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S3 Case 3 - Musculoskeletal > Pathophysiology of RA > Flashcards

Pathophysiology of RA Flashcards

1
Q

What is RA?

A

Chronic systemic inflammatory condition

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2
Q

What is normally affected first?

A

Interphalangeal joints of fingers + wrists

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3
Q

What happens to the affected joints?

A

Become warm, painful + swollen

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4
Q

What causes stiffness (particularly in the morning)?

A

Increased extracellular fluid

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5
Q

What does RA cause?

A

Progressive destruction bone/cartilage around joint

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6
Q

What are the comorbidities of RA?

A

CVD
Inflammation around heart + lungs

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7
Q

What is osteoarthritis?

A

Degenerated arthritis
= wear in the joints = degeneration of cartilage + bone

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8
Q

Where does osteoarthritis usually affect?

A

Hands, neck, hip, back + knees

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9
Q

What is protective in osteoarthritis?

A

Exercise

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10
Q

What is septic arthritis?

A

Secondary to infection
= invasion of joints by infectious agent = joint inflammation

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11
Q

What is post traumatic arthritis?

A

Secondary to physical injury

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12
Q

What do autoimmune conditions do?

A

Body cannot distinguish between self + non-self
= body generates Abs against itself

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13
Q

What mutation increases risk to develop RA?

A

HLA-DR4

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14
Q

What is RA triggered by?

A

Exposure of genetically susceptible individual to an arthritogenic antigen = breakdown of immunological self-tolerance = chronic inflammation

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15
Q

Describe the breakdown in tolerance

A

Initiating event = acute arthritis
CD4+T helper cell activation = autoimmune reaction
Release of inflammatory cytokines + mediators = joint destruction

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16
Q

Describe what happens in RA once mediators are released

A

Joints infiltrated with CD4+T cells
Macrophages secrete pro-inflammatory cytokines + help B cells produce arthritogenic Abs
Cytokines induce production of MMP + RANK ligand by fibroblasts
MMPs attack tissue
= activation of osteoclasts = joint destruction

17
Q

What are the 2 autoantibodies in RA?

A

Rheumatoid factor (RF)
Anti-citrullinated peptide Abs (ACPAs)

18
Q

What is RF?

A

Autoantibody specific for Fc portion of IgG

19
Q

What are ACPAs?

A

Citrullination increased in inflammation

20
Q

How are citrullinated proteins produced?

A

Arginine is converted to citrulline by PAD
PAD destabilises proteins = more prone to proteolysis

21
Q

How do smoking interact with ACPAs?

A

Smoking induces expression of PAD
Citrullinated proteins found in respiratory tract
HLA-DR4 mutation can activate CD4+T cells as result
They activate B cells
B cells produce Abs to own citrullinated proteins
= autoimmune response
= autoantibodies

22
Q

What are the stages of RA pathogenesis?

A

Pre-articular phase
Initiation phase
Progression

23
Q

What happens in the pre-articular phase?

A

Synovial membrane fibrous layer form joint capsule
PAD2 + PAD4 = citrullinate proteins
ACPAs present in blood

24
Q

What happens in RA initiation?

A

Initiated by joint damage
Damage = state of inflammation
= further activation of PAD
ACPAs + RF enter joint capsule
Lymphocytes respond to specific antigen
Action of T cells + immune complexes = symptoms of RA

25
Q

What happens in RA progression?

A

CD4+T differentiate into TH17 + TH1 = activate macrophages + neutrophils
= produce other pro-inflammatory cytokines

26
Q

What happens overall in RA pathogenesis?

A

Autoantibodies against citrullinated proteins present in blood BUT joints normal
Needs triggering - eg. microbial/mechanical
Damage provokes normal inflammatory response + Abs enter joint capsule
Inflammation
Continued = progressive tissue damage = destroys synovial joints

27
Q

What different drugs are used in RA therapy?

A

NSAIDs
Glucocorticoids
DMARDS
Biologics

28
Q

Why give glucocorticoids?

A

Give till DMARDs kick in

29
Q

What is the mechanism of action of methotrexate?

A

Supress neutrophil adhesion to blood vessels = prevention of entry into site of inflammation
Suppresses cytokine production
Reduces macrophage function
Reduces immune function

30
Q

What is the problem with methotrexate?

A

Immunological suppression = makes patient more susceptible to infection

31
Q

What is the mechanism of action of Sulfasalazine?

A

Supresses signalling pathway involved in synthesis of pro-inflammatory cytokines

32
Q

What are the side effects of Sulfasalazine?

A

GI disturbances
Blood dyscrasias

33
Q

What is the mechanism of action of Leflunomide?

A

Inhibits pyridine synthesis
= supresses expansion of autoimmune lymphocytes
= supresses autoimmunity

34
Q

What are the side effects of Leflunomide?

A

Hepatoxicity
Leucopenia, anaemia + thrombocytopenia

35
Q

What do biologics do?

A

Target specific components of immune signalling

36
Q

When are biologics used?

A

When conventional DMARDS are ineffective

37
Q

What is Anakinra?

A

Ab against IL-1

38
Q

What is Tocilizumab?

A

Ab that acts as competitive antagonist against IL-6

S3 Case 3 - Musculoskeletal (14 decks)

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