Rheumatoid arthritis Flashcards
1
Q
How many % of the global population is affected by RA?
A
~1%
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
3
Q
How many % of the RA patients is female?
A
60-70%
4
Q
What is the peak incidence of RA onset?
A
~50 years
5
Q
What is a characteristic arthritis pattern of RA?
A
Poly-arthritis in the small joints
6
Q
What is the synovial membrane?
A
The membrane encapsulating the synovial space around joints
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
8
Q
Of which two layers is the synovial membrane made up?
A
- Barrier layer consisting of fibroblasts & barrier-forming macrophages
- Sublining layer containing interstitial macrophages and blood vessels
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
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
11
Q
What are the three clinical phases of RA?
A
- Subclinical phase/pre-arthritis
- Early RA
- Established RA
12
Q
What are the immunological processes in the joint in the early RA clinical phase? (3)
A
- Hyperplastic synovial membrane
- Capillary formation
- Influx of inflammatory cells (neutrophils, lymphocytes)
13
Q
What are the immunological processes in the joint in the established RA clinical phase? (6)
A
- Plasma cell influx
- Synovial villus formation
- Extensive angiogenesis
- Bone erosion
- Pannus formation
- Neutrophils
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
15
Q
How can RA be diagnosed before symptom onset?
A
Auto-antibodies, specifically anti-CCP
16
Q
What causes RA?
A
Combination of environmental & genetic risk factors + environmental triggers
17
Q
Before clincal symptoms, RA has a pre-articular/lymphoid phase. What kind of responses can be detected during this stage? (4)
A
- Anti-CCP
- Rheumatoid factor
- Collagen-specific responses
- CP39-specific responses
18
Q
What triggers the transformation from asymptomatic RA to symptomatic RA?
A
Triggers largely unkown
19
Q
In addition to joint damage, which pathological processes (can) also occur in RA? (3)
A
- Cardiovascular disease
- Osteoporosis
- Functional decline
20
Q
What are ACPAs?
A
Anti-citrullinated protein antibodies
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
22
Q
What is hypothesized to be the mechanism of early bone resorption in RA?
A
ACPAs binding to citrullinated proteins on osteoclasts
23
Q
What is the role of IL-8 in early RA? (2)
A
- Binds to nocireceptor -> causes pain
- Attracts neutrophils
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
25
What is a commonly used mouse model for RA?
Collagen-induced arthritis (CIA)
26
Why was the Th1-pathway thought to be involved in RA?
Th1-cells are activated IL-12, blocking of IL-12 resulted in dampened immunoppathology -> resulted in hypothesis that Th1-cells are involved
27
What happens when IFN-γ is blocked in RA? What does this mean?
Worsening of disease -> Th1-cells likely not involved
28
Which subunits make up IL-12?
p35 + p40
29
Which subunit is targeted by anti-IL-12 medication?
p40
30
Which cytokine shares the p40 subunit with IL-12?
IL-23
31
What happens when anti-p40 is used to block IL-12?
Blocking of both IL-12 and IL-23
32
Which Th-subset is now thought to be responsible for RA? How are they activated?
Th17-cells, activated by IL-23
33
Which subunits make up IL-23?
p19 + p40
34
What happens when IL-23 is blocked early in RA pathogenesis? What happens when it is used later?
Can protect against disease when used in initiation phase, but no longer has an effect later in the pathogenesis
35
On which part of RA pathogenesis does the IL-23 exert its effects?
Determining pathogenicity of auto-antibodies by affecting their glycosylation (and not necessarily auto-antibody production itself)
36
Which two immunological phases of RA can be distinguised? What are their hallmarks?
1. Initiation phase = fuelled by Th/B-cells -> production of auto-active IgG
2. Effector phase = cartilage damage due to activity of inflammatory cells
37
Which cytokines are important in driving cartilage damage during the effector phase of RA? (2)
1. IL-2
2. TNF-α
38
Why is there a focus on early RA diagnosis?
Allows to stop disease pathogenesis through anti-IL-23 treatment
39
Which cytokine is produced in higher amounts in RA-patients? Which cells produce this cytokine?
IL-17, produced by CD4+, CCR6+, CD45RO+ Th17-cells
40
How do T-cell - fibroblast interactions in RA lead to a pro-inflammatory loop? (3)
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
How is the inflammatory loop between Th17-cells and fibroblasts of influence on RA chronicity?
Once this loop starts, RA progresses into a chronic inflammatory loop that promotes itself
42
How can the inflammatory loop between Th17-cells and fibroblasts be stopped?
Neutralizing mediators such as IL-17 or TNF-α
43
What is the overarching treatment strategy for RA?
Interfering with pathogenic pathways
44
Which RA-pathogenic pathways can be blocked/interfered with as part of therapy? (5) What is their global mechanism of action?
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
Which CD80/CD86 inhibitor is currently available for RA?
Abacept
46
Which anti-CD20 antibody is currently available for RA?
Rituximab
47
Which TNF-inhibitors are currently available for RA? (5)
1. Adalimumab
2. Certolizumab
3. Etanercept
4. Golimumab
5. Infliximab
48
Which IL-6 inhibitors are currently available for RA? (2)
1. Tocilizumab
2. Sarilumab
49
How many % of RA-patients have auto-antibodies?
70%
50
What is the role of antibodies in RA? (2)
1. Complement activation
2. Binding on Fc-receptor on macrophages
51
What is the current evidence for a role for B-cells in RA? (3)
1. Presence of auto-antibodies: RF/ACPA
2. Importance shown in epidemiological studies
3. Efficacy of therapies targeting antibody production
52
What is RF?
Rheuma factor -> auto-antibodies against the Fc-part of IgG
53
Which isotypes of antibodies can RF be?
IgA, IgG, IgM
54
Which antibody isotype of RF is mostly used as a clinical parameter?
IgM
55
Is RF only present in RA?
No; it is also present in other rheumatic diseases, and in 5% of healthy individuals
56
How many % of healthy individuals have a RF titer?
5%
57
What is the hypothetic physiological role of RF?
Clearance of excess immune complexes after infection by targeting their universal Fc-domain
58
What is CCP? Why is it used in RA diagonsis?
Cyclic citrullinated peptide, an artificial peptide used in diagnostic ELISA for detecting ACPAs
59
Why is it hard to establish animal models for the role of ACPAs?
Humans are the only organism in which the tolerance for citrullinated antigens can be broken
60
What is citrullination?
Natural process of post-translational modification, in which an arganine is changed into citrulline
61
Which enzymes are responsible for citrullination?
Peptidyl arginine deaminases (PDs)
62
True or false: ACPA is very specific and sensitive for RA
True; therefore, they are often used as a clinical test
63
True of false: ACPAs arise during the joint destruction phase of RA
False; ACPAs can be present many years before joint damage occurs
64
To which risk factor are ACPAs related? How does this work physiologically?
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
How is citrullination hypothesized to be a key factor in the triggering of RA?
Trigger (smoking, infection, etc.) causes increased citrullination in lungs & other immunological changes, leading to the production of ACPA
66
Do healthy joins express citrullinated proteins?
No; few citrullinated proteins are expressed in healthy joints
67
How is increased citrullination of proteins in joints triggered, leading to a pathogenic reaction when ACPAs are present?
Damage/infection of the joint causes citrullination, to which ACPAs (if present) can respond
68
Do ACPAs remain the same during the cause of RA?
No; each patient has a unique and individual ACPA profile that develops during the course of RA
69
True or false: certain ACPA fine specificities are more associated with RA than others
False; such an association has not yet been reached
70
True or false: the amount of ACPAs does not matter for the pathogenesis of RA
False; a certain critical mass of ACPAs seems to be required before RA-processes start to occur
71
What are the roles of B-cells in RA pathogenesis? (3)
1. Plasma cell presursors
2. Antigen presentation to T-cells
3. Cytokine production & stimulation via cell-cell interaction
72
Rituximab (anti-CD20) is more effective in [mild/severe] RA
Severe, it is most effective in individuals in which it can bring about a strong reduction in antibodies
73
CD20 is not expressed in plasma cells. How is it still effective against antibody production in RA?
Depletion of B-cells which are precursors to plasma cells
74
How much does having a first grade family member with RA increase a persons risk of RA?
2-10x
75
How much does RA reduce life expectancy if untreated?
~6-7 years
76
Which joints are most often involved in RA?
Small joints of the hand and feet (in a symmetrical pattern)
77
What are symptoms that can help distinguish inflammatory vs. non-inflammatory joint problems? (3)
1. Morning stiffness
2. Less symptoms when active
3. Most complaints in evening/night
78
How is RA most often diagnosed?
History + physical examination
79
Which laboratory markers can be used in RA diagnosis? (4)
Inflammation markers: CRP, ESR
Serology: RF, ACPA
80
Which is more sensitive and specific for RA: RF or ACPA?
ACPA
81
Which radiological investigation can be used in the diagnosis of RA?
X-ray for joint erosions
82
True or false: the RA classification is used in the clinic
False; it is mainly used for research purposes (making groups)
83
What are the three basic principles of the clinical management of RA?
1. Recognize disease as early as possible
2. Agressive treatment after diagnosis
3. Agressive treatment continued until disease is under control
84
What is a good response after treatment initiation associated with?
Low radiographic progression of RA
85
Which class of drugs is used to treat RA? What is their disadvantage, and how is this compensated?
DMARDs, which take time to become effective -> compensated with bridging therapies
86
What are the bridging therapies for RA that are used until DMARD effects kick in? (2) Which of them is always used?
1. Glucocorticoids
2. Methotrexate = always used
87
What are the effects of glucocorticoids in bridging therapy of RA? (2)
1. Rapid resolution of symptoms
2. Prevention of radiological progression (in case of long term use)
88
What is the mechanism of action of methotrexate?
Inhibition of the immune system through downregulation of NF-κB
89
How is methotrexate dosed after treatment initiation?
Starting at >10 mg/week, then escalating to 25-30 mg or maximal tolerable dosage
90
Methotrexate can give gastro-intestinal complaints. How is treatment altered in case of these complaints?
Subcutaneous administration -> gives lower peaks
91
What is are the advantages of using methotrexate in RA treatment over combination therapy? (3)
1. Faster decline in disease activity score
2. Lower disease burden
3. Lower costs
