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I&I WC1 > Rheumatoid arthritis > Flashcards

Rheumatoid arthritis Flashcards

1
Q

How many % of the global population is affected by RA?

A

~1%

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2
Q

What is the incidence of RA in males and in females?

A

0,5/1000/year in males
0,8/100/year in females

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3
Q

How many % of the RA patients is female?

A

60-70%

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4
Q

What is the peak incidence of RA onset?

A

~50 years

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5
Q

What is a characteristic arthritis pattern of RA?

A

Poly-arthritis in the small joints

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6
Q

What is the synovial membrane?

A

The membrane encapsulating the synovial space around joints

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7
Q

Which two types of synoviocytes can be found in the synovial membrane? What is their phenotype?

A

Type A = macrophage-type
Type B = fibroblast-type

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8
Q

Of which two layers is the synovial membrane made up?

A
  1. Barrier layer consisting of fibroblasts & barrier-forming macrophages
  2. Sublining layer containing interstitial macrophages and blood vessels
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9
Q

Which of the two layers of the synovial membrane is strongly disturbed in RA? What is the effect of this?

A

Barrier layer is disturbed, leading to infiltration of interstitial macrophages, neutrophils & monocytes into the joint

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10
Q

Are all lining macrophages of the synovial membrane of the same type?

A

No; there are various distinct populations that inhibit tissue niches

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11
Q

What are the three clinical phases of RA?

A
  1. Subclinical phase/pre-arthritis
  2. Early RA
  3. Established RA
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12
Q

What are the immunological processes in the joint in the early RA clinical phase? (3)

A
  1. Hyperplastic synovial membrane
  2. Capillary formation
  3. Influx of inflammatory cells (neutrophils, lymphocytes)
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13
Q

What are the immunological processes in the joint in the established RA clinical phase? (6)

A
  1. Plasma cell influx
  2. Synovial villus formation
  3. Extensive angiogenesis
  4. Bone erosion
  5. Pannus formation
  6. Neutrophils
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14
Q

Why is diagnosis in the pre-arthritis phase of RA interesting?

A

Pathological processes could still be stopped at this stage, improving prognosis

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15
Q

How can RA be diagnosed before symptom onset?

A

Auto-antibodies, specifically anti-CCP

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16
Q

What causes RA?

A

Combination of environmental & genetic risk factors + environmental triggers

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17
Q

Before clincal symptoms, RA has a pre-articular/lymphoid phase. What kind of responses can be detected during this stage? (4)

A
  1. Anti-CCP
  2. Rheumatoid factor
  3. Collagen-specific responses
  4. CP39-specific responses
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18
Q

What triggers the transformation from asymptomatic RA to symptomatic RA?

A

Triggers largely unkown

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19
Q

In addition to joint damage, which pathological processes (can) also occur in RA? (3)

A
  1. Cardiovascular disease
  2. Osteoporosis
  3. Functional decline
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20
Q

What are ACPAs?

A

Anti-citrullinated protein antibodies

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21
Q

What is hypothesized to be the role of ACPAs in RA?

A

Thought to bind to citrullinated proteins on osteoclasts, leading to bone resorption & release of IL-8

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22
Q

What is hypothesized to be the mechanism of early bone resorption in RA?

A

ACPAs binding to citrullinated proteins on osteoclasts

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23
Q

What is the role of IL-8 in early RA? (2)

A
  1. Binds to nocireceptor -> causes pain
  2. Attracts neutrophils
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24
Q

True or false: ACPAs need to be present in order to be able to diagnose RA

A

False; there are also ACPA-negative RA-patients

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25
Q

What is a commonly used mouse model for RA?

A

Collagen-induced arthritis (CIA)

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26
Q

Why was the Th1-pathway thought to be involved in RA?

A

Th1-cells are activated IL-12, blocking of IL-12 resulted in dampened immunoppathology -> resulted in hypothesis that Th1-cells are involved

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27
Q

What happens when IFN-γ is blocked in RA? What does this mean?

A

Worsening of disease -> Th1-cells likely not involved

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28
Q

Which subunits make up IL-12?

A

p35 + p40

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29
Q

Which subunit is targeted by anti-IL-12 medication?

A

p40

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30
Q

Which cytokine shares the p40 subunit with IL-12?

A

IL-23

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31
Q

What happens when anti-p40 is used to block IL-12?

A

Blocking of both IL-12 and IL-23

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32
Q

Which Th-subset is now thought to be responsible for RA? How are they activated?

A

Th17-cells, activated by IL-23

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33
Q

Which subunits make up IL-23?

A

p19 + p40

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34
Q

What happens when IL-23 is blocked early in RA pathogenesis? What happens when it is used later?

A

Can protect against disease when used in initiation phase, but no longer has an effect later in the pathogenesis

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35
Q

On which part of RA pathogenesis does the IL-23 exert its effects?

A

Determining pathogenicity of auto-antibodies by affecting their glycosylation (and not necessarily auto-antibody production itself)

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36
Q

Which two immunological phases of RA can be distinguised? What are their hallmarks?

A
  1. Initiation phase = fuelled by Th/B-cells -> production of auto-active IgG
  2. Effector phase = cartilage damage due to activity of inflammatory cells
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37
Q

Which cytokines are important in driving cartilage damage during the effector phase of RA? (2)

A
  1. IL-2
  2. TNF-α
38
Q

Why is there a focus on early RA diagnosis?

A

Allows to stop disease pathogenesis through anti-IL-23 treatment

39
Q

Which cytokine is produced in higher amounts in RA-patients? Which cells produce this cytokine?

A

IL-17, produced by CD4+, CCR6+, CD45RO+ Th17-cells

40
Q

How do T-cell - fibroblast interactions in RA lead to a pro-inflammatory loop? (3)

A
  1. Th17 produce IL-17 & TNF-α, which activates fibroblasts
  2. Activated fibroblasts produce IL-6, IL-8 & MMPs
  3. This leads to direct tissue damage & more Th17-activation
41
Q

How is the inflammatory loop between Th17-cells and fibroblasts of influence on RA chronicity?

A

Once this loop starts, RA progresses into a chronic inflammatory loop that promotes itself

42
Q

How can the inflammatory loop between Th17-cells and fibroblasts be stopped?

A

Neutralizing mediators such as IL-17 or TNF-α

43
Q

What is the overarching treatment strategy for RA?

A

Interfering with pathogenic pathways

44
Q

Which RA-pathogenic pathways can be blocked/interfered with as part of therapy? (5) What is their global mechanism of action?

A
  1. CD80/CD86 inhibitors, preventing costimulation of T-cells
  2. Anti-CD20 drugs deplete B-cells
  3. TNF-inhibitors block inflamamtory mediators and osteoclast activation
  4. IL-6 inhibitors block inflammatory mediators and osteoclast activation
  5. JAK-inhibitors bock intracellular signaling on fibroblasts
45
Q

Which CD80/CD86 inhibitor is currently available for RA?

A

Abacept

46
Q

Which anti-CD20 antibody is currently available for RA?

A

Rituximab

47
Q

Which TNF-inhibitors are currently available for RA? (5)

A
  1. Adalimumab
  2. Certolizumab
  3. Etanercept
  4. Golimumab
  5. Infliximab
48
Q

Which IL-6 inhibitors are currently available for RA? (2)

A
  1. Tocilizumab
  2. Sarilumab
49
Q

How many % of RA-patients have auto-antibodies?

A

70%

50
Q

What is the role of antibodies in RA? (2)

A
  1. Complement activation
  2. Binding on Fc-receptor on macrophages
51
Q

What is the current evidence for a role for B-cells in RA? (3)

A
  1. Presence of auto-antibodies: RF/ACPA
  2. Importance shown in epidemiological studies
  3. Efficacy of therapies targeting antibody production
52
Q

What is RF?

A

Rheuma factor -> auto-antibodies against the Fc-part of IgG

53
Q

Which isotypes of antibodies can RF be?

A

IgA, IgG, IgM

54
Q

Which antibody isotype of RF is mostly used as a clinical parameter?

A

IgM

55
Q

Is RF only present in RA?

A

No; it is also present in other rheumatic diseases, and in 5% of healthy individuals

56
Q

How many % of healthy individuals have a RF titer?

A

5%

57
Q

What is the hypothetic physiological role of RF?

A

Clearance of excess immune complexes after infection by targeting their universal Fc-domain

58
Q

What is CCP? Why is it used in RA diagonsis?

A

Cyclic citrullinated peptide, an artificial peptide used in diagnostic ELISA for detecting ACPAs

59
Q

Why is it hard to establish animal models for the role of ACPAs?

A

Humans are the only organism in which the tolerance for citrullinated antigens can be broken

60
Q

What is citrullination?

A

Natural process of post-translational modification, in which an arganine is changed into citrulline

61
Q

Which enzymes are responsible for citrullination?

A

Peptidyl arginine deaminases (PDs)

62
Q

True or false: ACPA is very specific and sensitive for RA

A

True; therefore, they are often used as a clinical test

63
Q

True of false: ACPAs arise during the joint destruction phase of RA

A

False; ACPAs can be present many years before joint damage occurs

64
Q

To which risk factor are ACPAs related? How does this work physiologically?

A

Smoking -> causes local inflammation in the lungs, leading to increased citrullination of proteins, which can lead to a breakdown of tolerance in genetically predisposed individuals

65
Q

How is citrullination hypothesized to be a key factor in the triggering of RA?

A

Trigger (smoking, infection, etc.) causes increased citrullination in lungs & other immunological changes, leading to the production of ACPA

66
Q

Do healthy joins express citrullinated proteins?

A

No; few citrullinated proteins are expressed in healthy joints

67
Q

How is increased citrullination of proteins in joints triggered, leading to a pathogenic reaction when ACPAs are present?

A

Damage/infection of the joint causes citrullination, to which ACPAs (if present) can respond

68
Q

Do ACPAs remain the same during the cause of RA?

A

No; each patient has a unique and individual ACPA profile that develops during the course of RA

69
Q

True or false: certain ACPA fine specificities are more associated with RA than others

A

False; such an association has not yet been reached

70
Q

True or false: the amount of ACPAs does not matter for the pathogenesis of RA

A

False; a certain critical mass of ACPAs seems to be required before RA-processes start to occur

71
Q

What are the roles of B-cells in RA pathogenesis? (3)

A
  1. Plasma cell presursors
  2. Antigen presentation to T-cells
  3. Cytokine production & stimulation via cell-cell interaction
72
Q

Rituximab (anti-CD20) is more effective in [mild/severe] RA

A

Severe, it is most effective in individuals in which it can bring about a strong reduction in antibodies

73
Q

CD20 is not expressed in plasma cells. How is it still effective against antibody production in RA?

A

Depletion of B-cells which are precursors to plasma cells

74
Q

How much does having a first grade family member with RA increase a persons risk of RA?

A

2-10x

75
Q

How much does RA reduce life expectancy if untreated?

A

~6-7 years

76
Q

Which joints are most often involved in RA?

A

Small joints of the hand and feet (in a symmetrical pattern)

77
Q

What are symptoms that can help distinguish inflammatory vs. non-inflammatory joint problems? (3)

A
  1. Morning stiffness
  2. Less symptoms when active
  3. Most complaints in evening/night
78
Q

How is RA most often diagnosed?

A

History + physical examination

79
Q

Which laboratory markers can be used in RA diagnosis? (4)

A

Inflammation markers: CRP, ESR
Serology: RF, ACPA

80
Q

Which is more sensitive and specific for RA: RF or ACPA?

A

ACPA

81
Q

Which radiological investigation can be used in the diagnosis of RA?

A

X-ray for joint erosions

82
Q

True or false: the RA classification is used in the clinic

A

False; it is mainly used for research purposes (making groups)

83
Q

What are the three basic principles of the clinical management of RA?

A
  1. Recognize disease as early as possible
  2. Agressive treatment after diagnosis
  3. Agressive treatment continued until disease is under control
84
Q

What is a good response after treatment initiation associated with?

A

Low radiographic progression of RA

85
Q

Which class of drugs is used to treat RA? What is their disadvantage, and how is this compensated?

A

DMARDs, which take time to become effective -> compensated with bridging therapies

86
Q

What are the bridging therapies for RA that are used until DMARD effects kick in? (2) Which of them is always used?

A
  1. Glucocorticoids
  2. Methotrexate = always used
87
Q

What are the effects of glucocorticoids in bridging therapy of RA? (2)

A
  1. Rapid resolution of symptoms
  2. Prevention of radiological progression (in case of long term use)
88
Q

What is the mechanism of action of methotrexate?

A

Inhibition of the immune system through downregulation of NF-κB

89
Q

How is methotrexate dosed after treatment initiation?

A

Starting at >10 mg/week, then escalating to 25-30 mg or maximal tolerable dosage

90
Q

Methotrexate can give gastro-intestinal complaints. How is treatment altered in case of these complaints?

A

Subcutaneous administration -> gives lower peaks

91
Q

What is are the advantages of using methotrexate in RA treatment over combination therapy? (3)

A
  1. Faster decline in disease activity score
  2. Lower disease burden
  3. Lower costs

I&I WC1 (20 decks)

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