Block 2 - MSK > RA - ONLINE MATERIAL > Flashcards

RA - ONLINE MATERIAL Flashcards

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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
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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
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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
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4
Q

Etiology: other possibilityes

A
  • altered/aberrant T cell repertoire
  • inability of Treg to control clonal expansion
  • B cell etiology - antiarticular response
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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
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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
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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
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8
Q

Visible changes on Xray

A
  • joint narrowing due to loss of cartilage
  • erosions adjacent to cartilage
  • jusxta articular osteopenia
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9
Q

Chronic changes, suite

A
  • increase pressure -> hypoxia in type B synoviocytes
  • increase in HIF1a -> VEGF -> angiogenesis (poorly ordered)
  • CXCL12
  • ECM
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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
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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
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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)
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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
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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
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15
Q

What aspect of the huistory is most suggestive of an inflammatory arthritis such as RA?

A
  • early morning stiffness
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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
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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
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18
Q

What are the joints most commonly affected by RA?

A
  • MCP of hand
  • proximal interphalangeal
  • wrist
  • elbow
  • shoulders
  • hips
  • knees
  • ankles
  • MTP
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19
Q

Typocal RA deformities

A
  • ulnar dviation, subluxation at MCP
  • swan neck deformity
  • boutoniere
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20
Q

Spine involvement

A
  • Cervical spine
  • Pannus at C1-C2
  • Atlanto-axial subluxation
  • sub-axial subluxation
  • potential compression of spinal cord
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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
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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
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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
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24
Q

Lung and heart disease

A
  • pleural effusion, pleuritis
  • fibrosis 5%
  • rheumatoid nodules
  • pericardial effusion, pericarditis
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25
Eye disease
- scleritis, episcleritis - scleromalacia perforans: inflammation of the sclera with thinning and rupture of sclera - Sicca syndrome: dry eyes,mouth - Sjogren syndrome - 10% of patient
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Other EA manifestation
- Vasculitis | - Felty's syndrome (splenomegaly +/- lymphadenopathy, neutropenia, leg ulcers, recurrent infection)
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Investigations
- 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
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Anti-CCP antibodies
- sensitivity 60-80% - specificity >90% - correlate with RF but not always cooccur - not useful for monitoring disease activity - better predictor than RF for severity
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RF
- 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
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Full blood count
- WCC usually normal | - thromocytosis associated with active disease
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ESR
- increased with disease activity | - increased with age
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CRO
- acute phase reactant - increases with disease activity - not affected by age
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Ferritin
- increases as acute phase reactant
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XRay
- Early: soft tissue swelling - middle: erosive changes - late: joint space narrowing
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DEfinite diagnosis of RA
- 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
RA X ray changes
- 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
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Chronic/severe RA
- 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
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Why is early treatment important
- 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
Treatment strategy
- analgesics - antiinflammatory drugs - NSAIDS - corticosteroids to control inflammation - DMARD
40
DMARD
- disease modifying anti-rheumatic drugs - delayed efficacy on symptoms - improve long term outcome - slow disease progression
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Markers of poor prognosis
- RF+, CCP+ - multiple swollen joint - high ESR/CRP - erosion at diagnosis - nodules or other EA manifestation
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Aims of treatment
- remission or low disease activity - no stiffness/synovitis - low ESR/CRP
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Treamtent strategy
- start with metotrexate - add 2nd DMA after 3 months if still active disease - biological agents after 6 months
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Methotrexate
- gold standard treatment - weekly dose - purine antagonist - up to 20 mg weekly - folic acid supplements to reduce side effects
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Side effects of methotrexate
- mouth ulcers, nausea - abnormal liver function - increased risk of infection - pneumonitis - monitor: FBC, liver function, Creatinine
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Other disease modifying drugs: Leflunomide
- alone or combinations - pyrimidine antagonist - side effect: diarrhoea, rash, abN liver function test, infection, cytopenia
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Other disease modifying drug: sulfasalazine
- alone in sero-negative or in combinations - side effects: rash, nausea, headache, 4-6 tabs/day - rare but serious: neutropenia
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Other disease modifying drugs: hydroxychloroquine
- used in combination therapy - side effects - GIT, rash - Monitor eyes - rare retinal complications
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Biological agents
- 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
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Benefits of biological agents
- 70-80% of patients respond - increased remission rate - reduced radiological damage - nromalisation of ESR, CRP - reduced cardiovascular events
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TB screening
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
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DMARD
- main drug targets are immune cells and inflammatory patheays - display delayed efficacy on symptom - signifcantly improve long term outcome by slowing disease progression
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Conventional DMARD
- methotrecate and leflunomide - Sulfasalazine - Hydroxychloroquine
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Biological DMARD
- TNFa inhibitor - IL6 inhinitor - CD20 blocker: Rituximab - CTLA4 inhibitor: abatacept
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Methotrexate
- 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
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Toxicity of methotrexate
- bone marrow suppression, liver accumulation - mouth ulcers, nausea - pneumonitis
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Leflunomide
- targets dihydroorotate dehydrogenase - prodrug: actively metabolised to teriflunomide - orally administered - half life 2 weeks - Inhibits de novo pyrimidine snthesis
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Toxicity of leflunomide
- GI - Skin rash, alopecia - minor infection - liver function abnormality - peripheral neuropathy, pneumonitis
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Sulfasalazine/Salazopyrin
- pro drug, actively metabolised to 5-ASA - unknown drug trget or MOA - poor bioavailibility - toxicity: GI, headah, rash, dizziness, depression, reversible infertility, thrombocytopenia
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Hydroxychloroquine: antimalarial
- 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
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Toxicity of hydroxychloroquine
- corneal deposits - retinal toxicity - GIT - time-limited use
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TNFa inhibitors
- etanercept - infliximab - adalimumab - certolizumab - Golimumab " mab" - monoclonal antibody
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TNF inhibitors side effects
- inkection site reaction common: hypersensitivity - infection - especially resp tract - recurrence of latent infection - TB - demyelination - drug induced SLE
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IL6 inhibitors - Tocilizumab
- drug target: IL6 receptor - IV administration, long half life (montjlu) - binds to IL6 receptor, preents JSK-STAT3 signalling and reduces cellular survival and proliferation
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Tocilizumab toxicity
- abnormal liver function test - neutropenia - increase risk of infection cellulitis others - increase cholesterol
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B cell inhibitor - Rituximab
- 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
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CTLA4 inhibitor - Abatacept
- 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
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Abatecept toxicity
- immunosuppression and infection - hypersensitivity reaction - respiratory function in COPD - headache
Block 2 - MSK
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