rheumatoid arthritis Flashcards
(25 cards)
what is rheumatoid arthritis *
NOT a condition of old people
it is a chronic automimmune disease
characterised by pain, stiffness and symettrical synovitis (inflammation of the synovial membrane) of synovial (diarthrodial) joints (the free moving joints)
usually aged 30-50yrs
clinical features of rheumatoid arthritis *
chronic arthritis
- POLYarthritis - swelling of the small joints of hand and wrist is common (poly means >5 joints affected)
- symettrical - eg both L and R hand evenly
- early morning stiffness in and around joints - for long periods (hrs)
- may lead to irreversible joint damage and destruction if untreated = loss of function = impact life - these are joint erosions on radiographs
extra-articular disease can occur
- rheumatoid nodules under skin
- vasculitis
- episcleritis (eye)
- affect lung
rheumatoid factor can be detected in blood
- IgM autoAb against IgG Ab - this IgM autoAb is diagnostic, but can be found in other conditions so depends on the context
epidemiology of rheumatoid arthritis
1% population affected - relatively common cause of significant disability in young adults
more common in females - effect of female hormones on immune system
describe the genetic component in rheumatoid arthritis *
higher concordance for identical to non-identical twins
heritability estimates up to 60%
specific HLA-DRB gene varients mapping to aa 70-74 of the DRbeta-chains are associated with rheumatoid arthritis
there are a number of HLA-DRB alleles associated - they all encode a shared aa sequence in the HLA-DR antigen binding groove - this is called a shared epitope
describe the environmental component of rheumatoid arthritis *
smoking - contributes to 25% of population attributable risk
it interacts with the shared epitope to increase the risk
what are the joints most commonly affected by rheumatoid arthritis *
MCP
PIP
wrost
knee
ankle
MTP
(shoulder can be affected)
early disease in hand and feety
describe the features of RA *
swelling over the MCP joints and PIPJS
deformity in toes
callus formation under head of metatarsals due to joint deformity
these are late stage pictures
describe the joint damage and destruction seen in RA *
swan neck deformity - hyperextension at PIP and hyper-flexion at DIP
boutonniere deformity - button like - hyper-flexion at PIPJ
xray - subluxation look like dislocation of the MCPJ, bilateral ulnar deviation of the fingers
describe the pathology in the synovium (primary site of pathology for RA) *
in synovial joints - PIPJ synovitis (swelling) - palpate the swelling = soft
in tensynovium surrounding the tendons - extensor tenosynovitis - swelling on back of hand - cant fully extend lttle and ring fingers because of extensor tendon damage
in bursa - olecranon bursitis
describe subcutaneous nodules *
there is a central area of fibrinoid necrosis surrounded by histiocytes (macraphage lineage) and peripheral layer of connective tissue
occur ion 30% of pts
associated with sever disease, extra-articular manifestations and rheumatoid factor
rheumatoid nodule - ulnar border of forarm is typical position - if present confirms RA and is invariably associated with rheumatoid factor
in hands - common location - around PIP joints
describe rheumatoid factor *
Ab that recognise the Rc part iof IgG
they are typicall IgM anti-IgG Ab
they form an immune complex - this activates complement - trigger inflammation
positive in 70% of disease at onest and further 10-15% become positive over the 1st 2 yrs of diagnosis
if positive called sero+ve RA
sero -ve is better prognosis - inflammation is more mild
describe the Ab to citrullinated protein Ag in RA *
Ab to citrullinated peptides (ACPAs) are highly specific for RA - anti-cyclic citrullinated peptide Ab (anti-CCP Ab)
citrulline is not found in normal proteins - created by convergion from arginine with enzyme: peptidyl arginine deiminases (PADs)
PADs are present in high concentrations in neutrophils and monocytes and consequently there is an increased citrullination of autologous peptides in the inflammed synovium
ACPA is strongly associated with smoking and the HLA shared epitope
teh shared epitope preferentially binds non-polar aa like citrulline bot not +ve charged like arginine - so ACPA is more likely to develop among individuals with citrulinated autoag who have a shared epitope
smokers have chronic airwauy inflammation - increase citrulination of peptides - this triggers the autoimmune reponse
describe HLA molecules and RA *
individuals are suseptible to RA because they carry the conserved aa sequence in their HLA-DRbeta ag-binding groove (shared epitope)
this epitope preferentially binds to citruline and citruline containing peptide antigens increased during inflammation
HLA-DRbeta is a class 2 allele - so presents to CD4 T cells - suggesting T cell involvement in the pathogenesis
the epitope is responsible for presenting specific peptides to T cells
what are the extra-articular features of RA *
malaise, fever, weight loss, SC nodules
uncommon:
vasculitis - inflammation of bv - can lead to tissue ischemia and necrosis of finger tips
ocular inflammation - episcleritis - red area of eye
neuropathies - inflammation damage peripheral nerves = weak/loss of sensation of hand/foot
amyloidosis - inflammation for a long time get increased serum amyloid a - can deposit in organs and cause organ failure eg renal/enlarged spleen
lung disease - nodules (do chest xray), fibrosis (SOB - fibrosis also caused by methotrexate so need to determine if drug or RA causing it), pleuritis (inflammation of plura - pain on inspiration)
fetty’s syndrome - triad of splenomegaly, leukopenia and RA
describe the radiographic abnormalities for RA *
very early - normal - want to catch it here - once see signs start to have missed boat for treatment
early - juxta-articular osteopenia - thin bone - reduced white colour
later- joint erosions at margins of the joint
later still - joint deformity and destruction
all carpal bones coelece, in MCPjs - less joint space and irregular, erosion, erosion of ulnar styloid, ragid irregularities of MCPjs
describe the pathology of RA *
bone erosion
proliferation of pannus - inflammatory tissue
synovium has hypertrophied
describe features of the synovial joint *
synovium - 1-3 cell deep lining containiong macrophage like phagocytic cells (type A synoviate) amd fibroblast-lke cells that produce hyaluronic acid (type B synoviate) - there is type 1 collagen
synovial fluid - hyaluronic acod rich viscous fluid
articular cartilagde - type 2 collagen and proteoglycan (aggrecan)
summarise the pathogenesis of rheumatoid arthritis *
synovial membrane is abnormal
the synovium becomes a pannus because of neovascualrisation (more bv carrying inflammatory cells), lymphangiogenesis, inflamm cells (activated t and b cells, plasma cells, mast cells and acrtivated macrophages)
recruitment, activation and effector function of these cells is controlled by a cytokine network
there is excess pro-inflamm vs anti-inflamm cytokines
TNF-alpha is the dominant cytokine
describe the role of TNF-a in RA *
it causes:
- osteoclast activation = bone resorption
- chondrocyte activation = metalloproteinase production and cartilage destruction
- angiogenesis
- leukocyte accumulation - induction/maintenance of HLA class 2 expression
- endo cell activation - upregulation of E-selectin and VCAM-1, leukocyte accumulation
- chemokine release = leukocyte accumulation
- proinflamm cytokine release
- hepcidin induction = acute phase response
- PGE2 production
descrieb TNFa inhibition *
achieved through parenteral administration (mainluy SC injection) of Ab/fusion proteins - was originally monoclonal Ab - IV
describe the biological therapy for RA *
block IL6 - inflammatory cytokine - tocilizumab and sariumab are Abs against IL6 receptors
IL1 blockade is less effective and have to do daily injection - the cost doesnt justify the marginal benefit, so not done in the UK
deplete B cells by IV admin of anti-CD20 this is Rituximab - 2 injetions 2 wks apart - works because the produce the Ab, also APC to T cells
inhibito TNFa - Ab (infliximab) and fusion proteins (etanercept - decoy receptor for TNF so mops it up
modulation of T cell co-stimulation (abatacept - fusion protein, extracellular domain of human cytotoxic T-lymphocyte-associated ag 4, linked to modified Fc - hinge, CH2, and CH3 domains of IgG1
describe management for RA *
goal is to prevent joint damage
MDT approach
physio - build back lost muscle through lack of use
OT - in advanced disease - make sure you can still function
hydrotherapy
surgery
med: early and aggressively
- disease modifying anti-rheumatic drugs (DMARDs) - started early in disease because level of joint destruction = inflammation x time, they are steroid sparing agents
- there are important roles for glucocorticoid therapy - steroids - aim to avoid long term because of SE, useful short term to control flare of disease/inflammation in 1 joint
- biological therapies
describe DMARD therapy *
they are drugs that may induce remission and prevent joint damage - they dont cure
tehy reduce the amount of inflammation in the synovium and slow or prevent structural damage in the synovium
slow onset of action
start with methotrexate in combination with hydroxychloroquine or sulphasalazine - they are immune modulators
leflunomide is uncommonly used
janus kinase inhibitors are new drugs - tofacitinib and baricitnib - rarely used
gold and penicillamine are rarely used
methotrexate upsets the liver and blood count therefore need to monitor these systems
what is the downside of biological therapies *
expensive treatrments - therefore use is limited to severe disease - have to fail 2 standard therapies - therefore give 2 standard drugs straight away
there is an increased risk of infection for all of them
TNF-a is associated with increased suseptibility to mycobacterial infection eg TB - so need to screen all patients for TB before starting treatment - may use prophylactic Ab for all at high risk
B cel depeltion associated with Hep B reactivation - so need to screen all patients for hep B before treatment
B cell depletion therapy can be associated with JC virus infection nad progressive leukoencephalopathy - neurological condition that affects the brain - can be fatal
