RA Flashcards
definition of RA
an illness causes by polyarticular inflammatory arthritis, associated with other systemic symptoms
who is most affected by RA?
women
requirements for RA diagnosis
patient with at least one joint with DEFINITE clinical synovitis that is not better explained by another disease
(joint distribution, RF/ACPA serology, symptom duration, ESR)
common features of joint distribution in RA
carpal, MCP, PIP joints affected. DIP joints spared. subluxation common
where does the synovium anchor within the joint?
at the margin of the cartilage and bone
early stage RA
inflammation within the joint. synovium thickens by hypertrophy and hyperplasia. joint distention due to inflammatory cells within fluid that is less viscous than normal.
middle stage RA
tremendous inflammation of synovium causes bony destruction and cartilage damage at the margin. synovium becomes thickened and looks like wet bread (called pannus).
late stage RA
tremendous damage to bone and cartilage. Vascular supply is outstripped by growth of synovium
RA vs OA vs Spondylitis
inflammatory disease of synovium affecting small joints of hands/feet
degenerative disease of cartilage affecting hands and weight bearing joints
inflammatory disease of synovium and enthuses, axial and peripheral joints affected
shared epitope hypothesis
HLA DR alleles that are associated with RA share an amino acid sequence that constitutes part of antigen binding groove
risk factors that might trigger immune response in RA
infectious agent, pesticides, smoking, gingivitis
smoking and RA
can cause citrullination in the lungs leading to anti CCP antibodies which direct against residues of type 2 collagen
periodontal disease and RA
cause and effect relationship is unclear
histology of normal synovium
thin membrane of 1-2 cells deep, supported by fibrous tissue.
histology of inflamed RA synovium
thickening of synovial cell layer (hypertrophy), proliferation of the synovium (hyperplasia), perivascular infiltrates of inflammatory cells, increased vascularity
how can RA be self perpetuating?
immune cells that infiltrate synovium may organize into germinal centers and perpetuate antigen presentation and autoimmune reaction
antibodies indicative of RA
RF and anti-CCP. (can form immune complexes that activate complement and attract other inflammatory cells to synovium)
RF (rheumatoid factor)
polyclonal antibody (IgM) that binds to Fc portion of IgG. enhances antigen presenting role of b cells. can self associate into immune complex that fixes complement and activates inflammation.
cytokines associated with RA
TNFa, IL6, Lymphotoxin, IFNy
what is the boss cytokine in RA?
TNFa
mechanism of cartilage destruction in RA?
cytokines activate collagenase/MMPs. when released from fibroblast, works from the outside in. when released from chondrocyte, works from the inside out.
mechanism of bone destruction in RA?
cytokines activate RANKL, which is an osteoclast differentiation factor
RANK
receptor on pre-osteoclasts and osteoclasts that signals for their differentiation and activation
RANKL
membrane bound or secreted protein from stromal cells, osteoblasts, T cells, and synovial fibroblasts that activates RANK
OPG (osteoprotegerin)
natural RANK antagonist that is secreted by many different cells, which functions by binding RANKL
non joint symptoms of RA patients?
accelerated atherosclerosis (likely due to systemic inflammation), increased risk of infection/malignancy, secondary sjogren’s vasculitis, increased pulmonary autoimmune disease.
treatment for RA
inhibit TNFa, inhibit B cell function (rituximab), inhibit co-stimulatory molecules, inhibit cytokine receptors, inhibit RANK activation
