RA - ONLINE MATERIAL Flashcards
1
Q
Associated gene polumorphisms
A
- Class II MHC: HLA-DR/P/Q/M -> 30% of genetic risk
- Class III MHCL TNF, C4, HS-70
- Hormone related genes: Prolactin, estrogen synthase, estrogen receptor, Corticoprotin RH
2
Q
Suite: non MHC related genes
A
- Lymphocyte associated: TCR, B cell, CTLA-4
- cytokine and cytokine receptors: TNF, CCR5, IL10, IL1, IL3
- othersL MBL, MMP3, NRAMP1
3
Q
Etiology: association with DRB1
A
- infectious agent in synovium
- arthritogenic antigen : cross reactivity with self
- continues presence of super antigen from EPV or MB TB
4
Q
Etiology: other possibilityes
A
- altered/aberrant T cell repertoire
- inability of Treg to control clonal expansion
- B cell etiology - antiarticular response
5
Q
Etiology: cyclic citrullinated peptides
A
- anti-cyclic citrullinated peptide antibodies
- citrullination is part of normal cell death but damage accelerates it. Its caused by deimidation of arginin via PADI enzyme which increases calcium
- PADI unfolds proteins for easy degradation
- includes cytoskeletal vimentin
- leakage of citrullinated peptides and PADI
6
Q
Acute changed in RA
A
- increased vascular flow: oedema, fibrin rice bodies
- endothelial activation: increased adhesion molecule expression, increased leukocyte adhesion, increased leukocyte transmigration
- vascular proliferation: high endothelial venules
- replication of Type B synoviocytes
- recruitment of type A synoviocytes
- fusion of both into giant cells
- involvement of immune response
7
Q
Chronic changes in RA
A
- recruitment of cells
- remodelling responses; large ratio of MMP/TIMP -> tissue degradation
- reduced apoptosis of synoviocytes
- proliferative response to hypoxia resulting from increase in HIF1a
- synoviocyte fusion
- formation of synovial pannus
- erosion of cartilage and bone
8
Q
Visible changes on Xray
A
- joint narrowing due to loss of cartilage
- erosions adjacent to cartilage
- jusxta articular osteopenia
9
Q
Chronic changes, suite
A
- increase pressure -> hypoxia in type B synoviocytes
- increase in HIF1a -> VEGF -> angiogenesis (poorly ordered)
- CXCL12
- ECM
10
Q
RA background
A
- most common chronic inflammatory joint disease
- 1% of pop
- F:M: 2-3:1
- onset increases with age
- peak onset 50-70
11
Q
Incidence of RA
A
- higher in NE, NA, and native american tribes
- incidenceL 40/100.000
- more common in lower education and low SES
12
Q
Etiology - environmental
A
- smoking is the strongest risk factor: follows a dose response. Associated with CCP and RF and with more severe disease
- alcohol lowers risk
- statins reduce risk of RA
- virus: EPV, Parvo B19 (not proven)
13
Q
Reproductive and endocrine etiology
A
- increase risk in women
- increse risk post-partum
- remission during pregnancy
- early menopause increase risk
- estrogen inhibits T supresor cells and enhances T-helper cell function
14
Q
Etiology - Genetic
A
- Genetic contribution 30%
- concordance monozygotic twins = 12-15%
- Concordance dizygotic twins = 3%
- HLADRB1 risk alleles: 0401, 0405
- havign 2 copies of allele increases risk
- influence development of seropositive RA
- associated with more severe disease
15
Q
What aspect of the huistory is most suggestive of an inflammatory arthritis such as RA?
A
- early morning stiffness
16
Q
RA Clinical features
A
- inflammatory history: morning stiffness for more than 30 min
- synovitis in 3+ joints
- symptoms last >6 weeks
- Viral illnesses can cause RA like symptoms
- other diseases have been excluded
17
Q
Onset of RA
A
- gradual onset 50%
- sudden onset 10-25%
- local soft tissue inflammation: carpal tunnel syndrome, bursitis
- systemic feature: fatigue, weight loss, fever, myalgia
18
Q
What are the joints most commonly affected by RA?
A
- MCP of hand
- proximal interphalangeal
- wrist
- elbow
- shoulders
- hips
- knees
- ankles
- MTP
19
Q
Typocal RA deformities
A
- ulnar dviation, subluxation at MCP
- swan neck deformity
- boutoniere
20
Q
Spine involvement
A
- Cervical spine
- Pannus at C1-C2
- Atlanto-axial subluxation
- sub-axial subluxation
- potential compression of spinal cord
21
Q
Morbidity and mortality in RA
A
- cardiovascular risk - main cause of mortality
- RA associated with 50-60% increased risk of CV mortality
- reduced with good control of inflammation
- Morbidity: CV disease, infection, lymphoma
22
Q
Extra-articular features of RA
A
- Systemic inflammatory condition - can affect other tissues
- Rheumatoid nodules commonest EA features
- presence of EA features is associated with worse prognosis
23
Q
Rheumatoid nodules
A
- occur in 30% of RA patients
- severe disease
- sero-positive disease (RF, antiCCP)
- occur typically on elbows but can occur anywhere
24
Q
Lung and heart disease
A
- pleural effusion, pleuritis
- fibrosis 5%
- rheumatoid nodules
- pericardial effusion, pericarditis
25
Q
Eye disease
A
- scleritis, episcleritis
- scleromalacia perforans: inflammation of the sclera with thinning and rupture of sclera
- Sicca syndrome: dry eyes,mouth
- Sjogren syndrome - 10% of patient
26
Q
Other EA manifestation
A
- Vasculitis
- Felty’s syndrome (splenomegaly +/- lymphadenopathy, neutropenia, leg ulcers, recurrent infection)
27
Q
Investigations
A
- Autoantibodies: RF, anti-CCP. Useful for diagnosis, prognosis, but not present in 100% of patients
- Non specific investigations: ESR, CRP -> markers of inflammation, useful for monitoring disease activity
28
Q
Anti-CCP antibodies
A
- sensitivity 60-80%
- specificity >90%
- correlate with RF but not always cooccur
- not useful for monitoring disease activity
- better predictor than RF for severity
29
Q
RF
A
- non specific
- positive in 70% of RA patient
- low specificity in gen pop
- false positive in up to 25% over 75 years
- present in infectionsm other autoimmune disease
- poor screening test
- titre/level not useful for monitoring disease activity
30
Q
Full blood count
A
- WCC usually normal
- thromocytosis associated with active disease
31
Q
ESR
A
- increased with disease activity
- increased with age
32
Q
CRO
A
- acute phase reactant
- increases with disease activity
- not affected by age
33
Q
Ferritin
A
- increases as acute phase reactant
34
Q
XRay
A
- Early: soft tissue swelling
- middle: erosive changes
- late: joint space narrowing
35
Q
DEfinite diagnosis of RA
A
- multiple joints with synovitis, especially small joints of hands and feet
- ESR and/or CRP elevated
- RF and/or CCP+
- symptoms > 6 weeks
- other diseases excluded
36
Q
RA X ray changes
A
- synovitis: soft tissue swelling, widened joint space
- hyperemia: juxta-articular osteoporosis
- Pannus: marginal erosion, diffuse joint space narrowing, central subchondral custs
- subcutaneous nodules
- fibrous fusion: loss of joint space
- ligament weakening/imabalnce: subluxation
- minor/absent bony repair
37
Q
Chronic/severe RA
A
- symmetrical
- marginal erosion
- diffuse loss of joint space
- subchondral cust
- MCP, PIP distribution
- marked ulnar volar subluxations
- soft tissue nodule pressure point
- fusion
- no osteophytes
38
Q
Why is early treatment important
A
- Damage occurs early
- 70% erode in 2 years
- 40% erosive at presentation
- significant BMD loss in 1st year
- disability occurs early
- spontaneous remission is rare:
39
Q
Treatment strategy
A
- analgesics
- antiinflammatory drugs
- NSAIDS
- corticosteroids to control inflammation
- DMARD
40
Q
DMARD
A
- disease modifying anti-rheumatic drugs
- delayed efficacy on symptoms
- improve long term outcome
- slow disease progression
41
Q
Markers of poor prognosis
A
- RF+, CCP+
- multiple swollen joint
- high ESR/CRP
- erosion at diagnosis
- nodules or other EA manifestation
42
Q
Aims of treatment
A
- remission or low disease activity
- no stiffness/synovitis
- low ESR/CRP
43
Q
Treamtent strategy
A
- start with metotrexate
- add 2nd DMA after 3 months if still active disease
- biological agents after 6 months
44
Q
Methotrexate
A
- gold standard treatment
- weekly dose
- purine antagonist
- up to 20 mg weekly
- folic acid supplements to reduce side effects
45
Q
Side effects of methotrexate
A
- mouth ulcers, nausea
- abnormal liver function
- increased risk of infection
- pneumonitis
- monitor: FBC, liver function, Creatinine
46
Q
Other disease modifying drugs: Leflunomide
A
- alone or combinations
- pyrimidine antagonist
- side effect: diarrhoea, rash, abN liver function test, infection, cytopenia
47
Q
Other disease modifying drug: sulfasalazine
A
- alone in sero-negative or in combinations
- side effects: rash, nausea, headache, 4-6 tabs/day
- rare but serious: neutropenia
48
Q
Other disease modifying drugs: hydroxychloroquine
A
- used in combination therapy
- side effects - GIT, rash
- Monitor eyes - rare retinal complications
49
Q
Biological agents
A
- genetically engineered antibodies to cytookine and immune targets
- TNF inhibitors - Ab to TNF
- IL6 antibodies
- B cell blocker - antiCD20
- CTLA4 Ab - blocks co-stimulatory signal between T cell and antigen presenting cell
50
Q
Benefits of biological agents
A
- 70-80% of patients respond
- increased remission rate
- reduced radiological damage
- nromalisation of ESR, CRP
- reduced cardiovascular events
51
Q
TB screening
A
TNF is important for granuloama formation
- TNF inhibitor increase risk of reactivation latent TB
- screening required prior to Reaction
- history of exposure or at risk
- CXR
- Mantoux > 5 mm
52
Q
DMARD
A
- main drug targets are immune cells and inflammatory patheays
- display delayed efficacy on symptom
- signifcantly improve long term outcome by slowing disease progression
53
Q
Conventional DMARD
A
- methotrecate and leflunomide
- Sulfasalazine
- Hydroxychloroquine
54
Q
Biological DMARD
A
- TNFa inhibitor
- IL6 inhinitor
- CD20 blocker: Rituximab
- CTLA4 inhibitor: abatacept
55
Q
Methotrexate
A
- inhibits dihydrofolate reductase
- oral administration
- long half life: weekly tablets
- renally eliminated - lower dose for patients with renal dysfunction
- inhibits the synthesis of thymidylate and purine nucleotides
- essential for DNA synthesis and cell proliferation
56
Q
Toxicity of methotrexate
A
- bone marrow suppression, liver accumulation
- mouth ulcers, nausea
- pneumonitis
57
Q
Leflunomide
A
- targets dihydroorotate dehydrogenase
- prodrug: actively metabolised to teriflunomide
- orally administered
- half life 2 weeks
- Inhibits de novo pyrimidine snthesis
58
Q
Toxicity of leflunomide
A
- GI
- Skin rash, alopecia
- minor infection
- liver function abnormality
- peripheral neuropathy, pneumonitis
59
Q
Sulfasalazine/Salazopyrin
A
- pro drug, actively metabolised to 5-ASA
- unknown drug trget or MOA
- poor bioavailibility
- toxicity: GI, headah, rash, dizziness, depression, reversible infertility, thrombocytopenia
60
Q
Hydroxychloroquine: antimalarial
A
- Targets lysosome
- orally administered
- half life of 40 days, renal excretion
- loading dose then daily maintenance
- increases intracellular lysosome pH -> diminishes enzyme processing of immune signalling proteins
- inhibit TLR9 signalling in DC, peptide loading for MHC -> prevents activation of innate immune cell
61
Q
Toxicity of hydroxychloroquine
A
- corneal deposits
- retinal toxicity
- GIT
- time-limited use
62
Q
TNFa inhibitors
A
- etanercept
- infliximab
- adalimumab
- certolizumab
- Golimumab
” mab” - monoclonal antibody
63
Q
TNF inhibitors side effects
A
- inkection site reaction common: hypersensitivity
- infection - especially resp tract
- recurrence of latent infection - TB
- demyelination
- drug induced SLE
64
Q
IL6 inhibitors - Tocilizumab
A
- drug target: IL6 receptor
- IV administration, long half life (montjlu)
- binds to IL6 receptor, preents JSK-STAT3 signalling and reduces cellular survival and proliferation
65
Q
Tocilizumab toxicity
A
- abnormal liver function test
- neutropenia
- increase risk of infection cellulitis others
- increase cholesterol
66
Q
B cell inhibitor - Rituximab
A
- targets CD20 on B cells
- long half life, IV dose every 6 motnhs
- binds to CD20 on B cells, resulting in ADCC-cell death
- toxicity similar to TNFa inhibitors
67
Q
CTLA4 inhibitor - Abatacept
A
- targets CD80/86 on APC
- SC weekly or IV monthly
- half life 13 days
- prevents activation and proliferation of T cells
- inhibits T cell mediated cytokine release
68
Q
Abatecept toxicity
A
- immunosuppression and infection
- hypersensitivity reaction
- respiratory function in COPD
- headache
