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Flashcards in RA Deck (46):
1

RA is a chronic inflammatory disease affecting primarily

synovium

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Epidemiology RA

female 30-50s

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Etiology of RA

genetic + envrio

HLA-D4 and smoking are the big ones
= predispose person to auto Abs against type 2 collagen and fibrinogen

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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

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Ab to Fc portion of IgG

rheumatoid factor

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What is the orignation of RF

bone marrow

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Auto Ab most specific to RA

ACPA

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predictor/assc with aggressive dz

high titers of RF and ACPA

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cause mast cell and basophil degranulation

ACPA

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systemic Ag that RA auto-Abs recognize

glucose phosphate isomerase

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joint Ag tht RA auto-Abs recognize

type II collage

(also fibrinogen, proteoglycans)

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How is the synovial lining altered in RA?

undergoes hyperplasia
FLS: invade and damage cartilafe by producing MMPs, serine proteases, cathepsins, aggrecanases

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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)

14

What infections are proposed to cause RA

mycobacterium, Parvo B19, MTB, EBV, retroviruses, enteric bacteria

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What other dz are assc with having increased titers of RF

SLE, Sjogren’s, Hep B and C, HIV, and chronic inflammation, SBE

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in synovium: create a toxic environment → cell damage → inflammation

ROS and nitrogen

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cause cells to accumulate in synovium

Deficiencies in apoptosis
(p53)

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provides nutrients to expanding synovium.

angiogenesis

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what stimulates angiogenesis

IL-8, FGF, and VEGF

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expressesa adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants

Microvascular endothelium in the synovium

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What cells are found in the synovial effusions of RA pts

neutrophils and mononuclear cells

22

Why do COX -2 inhib work as therapy for RA

prostaglandins and LTs are found in synovial effusions

23

What are the cellular origins of the cytokines found in synovial effusions?

macrophages, fibroblasts > T cells

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the key inflammatory mediator in RA

TNF-a

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Cytokines in Synovium

TNF-a
IL-1, 6, 8, 15, 17, 18, 33, 10
GM-CSF
INF-gamma
TGF-B
FGF

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cytokines that activate chondrocytes and osteoclasts → joint destruction

TNF-a, IL-1, 6, and 8
IL-17

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cytokines that Activate MMPs and release prostaglandins

TGF-B and FGF

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activates osteoclasts, chondrocytes, macrophages, fibroblasts

IL-17

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cytokines secreted by T cells

INF-gamma and IL-17

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IL-17 activates

osteoclasts, chondrocytes, macrophages, fibroblasts

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What are targets for RA therapy that would control cytokine signaling

NFkB
MAP kinase
AP-1
JAK
Syk

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What do synovial lining cells produce that contibute to bone destruction

MMPs, serine proteases, cathepsins, aggrecanases

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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)

34

invasive tissue of the synovium

What cells make it up

pannus

macrophages and mesenchymal cells

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systemic symptoms assc with RA

Fatigue, anorexia, weight loss, weakness, generalized aching and stiffness, low grade fever

36

Articular presentation of RA

morning stiffness > 30 mins
swelling, warmth, and erythema around joint
atrophy of muscles
+/- flexion contractures

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What joints are most characteristically involved in RA

wrist and proximal hand (MCP and PIP)

38

What finding is seen at MCP

ulnar deviation

39

What finding is seen at the PIP? DIP?

Swan-neck (PIP) and Boutonniere deformities (DIP)

40

What finding is seen at the wrist?

Volar subluxation with radial-ward rotation

41

describe the pattern of joint involvement in RA

Mono or oligio → poly and SYMMETRICAL

42

Why are flexion contractures seen in RA?

Fibrosis and tightening of tissues due to chronic inflammation

*Knee, hip, elbow

43

Describe the synovial findings in RA

•Exudative
•Yellow
•Elevated WBC
•Decreased viscosity (due to proteases that eat up HA)

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joints invovled in RA

knee, hip, elbows, shoulder, wrist, hand

45

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

46

activate complement and IgE

ACPAs