subsequent stimulus
Describe the pain pathways in neuropathic [4]
Pain is felt somewhere else, but pathology could be more proximal
Inflamamtion / mech. pressure causes the nerve to change behaviour: cell membrane becomes unstable and fires ectopic signals.:
* Alteration in ion channel expression
* Ectopic and spontaneous discharge
* Ephaptic conduction
* Collateral sprouting at primary afferents
* Sprouting of sympathetic neurones at DRG
RA Treatment:
Hydroxychloroquine blocks:
TLR7
TLR8
TLR9
TLR10
TLR11
TLR9
RA
Leflunomide inhibits which enzyme? [1]
What is the effect of this? [2]
Dihydroorotate dehydrogenase (DHODH): stops pyrimidine synthesis & therefore reduces pro-inflammatory cytokines: IL-1, TNF-A and IL-6; Blocks T cell proliferation
Which treatment for RA reduces pyrimidine synthesis?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
Infliximab
Leflunomide
Which treatment for RA that targets TLR-9?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
Infliximab
Hydroxychloroquine
Which treatment for RA that reduces dendritic cell activation?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
Infliximab
Hydroxychloroquine
Which is a treatment for RA that inhibits dihydro-orotate dehydrogenase?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
Infliximab
Leflunomide
Which treatment for RA is a tumor necrosis factor-alpha (TNF-alpha) inhibitor?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
Infliximab
Infliximab
Which treatment for RA leads to decreased T-cell proliferation and cytokine production?
Etanercept
Adalimumab
Anakinra
Rituximab
Abatacept
Tolizumab
Abatacept
Which treatment for RA is an IL-1 antagonist?
Etanercept
Adalimumab
Anakinra
Rituximab
Abatacept
Tolizumab
Anakinra
Which treatment for RA targets IL-6?
Etanercept
Adalimumab
Anakinra
Rituximab
Abatacept
Tolizumab
Tolizumab
Which treatment for RA targets upregulates CTLA-4, which switches T cell off?
Etanercept
Adalimumab
Anakinra
Rituximab
Abatacept
Tolizumab
Tolizumab
hyperflexion injuries to the vertebral body resulting from axial loading
This best describes a
Hangman fracture
Colles fracture
Smith fracture
Wedge fracture
Wedge fracture
What is the name for this type of fracture? [1]
Jefferson fracture
