RA Flashcards
RA is a chronic inflammatory disease affecting primarily
synovium
Epidemiology RA
female 30-50s
Etiology of RA
genetic + envrio
HLA-D4 and smoking are the big ones
= predispose person to auto Abs against type 2 collagen and fibrinogen
How does smoking contribute to the pathogenesis of RA? (potentially)
ok this might not be 100% right but I was piecing together info from the lecture and the textbook bc neither were very clear..
- Activates enzyme that converts arg to citrulline. Citrulline is deposited in synovium and is attached to collagen and fibrinogen. It is recognized as a foreign substance and immune response is mediated against it →inflammation in synovium → destruction of joint
- Also/Or smoking thought to cause citruallation: a process that modifies Ag (type II collagen and fibrinogen) to match the “shared epitope” of the HLA alleles
Ab to Fc portion of IgG
rheumatoid factor
What is the orignation of RF
bone marrow
Auto Ab most specific to RA
ACPA
predictor/assc with aggressive dz
high titers of RF and ACPA
cause mast cell and basophil degranulation
ACPA
systemic Ag that RA auto-Abs recognize
glucose phosphate isomerase
joint Ag tht RA auto-Abs recognize
type II collage
also fibrinogen, proteoglycans
How is the synovial lining altered in RA?
undergoes hyperplasia
FLS: invade and damage cartilafe by producing MMPs, serine proteases, cathepsins, aggrecanases
What is the shared epitope
5 aa sequence on Beta chain of HLA-D4 MHC class II haplotypes that correspond to an Ag that is anthrogenic (molecular mimic of type II collagen)
What infections are proposed to cause RA
mycobacterium, Parvo B19, MTB, EBV, retroviruses, enteric bacteria
What other dz are assc with having increased titers of RF
SLE, Sjogren’s, Hep B and C, HIV, and chronic inflammation, SBE
in synovium: create a toxic environment → cell damage → inflammation
ROS and nitrogen
cause cells to accumulate in synovium
Deficiencies in apoptosis
p53
provides nutrients to expanding synovium.
angiogenesis
what stimulates angiogenesis
IL-8, FGF, and VEGF
expressesa adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants
Microvascular endothelium in the synovium
What cells are found in the synovial effusions of RA pts
neutrophils and mononuclear cells
Why do COX -2 inhib work as therapy for RA
prostaglandins and LTs are found in synovial effusions
What are the cellular origins of the cytokines found in synovial effusions?
macrophages, fibroblasts > T cells
the key inflammatory mediator in RA
TNF-a
Cytokines in Synovium
TNF-a IL-1, 6, 8, 15, 17, 18, 33, 10 GM-CSF INF-gamma TGF-B FGF
cytokines that activate chondrocytes and osteoclasts → joint destruction
TNF-a, IL-1, 6, and 8
IL-17
cytokines that Activate MMPs and release prostaglandins
TGF-B and FGF
activates osteoclasts, chondrocytes, macrophages, fibroblasts
IL-17
cytokines secreted by T cells
INF-gamma and IL-17
IL-17 activates
osteoclasts, chondrocytes, macrophages, fibroblasts
What are targets for RA therapy that would control cytokine signaling
NFkB MAP kinase AP-1 JAK Syk
What do synovial lining cells produce that contibute to bone destruction
MMPs, serine proteases, cathepsins, aggrecanases
What mediates cartialge and bone destuction in RA
synovial lining cells by secreting MMPs, serine proteases, cathepsins, aggrecanases
osteoclasts (activ by RANKL (<–IL-17)
Pannus (composed of macrophages and mesenchymal cells)
invasive tissue of the synovium
What cells make it up
pannus
macrophages and mesenchymal cells
systemic symptoms assc with RA
Fatigue, anorexia, weight loss, weakness, generalized aching and stiffness, low grade fever
Articular presentation of RA
morning stiffness > 30 mins
swelling, warmth, and erythema around joint
atrophy of muscles
+/- flexion contractures
What joints are most characteristically involved in RA
wrist and proximal hand (MCP and PIP)
What finding is seen at MCP
ulnar deviation
What finding is seen at the PIP? DIP?
Swan-neck (PIP) and Boutonniere deformities (DIP)
What finding is seen at the wrist?
Volar subluxation with radial-ward rotation
describe the pattern of joint involvement in RA
Mono or oligio → poly and SYMMETRICAL
Why are flexion contractures seen in RA?
Fibrosis and tightening of tissues due to chronic inflammation
*Knee, hip, elbow
Describe the synovial findings in RA
- Exudative
- Yellow
- Elevated WBC
- Decreased viscosity (due to proteases that eat up HA)
joints invovled in RA
knee, hip, elbows, shoulder, wrist, hand
Extra articular manifestations of RA
RA has a RIPPLE effect throughout the body
Rheum nodules (skin, lung, heart valves) Interstitial fibrosis Palpable purpura (vasculitis) Pericarditis, PLeuritis Erosion of the Eyes, Entrapment (Nerve) syndromes
+ dry eyes and mouth
activate complement and IgE
ACPAs
