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Stage 3 Case 3 > RA > Flashcards

RA Flashcards

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1
Q

What is RA?

A

Chronic, systemic inflammatory condition Causes progressive destruction of bone /cartilage around joint

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2
Q

Which part of the body is affected first by RA?

A

Interphalangeal joints of fingers and wrist are usually affected first.

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3
Q

Which part of the body is later affected by RA?

A

Ankles and hips may be affected later

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4
Q

What kind of symptoms are associated with RA?

A
  • Affected joints warm, swollen and painful

- Increased extracellular fluid around joint causes stiffness particularly in the morning

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5
Q

Increased risk of co-morbidity associated with RA

A
  • Cardiovascular disease
  • Inflammation around lungs and heart
  • Systemic symptoms e.g. malaise / weight loss
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6
Q

What type of arthritis is RA?

A

Deforming arthritis

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7
Q

What is septic arthritis?

A
  • Secondary to infection

- Invasion of joints by an infectious agent resulting in joint inflammation

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8
Q

What is Post traumatic arthritis?

A

Secondary to physical injury

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9
Q

Two main T-helper cells involved in autoimmunity?

A

TH-1 and TH-17

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10
Q

What is RA triggered by?

A

Exposure of a genetically susceptible individual to an arthritogenic antigen resulting in a breakdown of immunological self-tolerance and a chronic inflammatory reaction

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11
Q

What is the genetic competent of RA?

A

Mutations in Major Histocompatibility Complex Class II are a strong predictor of
risk (HLA-DR4 allotype increased among RA patients)

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12
Q

What is normal in terms of tolerance in the body?

A

There is a balance between protection and tolerance.

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13
Q

What does initiating event do to the tolerance of self-antigens?

A

Breakdown of tolerance – acute arthritis

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14
Q

What may be the cause of most initiating events? (2)

A

Infection or injury (along with genetic competent)

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15
Q

What is important for the initiating event to occur?

A

Genetic component (not everyone with injury or infection will cause breakdown of tolerance)

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16
Q

What happens after the initiating event in terms of T-helper cells?

A

CD4+ T helper cells get activated causing autoimmune reaction.

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17
Q

What happens as the autoimmune reaction progresses?

A

Release of inflammatory cytokines and mediators leading to joint destruction and inflammation.

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18
Q

What does release of inflammatory cytokines and mediators cause?

A

Joint destruction and inflammation.

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19
Q

3 main steps in RA?

A
  1. Intiating event
  2. CD4+ T helper cells activated
  3. Releae of inflammatory cytokines and mediators
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20
Q

What is the main CD4+ T helper cells that infiltrate the joints?

A

Th17

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21
Q

What does Th17 activate?

A

Macrophages to secrete pro-inflammatory cytokines (IL-1 and TNF-alpha) and help B cells to produce further arthritogenic antibodies

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22
Q

What pro-inflammatory cytokines are secreted from macrophages (after Th17 ha activated it)?

A

IL-1 and TNF-alpha

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23
Q

What do cytokines (IL-1 and TNF-alpha) activate?

A

Synovial fibroblasts

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24
Q

What do Synovial fibroblasts release in response to the cytokines? (2)

A

Secrete matrix metalloproteases (MMP) – damage tissue

Secrete RANKL which activates osteoclasts -breakdown bone

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25
What does secretion of matrix metalloproteases (MMP) in synovial fibroblasts do?
Damage tissue
26
What does secretion of RANKL which activate osteoclasts in synovial fibroblasts do?
Breakdown bone
27
What are Treg T-helper cells?
Maintain the balance between self and non-self cells. So can supress and abnormal immune response
28
RA autoimmune reaction and joint destruction? (4)
1. Unknown trigger causes inflammation in the synovial membrane attracting leukocytes into tissue 2. CD4+ T helper cells activate macrophages to secrete proinflammatory cytokines 3. Cytokines induce MMP and RANKL by synovial fibroblasts 4. MMP attack tissue and, osteoclasts breakdown bone
29
Two autoantibodies found in RA?
``` Rheumatoid factor (RF) Anti-citrullinated peptide antibody (ACPA) ```
30
What is RF?
Rheumatoid factor which is and auto antibody that recognises the Fc portion of IgG antibody
31
What type of antibody can RF be? )3)
IgM, IgG and IgA
32
RA autoimmune reaction and joints destructions (genetic component)
Mutations in Major histocompatibility complex class II are strong predictor of risk (HLA-DR4 allotype increased among RA patients.)
33
Why is RF important in RA?
Cause formation of immunocomplexes that deposit within the joint?
34
Does RF indicate RA?
No, found 30% of SLE patients, but is found in most RA patients.
35
What is ACPA?
Anti-citrullinated peptide antibody, directed against peptides and proteins that are citrullinated.
36
When is citrullination increased?
With inflammation
37
Does smoking correlate with citrullination?
Yes (high risk factor that increases production of citrullinated proteins)
38
Why is smoking associated with citrullination? (7)
1. Induces the expression of PAD in the respiratory tract. 2. Citrullinated proteins are formed in the respiratory tract. 3. Presentaion of citrullinated self-peptides by MHC II (HLA-DRA) can activate specific CD4 T cells. 4. CD4 T cells help and activate B cells 5. B cell produce antibodies to our own citrullinated proteins 6. Stimuliates autoimmune response 7. Pre-artivcular phase
39
Which proteins in the extracellular matrix can be citrullinated? (3)
Fibrin, fibrinogen collagen and vimentin.
40
Citrulline
Amino acid related to arginine that is NOT used in protein synthesis
41
Citrullination
Mechanism that converts arginine into citrulline
42
What enzymes is citrullination catalysed by?
Peptidylargine deiminases (PAD)
43
What does PAD do to arginine (amino acid)?
Converts arginine (+) into citrulline (neutral), done by destabilizing proteins which makes them more prone to proteolysis.
44
What does the conversion arginine (+) to citrulline (-) do?
Makes them more prone to proteolysis. (More easily degraded). Exposes more epitopes.
45
What is proteolysis?
Protein is broken down partially, into peptides, or completely, into amino acids, by proteolytic enzymes. Exposes more epitopes.
46
What does exposure of more epitopes from pyrolysis do?
Recognised by B and T cells causing and autoimmune reaction
47
RA stages of pathogenesis
1. Pre-articular phase 2. Initiation phase 3. Progression
48
What is the pre-articular phase?
When autoantibodies are produced (ACPA and RF) and present in the blood but do not have access to the joint capsule. This can happen years before symptoms of RA.
49
What do PAD2 and PAD4 do in the synovial fluid? (pre-articular phase)
PAD2 and PAD4 in the synovial fluid citrullinate unknow proteins in the joint capsule.
50
What is RA initiation?
1. RA initiated by joint damage (wound/infection) 2. Damage induces a state of inflammation and lead to further activation of PAD. 3. Symtoms occur
51
What does increase in vascular permeability do in RA initiation?
Allows ACPA and RF to enter the joint capsule from the blood.
52
What does the ACPA, RF and lymphocytes entering the joint capsule do?
They will bind to the citrullinated proteins (citrullinated protein-autoantibody complex) and exacerbate inflammation.
53
What do lymphocytes (T cells) do in the Initiation phase?
Infiltrate the inflamed joint tissue and responds to their specific antigens.
54
What happens in RA initiation?
1. Joint damage (wound/infection) 2. Infalmmation causes activation of PAD 3. Incrased vascular permeability and ACPA and RF enter join capsule 4. Lymphoctes infiltrate and respond to specific antigens. 5. The action of T cell and deposition of immune complexes exacerbate the inflammation and lead to RA symptoms.
55
What do the CD4 T helper cells differentiate to when they have infiltrated the cells?
TH17 and TH1
56
What does TH17 release in RA progression?
IL-17 and recruiting neutrophils and monocytes, causing amplification of the inflammation.
57
What does IL-17 activate in RA progression?
Synoviocytes which releases RANKL
58
What does TH1 release in RA progression?
IFN-gamma and activating macrophages
59
What other pro-inflammatory cytokines and mediators macrophages and synoviocites produce in RA progression?
IL-1, IL-6, TNF, NO, PGE2 ,RANKL
60
What does the synovial membrane and fibrous layer?
Together form the joint capsule
61
What is the joint capsule made up of?
Synovial membrane and fibrous layer
62
What are PAD2 AND PAD4?
Enzymes found in the synovial fluid
63
4 drug classes that can be used for RA
NSAIDs Glucocorticoids DMARDs Biologics
64
What do NSAIDs do for RA?
Pein relief and reduces inflammation but does not affect the progression.
65
NSAID example
Aspirin daily
66
What do glucocorticoids do for RA?
Reduces inflammation. Reduce development of joint damage (damage to joint capsule in RA is permanent and so aim of therapy is to slow rate of damage as much as possible
67
What do DMARDs do for RA?
First line treatment: Pain relief, reduces swelling/stiffness and slows disease progression. (not that good for ongoing inflammation)
68
What do Biologics do for RA?
Targeted e.g. to inflammatory cytokines, reduces symports and slows proregression
69
Glucocorticoid example
Prednisolone daily
70
DMARDs example
Methotrexate weekly
71
Biologics example
Anti-TNF weekly to monthly
72
Methotrexate (DMARD) in RA (3)
- Suppresses neutrophil adhesion to blood vessels and so prevents entry to site of inflammation - Suppresses cytokine production - Reduces macrophage function
73
What does suppression of cytokine production and reduction of macrophage function do to immune function (methotrexate)?
Reduce immune function, which mean the patient is more susceptible to other infections.
74
Methotrexate side effect/cons
Immunological suppression means that patients more susceptible to other infections
75
Sulfasalazine (DMARD) in RA (4)
- Unclear mode of action - Metabolised in the gut to sulfapyridine - Both compounds can be found in synovial fluid -Sulfasalazine can suppress signalling pathways involved in synthesis of pro-inflammatory cytokines
76
Sulfasalazine side effect/cons
High doses – needed to be effective, - GI disturbances common - Induces reversible oligospermia - Blood dyscrasias – changes to numbers of white cells
77
Leflunomide (DMARD) in RA (5)
- Inhibits an enzyme involved in synthesis of uridine monophosphate (UMP) - Inhibits tyrosine kinases - These effects supress expansion of autoimmune lymphocytes - Suppresses autoimmunity - Lefunomide is a prodrug –converted to active form in intestinal mucosa and plasma
78
Leflunomide side effect/cons
- Many side effects including hepatotoxicity and teratogenicity - Also leukopenia, anaemia and thrombocytopenia - Monitoring of blood count / liver function therefore needed
79
Leflunomide monitoring
Monitoring of blood count / liver function therefore needed
80
Hydroxychloroquine in RA (5)
- Antimalarial drug - Appears to enter lysosomes inside cell and disturb pH - Macrophages depend upon acid protease for digestion of intracellular protein - Altered pH inside lysosome may alter processing of peptide antigens - Reduces activity of other immune cells
81
Hydroxychloroquine side effect/cons
- Major unwanted effect – retinal toxicity | - Mainly used as an alternative to previous drugs in patients with mild RA
82
Cons of biologics
Tend to be expensive so inly used when DMARDs do not work.
83
Anti-TNF (biological therapy)
- First biologics developed - antibodies against tumour necrosis factor α(TNF), an important mediator of inflammatory responses - or more complex fusion proteins that act in the same way
84
Anakinra (biological therapy)
Antibody against IL-1 receptor. IL-1 is a pro- | inflammatory cytokine released from activated macrophages
85
Tocilzumab (biological therapy)
Antibody that acts as competitive antagonist against the IL-6 receptor - Thereby preventing IL-6 binding and subsequent downstream signalling
86
Biological therapies
- Biologics target specific components of the immune signalling pathway that are important in the inflammation associated with RA - Used when conventional DMARDS are ineffective
87
RA pathogenesis summary (5)
1. Break in tolerance to self-citrullinated proteins in the body and production of autoantibodies 2. An injury to the joint 3. CD4+ T cells activation 4. Release of cytokines, RANKL and other enzymes 5. Osteoclast activation and bone destruction
88
Infliximab
Chimeric mAb
89
Adalimumab
Human mAb
90
Certolizumab pegol
Humanized mAb
91
Etanercept
TNFR fusion protein
92
Golimumab
Human mAb
93
5 different antibodies for biological therapy in RA
``` Infliximab Adalimumab Certolizumab pegol Etanercept Golimumab ```

Stage 3 Case 3 (8 decks)

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