Rheumatoid Arthritis Flashcards
What is rheumatodi arthritis?
disease of an aberrant immune response that leads to chornic progressive synovial inflammation and joint destruction
has the potential to cause severe pain, joint damage, disability, and increased mortality
What is the epidemiology of RA?
female > male (2.5:1)
worldwide distribution
0.5-1% disease prevalence in European and North American populations
peak incidence is 40-60 years of age
prevalence increases with age (7% at 75 years)
What are the possible causes of premature mortality in individuals with RA?
infection
GI bleed
lymphoproliferative disorders
CVD
What is the primary lesion in RA?
inflammation of the synovium
What are the two layers of synoviocytes in the intima, and what do they do?
type A - bone marrow derived with macrophage like synoviocytes that is 1-2 cells thick
type B - fibroblast-like synoviocytes synthesize extracellular matrix proteins (collagen, fibronectin, hyaluronic acid, molecules that facilitate the lubrication of the cartilage surface)
What is the composition of the sublining layer below the intima of the synovium?
loose connective tissue with numerous blood vessels, lymphatics, nerves, fibrous connective tissue
What happens to the synovium in RA?
hyperplasia of the synovialmembrane, up to 10 cells thick (both type A and B)
cellular infiltration into the synovium sublining - T and B lymphocytes, plasma cells, interdigitating and follicular dendritic cells, NK cells, macrophages
diffuse or organized cellular infiltrates into lymphoid aggregates and secondary lymphoid follicles
neoangiogenesis
What is the pannus?
inflammatory synovial membrane in RA
thickened synovial membrane forms villous projections that protrude into the joint space, and extend to cartilage and bone
pannus invades and destroys periarticular bone and cartilage -> marginal erosions (juxta-articular lesions)
lining produces inflammatory cytokines and proteases that work with activated chondrocytes and osteoclasts to cause joint destruction
What is the pathogenesis of RA?
aberrant immune response in a genetically predisposed host
genetic susceptibility + trigger -> autoimmune disease (RA)
peristence and progression of RA are regulated by immune mediators
What is the shared epitope hypothesis?
the genetic system conferring the most risk is thought to be certain major histocompatibility complex alleles (MHC, or HLA for human leukocyte antigen)
conserved amino acid sequence on the HLA is high in RA (QKRAA)
third hypervariable region of DRbeta chains at amino acids 70-74
presence of SE is associated with increased susceptibility and severity of RA
How does the shared epitope cause increased susceptibility of RA?
epitope borders the antigen binding cleft of the HLA-DR molecule
the theory is that MHC molecules with the shared epitope could bind efficiently to arthritogenic peptides
it is possible that SE confers a positive charge to the peptide binding cleft of the class II MHC that prevents the binding of peptides containing arginine
What is the rol eof petidylarginine deaminases (PADIs)?
convert arginine to an uncharged citrulline thereby permitting hte citrullinated protein to be loaded on the MHC and presented to autoreactive T cells
What is PADI4?
a functional variant of tyrosine phosphatase N22 (PTPN22) and is an RA susceptibility gene
intracellular tyrosine phosphatase that negatively regulates T cell activity
defect could generate autoimmunity by modulating negative selection in the thymus
2-fold increased risk of RA for heterozygotes PTPN22 polymorphism
4-fold increased risk RA for homozygotes PTPN22
What are some potential environmental triggers of RA?
hormal influences
cigarette smoking - best characterized, increases risk of anti-CCP autoantibody (has the shared epitope)
bacterial or viral infectious agents could be potential initiating factors - increased EBV load, which can lead ot RF productino
What are the classical symptoms of RA?
insiduous onset symmetric polyarthritis
joint swelling
eventual decreased range of motion
morning stiffness > 1 hour
stiffness after rest (gelling)
pain and swelling worse in the morning
pain in the balls of the feet upon first ambulating in the morning
What are common findings of the joint exam in RA?
inflammatory synovitis
symmetric joint swelling and tenderness
palpable swelling and synovial bogginess as opposed to joint enlargement due to bony hypertrophy (osteophytes)
later in course can have deformity, decreased ROM, and malalignment
synovial fluid WBC > 2000
nodules at pressure points
What joints are affected in early RA?
wrists affected, MCPs, PIPs, MTPs, thumb interphalangeal joints
What joints are affected in later RA?
larger joints
ankles, knees, elbows, shoulders, and occasionally sternoclavicular, temporomandibular, and cervical spine
What joints are almost always spared in RA?
DIP joints
thoracolumbar spine
What are physical findings commonly found in RA?
swan neck and Boutenniere’s deformities
hand nodules with ulnar deviation and subluxation
nodules on tendon sheath
extra-articular manifestations
episcleritis
abrupt onset of inflammation in the episclera of the eye
scleritis
painful, destructive, and potentially blinding disorder that may also involve the cornea, adjacent episclera, and underlying uveal tract
scleritis has striking, highly symptomatic clinical presentation
scleromalacia
marked scleral thinning and adjacent scleral and conjunctival injection
darker pigmented uveal tissue has herneated through the softened sclera, and perforation is imminent
nonconcentric pupil
What are early radiologic findings of RA?
soft tissue swelling
periarticular osteopenia
no erosions
progresses to thinning of cortex and loss of bone with marginal erosion and joint space narrowing
What is rheumatoid factor?
any antibody that targets the Fc region of IgG
high titer positive RF leads to a poor prognosis (more aggressive and erosive disease, poorer long-term function, extra-articular disease)
sensitivity 66% and specificity 82%
