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Module 204 MSK & Immune system > Rheumatoid arthritis symposium > Flashcards

Rheumatoid arthritis symposium Flashcards

1
Q

What is autoimmunity?

A

Immune response to self-antigens

Represents a breakdown of immunological tolerance

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2
Q

What is the consequence of chronic cytokine release?

A

Tissue destruction

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3
Q

What is rheumatoid arthritis?

A

Inflammation of synovial joints

Systemic inflammation

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4
Q

Who is affected by RA?

A

1% of population
3X more common in women
Diagnosis common at 40-50 years

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5
Q

What are some long-term complications of rheumatoid arthritis?

A 
Acute-phase response in liver
Production of free fatty acids and adipoctokines leading to insulin resistance
Low bone mineral density and fractures
Low stress tolerance and depression
Atherogenesis, MI, stroke
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6
Q

Describe the pattern of joint damage in RA

A

Usually multiple joints in a symmetrical fashion
Morning stiffness
Swelling, heat, redness, pain
Loss of funciton

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7
Q

What is synovitis?

A

Swelling over extensor tendons, wrist and MCP joints

Synovium hyperplasia

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8
Q

Describe synovial fibroblasts in synovitis

A

Reduced apoptosis
Enhanced anchorage
Upregulated adhesion molecules
Increased proliferation

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9
Q

What is the pathology of rheumatoid arthritis?

A 
Pannus
Synovial fluid rich in neutrophils
Synovitis
Cartilage erosion
Bone erosion
Cartilage loss
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10
Q

What is pannus?

A

Inflammed synovial membrane due to cells infiltrating from blood

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11
Q

What is the composition of synovial tissue?

A

Macrophages - 40%
Fibroblast and endothelial cells -10-15%
T-lymphoctes - 40%
B lymphocytes and plasma cells - 5%

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12
Q

What are the key populations of T cells in RA synovial?

A

Th17 and Th1 cells

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13
Q

What is IL-17 known to do?

A

Activate synovial fibroblasts and osteoclasts which remove bone
Favour cartilage resorption

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14
Q

Describe B-cells in RA

A

B cells form diffuse or follicular infiltrates in synovium

Produce cytokines and are important for antigen presentation e.g. IL-6

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15
Q

What does monoclonal anti-CD20 do to B cells?

A

Depletes B-cells and is an effective treatment

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16
Q

Describe cartilage erosion

A

Fibroblasts make matrix metalloproteases which break down collagen network in cartilage
Chondrocytes undergo apoptosis
Fibroblasts adhere to and invade cartilage leading to biochemical dysfunction and joint space narrowing.

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17
Q

What cytokines produce osteoclast differentiation and activation?

A 
IL-17
RANKL
TNF-alpha
IL-1
IL-6
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18
Q

What percentage of patients are affected by bone erosion within 1 year of diagnosis?

A

80%

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19
Q

What are the clinical markers of RA?

A

Elevated ESR
Elevated CRP
Rheumatoid factor
Cyclic citrullinated peptide antibodies

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20
Q

What is rheumatoid factor?

A

Made by B cells and directed against Fc portion of another antibody to form immune complex
2 varies: IgM or IgG

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21
Q

Why is rheumatoid factor not that useful for diagnosis of RA?

A

Not specific for RA
Also present in other autoimmune diseases and in some healthy individuals
Some RA patients are seronegative
Levels don’t correlate with disease activity

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22
Q

Describe use of CCP antibody for diagnosis of RA

A

Antibodies directed against CCP found in 60-70% of patients with RA
Rarely found in healthy people who don’t go on to develop RA
Detectable in blood many years before disease onset
Anti-CCP positive RA has a more aggressive clinical course of disease

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23
Q

What is citrullination?

A

Process of replacing protein arginine residues with citrulline residues
Occurs normally in body but if it occurs on an unusual part of the protein they may be recognised as foreign leading to antibody response

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24
Q

What citrullinated self-proteins are most likely in RA?

A 
alpha-enolase
Keratin
Fibrinogen
Fibronectin
Collagen
Vimentin
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25
Q

What are the possible mechanisms for anti-CCP antibodies enhancing development and severity of inflammation when mild synovitis is already present?

A

Activation of inflammatory cells by anti-CCP immune complexes
Anti-CCP mediated neutrophil cell death producing NETs
Direct binding of anti-CCPs to drive osteoclastogenesis

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26
Q

Describe the incidence of RA worldwide

A

1%
Less common in South America and asia
high incidence in North Americans in north america

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27
Q

What polymorphisms are associated with RA?

A 
HLA-DRB1 SE
PTPN22
CTLA4
STAT4
TRAF1
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28
Q

What is HLA-DRB1 SE?

A

Human leucocyte antigen

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29
Q

What is PTPN22?

A

Protein tyrosine phosphatase 22 which regulates T-cell activation

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30
Q

What is CTLA4?

A

Co-stimulation suppressor that regulates interactions between T cells and APCs

31
Q

What is STAT4?

A

Transducer of cytokine signals that regulate proliferation, survival and differentiation of lymphocytes

32
Q

What is TRAF1?

A

Regulator of TNF-alpha receptor superfamily signalling

33
Q

Describe the incidence of RA in twins

A

Monozygotic twins: 12-15%
Dizygotic twins: 3-5%
Suggests there is a genetic component but it is only weak

34
Q

Describe the influence of hormones on developing RA

A

Testosterone considered protective against autoimmune diseases
Risk of developing RA is increased during period just after giving birth
RA patients often experience remission during pregnancy
Risk of developing RA after menopause isn’t influence by HRT

35
Q

Describe the influence of smoking on developing RA

A

Heavy smoking increases risk of RA among people with susceptibility genes of HLA-DR4 alleles
2TCDD in cigarette smoke activates synovial fibroblasts which induce pro-inflammatory cytokines

36
Q

Describe the suggestion of an infectious trigger of RA

A

Evidence is hard to find as infection may no longer be present once disease is established
Bacterial components identified in joint tissue in both RA and healthy joint tissue

37
Q

Give examples of infections that could trigger RA

A 
Human parvovirus B19
Human retrovirus 5
Alphaviruses
Hepatitis
Chronic hepatitis C virus
Epstein-Barr virus
Mycoplasma
E.coli
Rubella virus
Porphyromonas gingivitis
38
Q

What are the 2 groups of pharmacological therapies for RA?

A

Anti-inflammatory drugs which provide symptom relief

Disease-modifying anti rheumatic drugs which slow clinical and radiographic progression of RA

39
Q

What are some synthetic agents of DMARDs?

A

Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide

40
Q

What are some non-selective COX 1/2 inhibitors?

A

Aspirin
Ibuprofen
Diclofenac

41
Q

Give an example of an NSAID COX-2 selective inhibitor

A

Celecoxib

42
Q

What are the 2 types of anti-inflammatory drugs used?

A

NSAIDs

Steroid anti-inflammatory drugs, immunosuppressants

43
Q

Give examples of steroids used

A

Prednisolone
Depomedrone
Triamcinolone

44
Q

Why should long-term use of steroids be avoided?

A

Due to risk of infections and osteoporosis

45
Q

What is the mechanism of methotrexate?

A 
Inhibits cell proliferation
Increases adenosine level
Reduces production of polyamines
Induces apoptosis of activated CD4 and CD8 T-cells
Reduces inflammation
46
Q

What are the 2 components of sulfasalazine?

A

Sulfapyridine

5-amino salicylic acid

47
Q

What is hydroxychloroquine used to treat?

A

Malaria

SLE

48
Q

What is a possible mechanism of hydroxychloroquine?

A

Increases lysosomal pH

49
Q

What is the mechanism of leflunomid?

A

Lymphocyte inhibitor
Inhibits de novo pyrimidine synthesis
Most effective in reducing B-cell populations (also has an effect on T-cells)

50
Q

Describe DMARD combination therapy

A

More effective than single drug without extra side effects

51
Q

What is the most effective DMARD combination?

A

MTX
Sulfasalazine
Hydroxychloroquine

52
Q

What are the adverse effects of synthetic DMARDs?

A 
Nausea
Loss of appetite
Diarrhoea
Rash, allergic reaction
Headache
Hair loss
Risk of infections
Hepatotoxicity
Kidney toxicity
53
Q

What is TNF blockade used to treat?

A

RA
Crohn’s disease
Ankylosing spondylitis
Psoriasis

54
Q

When is biological therapy recommended?

A

If patient failed to respond to at least 2 standard DMARDs

RA disease activity score measured ≥5 on 2 or more occasions

55
Q

Give examples of TNF blockers

A 
Etanercept
Infliximab
Adalimumab
Certolizumab pegol
Golimumab
56
Q

What does Infliximab do?

A

Neutralises free, membrane and receptor bound TNA-alpha leading to antibody dependent cell-mediated cytotoxicity

57
Q

What is infliximab also used for?

A

Crohn’s disease
UC
Plaque psoriasis
Ankylosing spondylitis

58
Q

What does Etanercept do?

A

Binds free and membrane bound TNF reducing accessible TNF

59
Q

What is etanercept also used for?

A

Juvenile idiopathic arthritis
Plaque psoriasis
Psoriatic arthritis
Ankylosing spondylitis

60
Q

What is adalimumab also used for?

A 
Juvenile idiopathic arthritis
Plaque psoriasis
Psoriatic arthritis
Ankylosing spondylitis
Crohn's disease
61
Q

What is golimumab also used in?

A

Psoriatic arthritis

Ankylosing spondylitis

62
Q

What should patients be screened for before starting TNF therapy?

A 
History of TB
Multiple sclerosis
Recurrent infections
Leg ulcers
Past history of cancer
63
Q

What is rituximab?

A

Monoclonal antibody against B cells

64
Q

How does rituximab work?

A

Depletes B cells
Opsonises B cells which are attacked and killed via:
- complement mediated cytotoxicity
- antibody dependent cell-mediated cytotoxicity
- apoptosis

65
Q

What is rituximab also used to treat?

A

SLE

66
Q

What is abatacept?

A

T-cell co stimulation blocker

67
Q

How does abatacept work?

A

T-cell co stimulation blocker which increases threshold for T-cell activation
Competitive inhibitor of Cd28
Suppresses proliferation of synovial recirculating T cells
Reduces level of inflammatory mediators

68
Q

What is tociluzimab?

A

IL-6R blocker

69
Q

What is tociluzimab also used in?

A

Systemic juvenile idiopathic arthritis

70
Q

What is anakinra?

A

IL-1R antagonist

Recombinant IL-1ra

71
Q

How does anakinra work in RA?

A

Reduces bone erosion
Decreases osteoclast production
Blocks IL-1 induced MMP release from synovial cells

72
Q

What are the adverse effects of biological therapies?

A 
Increased risk of infections
Nausea
Headache
Hypertension
Allergic reactions
73
Q

When are biological therapies contraindicated?

A

Pregnancy

Breastfeeding

Module 204 MSK & Immune system (44 decks)

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