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JMP Y2S1 > Week 34- Autoimmunity and Joints > Flashcards

Week 34- Autoimmunity and Joints Flashcards

1
Q

How abundant is collagen in humans?

A

25% of body protein

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2
Q

What impact does arrangement of collagen fibres have?

A

Linear –> tendon –> ligament

Random arrangements –> loose connective tissue

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3
Q

What are some characteristic of collagen?

A

Insoluble
Stable
Long biological half life (cartilage collagen 117 years, skin collagen 15 years)
High tensile strength or contractibility

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4
Q

What is the primary structure using collagen as an example?

A

Primary structure is the amino acid sequence

In collagen it has the following (Gly-X-Y)n at its core (X and Y commonly proline and hydroxyproline)

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5
Q

What is the secondary structure using collagen as an example?

A

Local folding of the amino acid chain:
In collagen –> arranged as a left handed helix (alpha chain) with three amino acids per turn with glycine as every first amino acid. Each helix is a monomer of collagen

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6
Q

What is the tertiary- Quarternary structure using collagen as an example?

A

Each monomer forms a triple helix –> these are wrapped around each other to form a triple stranded helical rod (Tropocollagen)

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7
Q

What is the sequence of events for collagen synthesis? (7 steps)

A
  1. First synthesised in the rough ER as pre-pro-collagen alpha chain mainly of a repeating tripeptide (Gly-X-Y)
  2. Hydrophobic sequence is cleaved to produce the pro-collagen alpha chain
  3. Pro-collagen chain is hydroxylated on the prolines (X) and Lysines (Y)
  4. Alpha chain is then glycosylated and three alpha chains then form a timer (triple helix)
  5. Trimer is secreted (exocytosis) and the ends are cleaved –> leaving behind the insoluble tropocollagen
  6. Lysyl oxidases then covalently crosslinks the tropocollagens by the hydroxylsines to produce collagen fibrils
  7. Fibrils aggregate to form final bundles of collagen
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8
Q

What is the key stages of collagen synthesis?

A
  1. Posttranslational modification and folding of procollagen
    1. Cleavage of procollagen and formation of collagen fibrils
    2. Collagen processing (cross linking)
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9
Q

What are the three major categories of connective tissue?

A
  1. Connective tissue proper (CTP)
    1. Fluid connective tissue (FCT)
    2. Supporting connective tissue (SCT)
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10
Q

Examples of connective tissue proper?

A
  1. Loose –> areolar, reticular, adipose

2. Dense –> regular, irregular, elastic

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11
Q

Example of Fluid connective tissue?

A

Blood

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12
Q

Example of supportive connective tissue?

A

Cartilage and Bone

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13
Q

What is the common tissue of origin for all connective tissue?

A

Mesenchyme

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14
Q

What are the three structural elements of connective tissues?

A
  1. Cells
    1. Ground substance –> unstructured material that fills space between cells
    2. Fibres –> reticular, elastic, collagen
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15
Q

What connective tissue types are needed for ECM?

A

Fibres and Ground substance –> not cells

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16
Q

What are the different classifications for cells of the connective tissue?

A
  1. Fixed cells –> such as fibroblasts and adipose cells

2. Wandering cells –> derived from bone marrow and reach connective tissue via peripheral circulation (immune cells)

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17
Q

What is the main role of fibroblasts?

A

Maintain structural integrity on connective tissue by continuously secreting a non rigid ECM rich in collagen –> causing a continuously remodelling of the ECM as they produce to replace the degradation.

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18
Q

What is the role of the fibroblasts when a tissue is injured?

A

Nearby fibroblasts proliferate and migrate into the wound
Produce large amounts of collagenous matrix
Helps isolate and repair damaged tissue

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19
Q

What cells produce ground substance?

A

Fibroblasts

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20
Q

What is the composition of ground substance?

A
  1. Interstitial fluid
    1. Adhesion proteins (fibronectin and laminin)
    2. Proteoglycans (proteins covalently attached to glycoaminoglycans and multiple sites)
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21
Q

What is the role of the ground substance?

A
  1. Dictates the hardness and viscosity of a tissue
    1. Regulates the movement of substances between cells –> (acts as a molecular sieve for nutrients and metabolite diffusion)
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22
Q

What kind of cartilage is on the articulations of a joint?

A

Hyaline

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23
Q

What does joint cartilage consist of and importantly what is absent?

A

Consists of –> specialised cells (chondrocytes) embedded in a matrix of fibrous collagen within a concentrated water-peptidoglycan “gel”
Devoid of –> blood vessels, lymphatics and nerves

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24
Q

What % of tissue volume does chondrocytes take up in a joint and what is their role?

A

5%
Maintains matrix via secretions and turnover –> chondrocytes synthesise and degrade the matrix via regulation by mechanical stress on the joint and factors/hormones in the synovial fluid

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25
Q

What is the critical role of the functional matrix within a joint?

A

Chondrocytes support and survival:

1. Cells need to resist high levels of mechanical stress
2. Metabolites and nutrients must be able to diffuse through matrix
3. Contains proteoglycans to give structural integrity
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26
Q

What forces can collagen deal with and not deal with?

A

Can –> compressibility and elasticity

Can’t –> shear or hold tension

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27
Q

What are Proteoglycans?

A

Large macromolecules consisting of a protein core to which are attached multiple chains of glycosaminoglycans and oligosaccharides

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28
Q

What is the function of proteoglycans within a joint?

A
  1. Structural building blocks of connective tissue
  2. Serve as joint lubricant
  3. Negative charge on the repeating glycosaminogylcan units attract water –> serve as cushion for impact by absorbing and deabsorbing water
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29
Q

What is the most well studied proteoglycan?

A

Arregcan –> found alongside collagen as the main component of cartilage

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30
Q

What shape do proteoglycans composed of branching glycosaminoglycans (GAGs)?

A

Bottle brush shape

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31
Q

What is the steps in cartilage homeostasis during joint mobility?

A
  1. Proteoglycans (aggrecan) and GAGs
    1. Joints are compressed –> water is released (aids joint lubrication)
    2. When joint is in resting position water interacts again with GAGs
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32
Q

What is the role of bones?

A
  1. Very dense, specialised connective tissue
  2. Supports and protects
  3. Provides levers for muscles to act on
  4. Stores calcium and phosphorus
  5. Marrow inside bone site of haematopoiesis
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33
Q

What is bone matrix comprised of?

A

60% solid mineral particles (Calcium phosphate as hydroxyapatite) (resists compression)
Contains overlapping type I collagen fibrils which resist pulling forces

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34
Q

What bone cells are within the channels through bones hard ECM?

A

Osteoclasts and Osteoblasts

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35
Q

What is the general steps in bone homeostasis?

A
  1. Blood calcium dictates bone metabolism
    • Low blood calcium –> PTH is released –> increased osteoclast activity
    • High blood calcium –> calcitonin is released –> stimulates calcium salt deposition in bone
  2. Blood calcium levels return to normal range
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36
Q

What are ligaments?

A

Tough fibrous band of connective tissue that serves to support the internal organs and hold bones together in proper articulation at the joints

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37
Q

What are ligaments composed of?

A

Composed of dense fibrous bundles of collagenous fibres and spindle-shaped cells known as fibrocytes, with little ground substance.

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38
Q

What are the role of ligaments at a joint?

A

At joints, ligaments form a capsular sac that encloses the articulating bone ends and a lubricating membrane, the synovial membrane

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39
Q

What is Osteoarthritis?

A

degeneration of joint cartilage and the underlying bone, most common from middle age onward. It causes pain and stiffness, especially in the hip, knee, and thumb joints

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40
Q

What are some contributing factors to Osteoarthritis?

A
  1. Ageing
    1. Genetic factors
    2. Trauma
    3. Immune system
    4. Infection
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41
Q

What are the three stages of Osteoarthritis?

A

Stage 1 –> Proteolytic breakdown of the cartilage matrix
Stage 2 –> fibrillation and erosion of cartilage surface, with subsequent release of proteoglycan and collagen fragments into the synovial fluid.
Stage 3 –> breakdown products of cartilage induce a chronic inflammatory response in the synovium

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42
Q

What is the primary target of osteoarthritic cartilage degradation?

A

The ECM of the articular cartilage (crucial for the biomechanical properties of the joint)

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43
Q

What are the two phases of the degradation of cartilage in Osteoarthritis?

A

Biosynthetic phase

Degradative phase

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44
Q

What are the steps in the biosynthetic phase of OA degradation?

A
  1. Functional extracellular matrix is disturbed by physical/ molecular means (affects chondrocyte metabolism
  2. Chondrocytes attempt to repair the matrix through synthesising
  3. New synthesis does not result in repair due to ECM complexity and newly synthesised molecules often are damaged/altered
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45
Q

What are the steps in the degenerative phase of OA degradation?

A
  1. OA chondrocyte metabolism altered –> matrix degrading proteases upregulated
  2. Normal matrix synthesis is inhibited
  3. More ECM loss than synthesis
  4. Severe biochemical changes in cartilage matrix:
    • Reduced GAGs
    • Reduced binding of GAGs to collagen
    • Changes in water content
  5. Results in less cushion effect –> further injury
  6. Vicious cycle
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46
Q

What is immune tolerance?

A

Failure to mount an immune response to an antigen

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47
Q

What is the two arms of immunological tolerance?

A

Central

Peripheral

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48
Q

What is Central tolerance?

A
  1. Occurs during lymphocyte development
  2. T and B progenitors are produced with a broad array of antigen receptors (TCR and IgM)
  3. Cells with self reactive TCRs are removed
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49
Q

Where does negative selection occur for T cells vs B cells?

A

T cells = thymus

B cells = bone marrow

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50
Q

What is peripheral tolerance?

A

It is a further level of selection when T cells pass the central tolerance and occurs in the peripheries of the body.

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51
Q

What is APC?

A

Antigen presenting cell

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52
Q

What is the three mechanisms by which peripheral tolerance can function?

A
  1. Anergy –> APC signalling via CTLA provides “off signals” to T cell
    • –> T cell remains in circulation but is functionally unresponsive to antigen
  2. Deletion –> APC provide death signal –> T cell undergoes apoptosis
  3. Suppression -> activation of regulatory T cells (Tregs) limits activation of reactive T cells
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53
Q

Under what situation does Deletion peripheral tolerance happen?

A

Occurs during persistent/ repeated stimulation as a mechanism to prevent hyper-reactivity

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54
Q

Is restoring tolerance a potential treatment for autoimmune disease?

A

Yes

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55
Q

How does peptide-induced tolerance work to restore tolerance?

A
  1. Soluble peptide that targets auto-reactive T-cells is delivered
  2. Apoptosis or Anergy results
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56
Q

What does antigen-coupled cell-induced tolerance achieve?

A
  1. T cell tolerance

2. Activates Th2 and Treg cells to supress autoimmune inflammation

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57
Q

What does Altered peptide ligand (APL)- induced tolerance achieve?

A
  1. Activates Th2 and Treg cells with overlapping specificity
  2. Leads to suppression of autoimmune inflammation
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58
Q

What happens when tolerance fails?

A

Autoimmune disease

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59
Q

What is thought to initially induce an autoimmune disease?

A

An initial stressor (trigger) –> triggers can also exacerbate existing autoimmune disease

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60
Q

What does the adaptive immunity involve activation and signalling between?

A
  1. APC and antigen specific T cells

2. Antigen specific T cells and B cells

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61
Q

What are some mechanisms that autoimmunity can be triggered by?

A
  1. Sequestered antigen
  2. Molecular mimicry
  3. Bystander Activation
  4. Altered Cytokine Activation
  5. Environmental triggers (lack of childhood exposure)
  6. Epitope spreading
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62
Q

What is the mechanism of sequestered antigen triggered autoimmunity?

A
  1. Some tissues are “immune privileged” –> immune cell migration into these tissues is limited –> limited tolerance occurs to tissue-specific antigens (autoimmunity not selected well here) These tissue specific antigens are hidden within these tissues
  2. Disruption to the tissue barrier
  3. Tissue specific antigens are released
  4. Carried to the lymph nodes (where T-cells are activated)
  5. Effector T-cells return to the tissue and again encounter this antigen and begin an autoimmune attack
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63
Q

What is the mechanism of Molecular mimicry triggered autoimmunity?

A
  1. Some antigens generate adaptive immune responses that are “cross reactive” with self antigen (self antigens share structural similarity with the antigen)
  2. An adaptive immune response develops against the pathogen
  3. The immune response also acts against self-antigens as they are similar
  4. Autoimmunity continues after the original infection is cleared
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64
Q

What is the mechanism of Bystander activation triggered autoimmunity?

A
  1. Inflammatory mediators are released during infection
  2. Mediators activate dendritic cells
  3. Dendritic cells provide danger signals to activate antigen presentation against the pathogen
  4. Bystander dendritic cells (close by) which are presenting self antigen are activated
  5. Leads to activation of self-reactive T cells (autoimmune tissue damage)
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65
Q

What is the mechanism of Altered Cytokine Activation triggered autoimmunity?

A
  1. Increased inflammatory cytokine levels –> increased adaptive immune activation
  2. Decreased anti-inflammatory cytokine levels –> reduces tolerance mechanisms
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66
Q

What effects can cytokines have on the immune system?

A

Both inflammatory and anti-inflammatory depending on what cytokine

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67
Q

What are the two ways auto immune diseases differ?

A
  1. Type of adaptive immune response –> T cell mediated or antibody mediated
  2. Target antigen –> Tissue localisation or expressing cell type
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68
Q

What are the broad classifications of autoimmunity disease?

A
  1. Local/Organ specific –> single tissue/organ eg Type 1 diabetes –> targets insulin producing islet cells in the pancreas.
  2. Systemic –> targets multiple tissues/organ systems throughout the body –> eg systemic lupus erythematosus (SLE) -> targets histones or DNA found in all cell types.
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69
Q

What does connective tissue contain?

A

Extensive ECM to support and protect organs

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70
Q

What is the antigen in Rheumatoid arthritis?

A

Within joint/ bone –> specific antigen is unknown

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71
Q

On immune activation in RA what happens?

A
  1. Localised damage within the joint synovium attracts the immune cells
  2. Auto-reactive CD4+ T cells activation –> activated tissue macrophages
  3. Inflammatory cytokine release causes ongoing tissue damage:
    - Tumour necrosis factor-alpha (TNF-alpha) stimulates inflammation
    - Matrix matalloproteinases (MMPs) degrade ECM
    - RANK ligand activates osteoclasts that dissolve bone
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72
Q

What is systemic lupus erythematosus?

A

Chronic autoimmune disease that effects multiple body systems

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73
Q

What is the prevalence of systemic lupus?

A
  1. Rare disease (0.1% total pop)
  2. Increased prevalence in indigenous Australians and descendants from south east Asia
  3. 90% of cases are in women
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74
Q

What are some symptoms of systemic lupus?

A
  1. Relapsing/remitting pattern of symptoms
  2. Malaise, fatigue, fever, weight loss
  3. Intermittent arthritis (95% of cases)
  4. Cutaneous erythramatosus rash (butterfly facial rash)
  5. Nephritis
  6. Anaemia
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75
Q

What testing is done for diagnosis of systemic lupus erythematosus (SLE)?

A
  1. Autoantibody testing:
    - Anti-nuclear antibody (ANA)
    - Anti-dsDNA antibody (dsDNA)
  2. Low complement levels in blood
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76
Q

How does the autoimmune reaction function in Systemic lupus erythematosus (SLE)?

A
  1. Adaptive immune response against antigens:
    - Histone H1 (component of DNA chromatin packaging)
    - DNA
  2. Activation of histone-specific helper T cells
  3. Activation of H1 or DNA-specific B cell response
  4. Production of anti-H1/DNA antibody
  5. Immune response can then target any cell
77
Q

Why is UV light exposure “worse” for patients with SLE?

A
  1. 90% of patients with SLE have skin lesions
  2. UV exposure exacerbates skin lesions:
    - Induces epithelial cell death –> release of self DNA
    - Anti-H1/DNA antibodies then bind to this free DNA
    - Immune complex forms and leads to immune activation
78
Q

How is SLE treated?

A

Mild disease –> low dose glucocorticoids

Severe/life threatening disease --> high dose glucocorticoids with add-on therapies 
Approaches all aim to limit inflammation and control symptoms:
1. Avoidance of triggers
2. NSAIDS
3. Antimalarials
4. Corticosteroids
5. Non-biologic DMARDs
6. Biologic DMARDs
79
Q

What is the suspected mechanism of hygiene hypothesis driven autoimmunity?

A
  1. Lack of early childhood exposure to infectious agents and symbiotic organisms (gut microbes/probiotics)
  2. Leading to the suppression of natural immune system development
  3. Increased susceptibility to allergic and autoimmune disease
80
Q

Define Rheumatoid arthritis

A

Systemic chronic progressive autoimmune inflammatory disorder affecting synovial joints associated with rheumatic factor (autoantibody) causing chronic inflammation with erosion of articular cartilage.

81
Q

What are some features of systemic inflammatory features?

A
  1. Subcutaneous nodules
  2. Anaemia
  3. Lymphadenopathy
  4. Spenomegaly
  5. Sjogren’s syndrome –> dry mouth and eyes + dysphagia (trouble swallowing)
  6. Uveitis (eye inflammation)
  7. Vasculatisis
  8. Pulmonary pathology
  9. Amyloidosis
82
Q

What is the 5 stages of Rheumatoid arthritis?

A
  1. Unknown antigen reaches synovial membrane
  2. T-cell proliferation associated with increased B cell and angiogenesis
  3. Chronic inflammation with inflammatory cytokines
  4. Pannus formation (abnormal tissue between the bone and joint)
  5. Cartilage and bone destruction
83
Q

What is a pannus?

A

Apannusis a membrane of granulation tissue composed of mesenchyme- and bone marrow-derived cells

84
Q

What are some clinical manifestations of RA?

A
  1. Affects almost any joint
  2. Joints are warm, oedematous with reduced ROM
  3. Increased joint stiffness which lasts for > 1 hour after some inactivity
85
Q

How does an xray look of someone with RA?

A
  1. Very small gaps between joints

2. Fading looking bones around joints

86
Q

What does RA look like histologically?

A
  1. Thickening of the synovial membranes
  2. Hyperplasia of surface synoviocytes
  3. Intense inflammatory cell infiltrate
  4. Fibrin deposition and necrosis
87
Q

How is RA diagnosed based of examination?

A
  1. Present joint swelling and pain of at least 3 joints
  2. Symmetrical involvement of metacarpophalangeal or metatarsophalangeal joints
  3. Morning joint stiffness lasting over 30mins
88
Q

How is RA diagnosed with tests?

A
  1. Antibody –> Rheumatic factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)
  2. Xrays
  3. MRI scans
  4. Ultrasounds
  5. Blood tests to exclude other systemic illness (FBC, ESR, CRP)
89
Q

What is Osteoarthritis?

A

Osteoarthritis is a common, degenerative joint disease, primarily affecting articular cartilage of synovial weight bearing joints especially hips and knees. The erosion of cartilage leads to secondary changes in underlying bone but with limited inflammatory changes.

90
Q

What is the pathology/cause of OA?

A
  1. Enzymatic degradation of hyaline cartilage usually within weight bearing joints
  2. Contributing factors:
    - Genetics
    - Hormones
    - Injury
  3. These factors alters balance between pro and anti inflammatory factors
  4. Matrix Metalloproteinases (MMP’s) –> enzymes that hydrolyse or destroy collagen
91
Q

What are the clinical manifestations of OA?

A
  1. Joint pain
  2. Joint stiffness
  3. Decreased range of motion
  4. Effusion around joint
  5. Bouchard’s and Heberden’s nodes (lumps around knuckle and joint above knuckle respectively)
  6. Secondary effects –>obesity, muscle atrophy, seizing of joints
92
Q

How does the onset between OA and RA compare?

A

OA –> degenerative can develop over years

RA –> autoimmune can develop over weeks

93
Q

How does location differ between OA and RA?

A

OA –> mostly asymmetrical –> usually limited to one or two sets of joints

RA –> mostly symmetrical –> often affecting multiple joints

94
Q

How does duration of symptoms usually compare in OA vs RA?

A

OA –> pain and stiffness relieved after minutes of immobility –> lasts <20 with inactivity

RA –> pain and stiff ness last longer than an hour of immobility –> exacerbated by periods of prolonged activity

95
Q

What is the physical characteristic of the affected areas in OA vs RA?

A

OA –> joints hard and cool –> decreased ROM –> slight oedema

RA –> Joints swollen and hot –> decreased ROM –> muscle strength often lost

96
Q

What are some of the associated symptoms in OA vs RA?

A

OA –> fatigue and loss of joint function –> no extra articular clinical manifestations

RA –> Initially flu like symptoms, joint aches, fever, anorexia –> can have extra articular manifestations, heart, lungs, bone, blood

97
Q

How does treatment of OA and RA compare?

A

OA –> simple analgesia –>intra-articular corticosteroids may be required –> joint replacement often needed

RA –> simple analgesia and NSAIDs –> antirheumatic drugs (DMARDs) early –> may require corticosteroids and joint replacement

98
Q

What is gout?

A

Urate crystal induced arthropathy (joint disease)

99
Q

What is the mechanism of Gout?

A
  1. Accumulation of uric acid in blood (overproduction or underexcretion) (uric acid is an end product of purine metabolism in the liver)
  2. Unexcreted uric acid –> stored as urate –> deposited in soft tissue as crystals
  3. Most commonly affects Metatarsophalangeal joint of big toe
100
Q

What typically causes gout?

A
  1. Chronic renal damage
  2. Purine-rich food –> alcohol, liver, mushrooms and legumes
  3. Genetic predisposition
101
Q

Who is normally impacted by gout?

A

Males (90%) –> onset 40-60 years

102
Q

What situations is immunosuppression used in?

A
  1. Treatment of autoimmune conditions

2. Prevention/treatment of transplant rejection

103
Q

What situations is immunomodulatory therapy used?

A

Autoimmune conditions
Viral conditions
Cancer

104
Q

What is Rheumatoid arthritis characterised by?

A
  1. Autoimmune attack on a joint
  2. Inflammation
  3. Release of growth factors to remodel joint
  4. Inappropriate accumulation of fibrovascular or granulation tissue (pannus)
105
Q

What is a DMARDs?

A

Disease-modifying anti-rheumatic drugs

106
Q

What is the first used DMARD generally?

A

Methotrexate for monotherapy and can consider concurrent short term glucocorticoids

107
Q

What is the treatment normally for established Rheumatoid arthritis with moderate-high activity?

A

Combination therapy preferred –> immunosuppressant drugs, biologic DMARDs with/without methotrexate or other DMARDs
–> monitoring essential

108
Q

Why is NSAIDs an original mainstay of therapy in early stages?

A

Reduce inflammation at affected joints –> blocks COX enzymes –> less prostaglandin formation –> prostaglandins are pro-inflammatory –> hence less inflammation at joints.

109
Q

What is the problem of using NSAIDs in Rheumatoid arthritis?

A

They have no impact on disease progression only symptomatic relief

110
Q

What is the benefit of DMARDs over NSAIDs?

A

DMARDs appear to alter disease progression –> patient goes into remission –> unclear on overall long term prognosis.

111
Q

What is the difference with biologic DMARDs?

A

Target specific components of immune cascade

112
Q

Where was cyclosporine isolated from?

A

Tolypocladium inflatum (a fungus)

113
Q

What is cyclosporine?

A

Calcineurin inhibitor

114
Q

What is Calcineurin?

A

A phosphatase that dephosphorylates cytoplasmic subunit of nuclear factor of activated T cells (NFAT) –> NFAT is responsible for transcription of cytokine genes

115
Q

What is the mechanism of action of cyclosporine?

A
  1. Cyclosporine docks with cyclophilin
  2. Complex blocks calcineurin
  3. Reduces transcription of cytokines (eg IL2)
  4. Reduces inflammatory/immune response:
    - supresses cytokine production
    - reduced proliferation and function of T cells
116
Q

What is Tacrolimus?

A

Fungal macrolide antibiotic

117
Q

What is the mechanism of Tacrolimus?

A

Blocks FK-binding proteins (FKBP) instead of cyclophilin

–> other steps the same as cyclosporine

118
Q

Why would tacrolimus be used over cyclosporine?

A

More potent immunosuppression than cyclosporine

119
Q

What effect does corticosteroids/glucocorticoids have in RA?

A

Control availability of cytokines and other relevant immune system compounds
–> suppresses immune function

120
Q

What is Azathioprine metabolised to?

A

6-mercaptopurine (6-MP)

121
Q

What can be said about azathioprine and its metabolite 6-MP?

A

They both function

122
Q

What is the mechanism of action for azathioprine?

A
  1. Blocks new purine synthesis –> reduce AMP and GMP levels
  2. Converted to fraudulent nucleotide that is incorporated into DNA, RNA
  3. Accumulation of errors overwhelming for the cell
  4. Inhibits proliferation and activity
  5. Inhibits proliferation and activity of B and T cells
123
Q

What is mycophenylate?

A

Semi-synthetic derivative of fungal antibiotic

124
Q

What is the mechanism of mycophenylate?

A

Inhibits ionsine monophosphate dehydrogenase –> the enzyme which is the rate limiting step in guanosine biosynthesis

125
Q

How does mycophenylates inhibition of ionsine monophosphate dehydrogenase produce its effect?

A
  1. Reduces nucleotide availability
  2. Reduces capacity to replicate DNA
  3. Reduces replication of immune cells
  4. Decreases immune response
126
Q

What is an example of a tumour necrosis factor alpha (TNF-alpha) Antagonist?

A

Infliximab etc

127
Q

What is TNF-alpha and why would antagonising it reduce pro inflammatory activity?

A

TNF-alpha is a cytokine secreted by macrophages, mast cells and activated T-helper cells –> antagonist behaviour reduces cytokines released –> reduces immune response

128
Q

What does TNF-alpha release do to macrophages?

A

Stimulates them to release cytotoxic metabolites

129
Q

What is an example of targeted synthetic DMARDs?

A

Tofacitnib

130
Q

What is the mechanism of Tofacitnib?

A
  1. Inhibits janus kinases 1 and 3 (JAK 1 and JAK 3)
  2. Prevents activation of STAT (signal transducer and activator of transcription)
  3. Prevents STAT-mediated transcription of cytokines
  4. Reduced pro immune response
131
Q

What is the mechanism of action of Hydroxychloroquine?

A
  1. Blocks Toll like receptors (TLR) –> reduces translation of subset of mRNAs required for cell cycle progression
  2. Blocks PLA2 –> reduces arachidonic acid availability –> reduces prostglandins –> reduced inflammatory response and immune cell recruitment
  3. Interferes with antigen presentation –> suppresses T cell responses (particularly T17)
    - Reduces chemotaxis to reduce immune cell recruitment
    - Stabilises lysosomal membranes to prevent degradative enzyme release
    - Free radical scavenger –> reduces tissue damage
132
Q

What is the base clinical presentation of OA?

A
  1. Deep aching joint pain and stiffness (hard and cool joints)
  2. Decreased ROM
  3. Oedematous Bouchard’s and Heberden’s nodes
  4. Longer history of joint pain (can take years)
  5. Asymmetric
133
Q

What is the base clinical presentation of RA?

A
  1. Tends to be a symmetrical distal polyarthritis (i.e. affecting multiple joints)
  2. Joint pain, hot, swelling + stiffness (especially in the morning >30 min)
  3. Decreased ROM
  4. Tends to be worse after rest and better with activity
  5. Also associated with systemic symptoms (i.e. fatigue, weight loss, flu-like illness)
134
Q

What is the base clinical presentation of Gout?

A
  1. sudden, severe attacks of pain, swelling, redness and tenderness in the joints, often the joint at the base of the big toe.
  2. An attack of gout can occur suddenly, often waking you up in the middle of the night with the sensation that your big toe is on fire.
135
Q

What is the base clinical presentation of pseudo-gout?

A
  1. Most commonly affects the Knees
  2. Less often, wrists and ankles.
  3. During a pseudogout attack, joints are usually swollen, warm and severely painful
  4. Due to calcium crystal issues
136
Q

What is the base clinical presentation of septic arthritis?

A
  1. Chills
  2. Fatigue and generalized weakness
  3. Fever
  4. Inability to move the limb with the infected joint.
  5. Severe pain in the affected joint, especially with movement.
  6. Swelling (increased fluid within the joint)
  7. Warmth (the joint is red and warm to touch because of increased blood flow)
137
Q

What is the base clinical presentation of viral arthritis?

A
  1. Sudden
  2. Short duration
  3. Does not reoccur
  4. The presentation might involve fever, rash, and lymphadenopathy.
138
Q

What is the base clinical presentation of reactive arthritis?

A
  1. Reactive arthritis is a condition that causes inflammation, pain and swelling of the joints. It usually develops after an infection, often in the bowel or genital areas. The infection causes activity in the immune system.
  2. Pain, swelling and stiffness in joints
  3. Pain in buttocks and back
  4. Pain in tendons
  5. Rash on the hands or soles of feet
  6. Pain and redness in the eyes
139
Q

What is the base clinical presentation of ankylosing spondylitis?

A
  1. Early signs and symptoms of ankylosing spondylitis might include pain and stiffness in your lower back and hips, especially in the morning and after periods of inactivity.
  2. Neck pain and fatigue also are common.
  3. Enthesitis = inflammatory process affecting sites of insertion of ligaments and tendons into bone; lower limbs with the heel, knee, ischial tuberosities commonly affected
140
Q

What are some non pharmacological management strategies in RA?

A
  1. Rest –>when joints are inflamed
  2. Exercise –> ROM, strength and endurance of the affected joints
  3. Nutritional/dietary therapy –> weight loss to reduce stress on joints
  4. Surgery –> to restore function
141
Q

What is autoimmunity?

A
  1. Immune reaction to self

2. Tissue damage occurs

142
Q

What is allergy?

A
  1. Hypersensitivity immune reaction to an antigen

2. Tissue damage does not occur

143
Q

Who is affected by RA in Australia?

A
  1. 75 years and older

2. 2.3% in women vs 1.5% in men

144
Q

What investigations are usually done to differentiate RA?

A
  1. Erythrocyte sedimentation rate (elevated –> indicates inflammatory process
  2. C-Reactive protein (inflammatory marker)
  3. Antibody tests –> Rheumatoid factor (RH) and anti-cyclic citrullinated peptide (anti-CCP)
  4. Xrays –> joint distance etc
145
Q

What investigations are often done for osteoarthritis?

A
  1. Exclusionary blood tests (rules out RA etc)
  2. Joint fluid analysis
  3. Xrays –> loss of artilage, narrow joint space, bone spurs
146
Q

What investigations are often done for gout?

A
  1. Joint fluid test
  2. Blood tests –> uric acid and creatinine
  3. Xray, Ultrasound, CT
147
Q

What investigations are often done for septic arthritis?

A
  1. Joint fluid analysis –> appearance and culture
  2. Blood culture
  3. FBC
  4. CRP
  5. Xray –> if in early stages will appear normal
148
Q

What investigations are often done for viral arthritis?

A
  1. Serology –> IgG and IgM
  2. Exclusionary
  3. Follow up serology later
149
Q

What investigations are usually done for reactive arthritis?

A
  1. No real test
  2. HLA- B27 antigen (increased risk of autoimmune disorders)
  3. CRP
  4. Joint fluid analysis
  5. Chlamydia test
  6. Stool culture
  7. RF for exclusion
150
Q

What investigations are normally done for Ankylosing spondylitis?

A
  1. Investigations similar to others
  2. CRP
  3. ESR (erythrocyte sedimentation rate)
  4. FBC
  5. X-rays
  6. Main diagnosis achieved through history of lower back pain and exclusionary testing
151
Q

What is an ESR test and what is it used for?

Erythrocyte sedimentation rate

A
  1. Results are mm of clear plasma visible at the top of the tube after 1 hour
  2. There is a faster sedimentation rate when there is an increased level of protein
  3. This extra protein can be due to increased inflammatory proteins (CRP and fibrinogen)
  4. Hence this test is a crude measure for systemic inflammatory markers
152
Q

What is a CRP test and what is it used for?

A

C reactive protein levels

  1. Results are levels of CRP
  2. Higher CRP in times of higher inflammation
  3. Used in detection of acute inflammation conditions as well as chronic conditions with flare ups
  4. Can be measured to measure response to inflammatory disorder treatment
153
Q

What is a Rheumatoid factor test and what is it used for?

A
  1. Detecting presence of an IgM autoantibody
  2. Used to detect inflammation and autoimmune activity
    High levels help to diagnose RA
154
Q

What is an anti-CCP antibodies test and what is it used for?

A
  1. Detecting presence of autoantibodies for cyclic citrullinated peptide.
  2. Higher than normal levels suggest RA
  3. Test can be used to identify people with a more rapidly erosive form of the disease
155
Q

What is a HLA-B27 test and what is it used for?

A
  1. Detecting levels of human leukocyte antigen B27

2. Helps predict likelihood of immune disorder from the presence of a HLA antigen on the surface of self cells.

156
Q

What is an ANA test and what is it used for?

A
  1. Anti-nuclear antibody presence –> a group of autoantibodies
  2. Helps determine a suspected autoimmune disorder
157
Q

What is an ENA test and what is it used for?

A
  1. Extractable nuclear antigen panel
  2. Extractable (removed from the nucleus with saline solution)
  3. Presence of certain antibodies on the panel can help distinguish between certain autoimmune diseases
158
Q

What is an anti-dsDNA test and what is it used for?

A

Used to help diagnose lupus in a person who had a positive result on a test for antinuclear antibody (ANA) and has clinical signs of lupus

159
Q

What is the observed joint changes on imaging for Rheumatoid arthritis?

A
  1. X-rays
    - nothing for short term
    - can detect bone erosion, narrowing joint space
  2. Ultrasound
    - Detect synovial tissue inflammation
  3. MRI
    - Detects inflammation and soft tissue changes
    - Can also show bone damage
160
Q

What is the observed joint changes on imaging for ankylosing spondylitis?

A
  1. X-rays
    - Can detect small bony spurs called syndesmophytes, which are thin projections of bone that stick out from the corners of the vertebrae.
    - Inflammation induced spinal joint fusion
    - Can assist determining disease progression
  2. Ultrasound less important
  3. MRI
    - Can assess inflammation
161
Q

What is the observed joint changes on imaging for gout?

A
  1. X-ray
    - TOPHI –> soft tissue masses created by urate deposition –> can be seen due to calcium precipitation with urate crystals
    - “punched out” erosions –> erosions can appear as holes punched in the bone/cartilage
    - Joint spaces –> preserved until late in disease
    - Unlike RA mineralisation is maintained (no osteopenia)
  2. Ultrasound
    - Can detect urate accumulation
    - Detects tophi
162
Q

What is the observed joint changes on imaging for pseudo-gout?

A

X-ray:

  • Can reveal joint damage and crystal deposits in the joints cartilage
  • Often unnecessary to confirm diagnosis
163
Q

What is the observed joint changes on imaging for septic arthritis?

A
  1. Xray
    - Conventional radiographic findings of septic arthritis may include soft tissue swelling
    - oedema,
    - capsular distention
    - displacement of the articular structures which may suggest the presence of joint effusion
    - Late stage septic arthritis may show bony changes and calcium deposits
  2. OR Ultrasound
    - Hip joint effusion
    - Synovial thickening
    - Hyperemia
  3. MRI
    - Location and extent of diease
164
Q

What is the observed joint changes on imaging for reactive arthritis?

A

-A large bulky paravertebral area of ossification “floating osteophyte” is often seen.
It can have a very similar appearance to psoriatic arthritis with the classic features of ill-defined erosions, enthesopathy, bone proliferation, early juxta-articular osteoporosis, uniform joint space loss and fusiform soft tissue swelling

-Both psoriasis and reactive arthritis can cause aSacroiliitiswhich is usually asymmetric

165
Q

What is the observed joint changes on imaging for osteoarthritis?

A
  1. X-ray
    - Osteophyte formation
    - Joint space narrowing
    - Subchondral sclerosis
    - Cysts
166
Q

What is the main x-ray different between OA and RA?

A

OA –> no osteoporosis and erosions

RA –> osteoporosis and erosions

167
Q

What is Bouchards nodes?

A

hard, bony outgrowths or gelatinous cysts on the proximal interphalangeal joint (PIP)

168
Q

What is Heberden’s nodes?

A

bony swellings of the joint closest to the fingertip, also known as the DIP joint or distal interphalangeal joint

169
Q

What does symmetrical mean in medical terms?

A

Present on both hands say –> doesn’t need to be super identical

170
Q

What is subchondral sclerosis?

A

Subchondral sclerosisis a thickening of the bone in joints. It can affect people who have osteoarthritis and result in painful bone spurs.
Subchondral sclerosisis commonly seen in joints of the knee, hip, spine, and foot.

171
Q

What is osteophytes and osteophyte formation?

A

a bony projection associated with the degeneration of cartilage at joints.

172
Q

What is a plaque in dermatology?

A

Askin plaqueis an elevated, solid, superficial lesion that is typically more than one centimetre in diameter (a little more than half an inch) and associated with a number ofskinconditions, most commonly psoriasis

173
Q

What does psoriasis look like and where does it present?

A

Psoriasis isan immune-mediated disease that causes raised, red, scaly patches to appear on the skin.Psoriasistypically affects the outside of the elbows, knees or scalp, though itcanappear on any location

174
Q

Can widening of a joint be painful? Give example

A

Yes –> illiosacral joint

175
Q

What is an Odds ratio?

A

An odds ratio is a comparison of the odds in two groups “intervention” and “control” to calculate whether the intervention had an affect on the odds of a certain outcome eg:

Intervention –> 10 people got an outcome and 2 didn’t (odds of 5)
Controls –> 5 got the outcome and 5 didn’t (odds of 1)
Odds ratio is then
Intervention odds/control odds = 5

176
Q

What does an odds ratio of 1 mean?

A

There was no difference made by the intervention

177
Q

What does an odds ratio over 1 mean?

A

Intervention made outcome more likely

178
Q

What does an odds ratio of less than 1 mean?

A

Intervention made outcome less likely

179
Q

What is Relative risk/risk ratio?

A

is the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group.

180
Q

What is a relative risk/risk ratio use to show?

A

to estimate the strength of the association between treatments or risk factors, and outcomes.

181
Q

What does a RR of 1 mean?

A

RR = 1 means that exposure does not affect the outcome

182
Q

What does a RR of less than 1 mean?

A

RR

183
Q

What does a RR of more than 1 mean?

A

RR >1 means that the risk of the outcome is increased by the exposure

184
Q

What is Absolute risk?

A

Risk of developing the disease over a time period/lifetime

185
Q

How do Relative risk and Absolute risk differ?

A

Relative risk –> risk compared to another group (overweight, age, exposure)
Absolute risk –> The actual risk a disease poses –> not compared to another group

186
Q

What is a Hazard rate?

A

Rate of adverse effect or death over time

187
Q

What is a hazard ratio?

A

The hazard ratio is a comparison between the probability of events in atreatment group, compared to the probability of events in acontrol group. –> pretty much a relative risk over time –> can show risks at time points over the study.

188
Q

How do hazard ratios differ from RR or OR?

A

Hazard ratios differ fromrelative risks (RRs) and odds ratios (ORs) in that RRs and ORs are cumulative over an entire study, using a defined endpoint, while HRs represent instantaneous risk over the study time period, or some subset thereof. Hazard ratios suffer somewhat less from selection bias with respect to the endpoints chosen and can indicate risks that happen before the endpoint.

JMP Y2S1 (24 decks)

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