LOCO1 Flashcards by patrick ellis

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

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State 6 surgical interventions for OA [6]

Arthroscopic lavage
Arthroscopic lavage plus debridement
Microfracture
Mosiacplasty (osteochondral transplant)
Chondrocyte grafts
Joint replacement

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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

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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

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OA treatment

Adalimumab targets which cytokine? [1]

TNF inhibition

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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

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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

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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.

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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

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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

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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

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Which IL1 biologicals can be used to treat acute gout? [3]

Rilonacept, canakinumab, anakinra

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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

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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.

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This sign is suggestive of

Osteoarthritis
Gout
Pseudogout
Rheumatoid arthritis
Osteoporosis

Rheumatoid arthritis: Bakers cyst

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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

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Recombinant PTH used to treat OP is called? [1]

Teriparatide

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Name drug A used to treat osteoporosis [1]

Denosumab

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Name drug A used to treat osteoporosis [1]

Teriparatide

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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

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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

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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”

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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+

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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

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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**

LOCO1 Flashcards

(63 cards)