The Pathophysiology of Rheumatoid Arthritis

1
The Pathophysiology of Rheumatoid Arthritis

2
RA Is Characterised by Synovitis and Joint
Destruction
NORMAL
RA
Inflamed synovial membrane
Synovial membrane

• Major cell types
• T lymphocytes
• macrophages

Pannus
Cartilage

• Minor cell types
• fibroblasts
• plasma cells
• endothelium
• dendritic cells

Synovial fluid

• Major cell type
• neutrophils

Capsule
Cartilage thinning
Adapted from Feldmann M, et al. Annu Rev Immunol.
199614397-440.
3
Numerous Cellular Interactions Drive the RA
Process
Immune complexes Bacterial products IL-1, TNF-?,
etc
Rheumatoid factors
B cell
IL-1
Soluble factors and direct cellcell contact
T cell
HLA
-DR
Antigen- presenting cells
Macrophage
B cell or macrophage
IL-1 and TNF-?
Synoviocytes
Chondrocytes
Pannus
Articular cartilage
Production of collagenase and other neutral
proteases
Arend W. Semin Arthritis Rheum. 200130(suppl
2)1-6.
4
IL-1b and TNF-a Proinflammatory Cytokines in the
Rheumatoid Joint
High endothelial venule
B
o
n
e
O
s
t
e
o
c
l
a
s
t
s
O
s
t
e
o
b
l
a
s
t
s
Synovial membrane
C
a
r
t
i
l
a
g
e
IL-8
PGE2
IL-6
N
e
u
t
r
o
p
h
i
l
s
a
T
N
F
-
I
L
-
1?
Capsule
Synovial space
C
h
o
n
d
r
o
c
y
t
e
s
Pannus
Osteoblasts
Osteoclasts
B
o
n
e
PGE2 prostaglandin-E2
Dinarello C, Moldawer L. Proinflammatory and
Anti-inflammatory Cytokines in Rheumatoid
Arthritis A Primer for Clinicians. 3rd ed.
Thousand Oaks, Ca, USA Amgen Inc. 2001.
5
IL-1 and TNF-? Have a Number of Overlapping
Proinflammatory Effects
Proinflammatory effects of IL-1
Proinflammatory effects of TNF-?
?COX-2?PGE2?NO?Adhesion molecules?Chemokines?
Collagenases?IL-6
?TNF-??Osteoclast activation ?Angiogenic
factors
?IL-1 ?cell death
COX-2 cyclo-oxygenase type 2 PGE2
prostaglandin-E2 NO nitric oxide
6
IL-1 Plays a Pivotal Role in the Inflammatory and
Destructive Processes of RA
IL-1
Activates monocytes/macrophages
Activates chondrocytes
Induces fibroblast proliferation
Activates osteoclasts
Inflammation
Synovial pannus formation
Cartilage breakdown
Bone resorption
7
Patients With Erosive RA Have Higher Levels of
IL-1 Than Patients Without Erosions
Mean Cytokine Concentrations in Synovial Fluid
700
700
600
600
500
500
TNF-? (pg/mL)
400
IL-1 (pg/mL)
400
300
300


200
200
100
100
0
0
Patients With Erosions (n 8)
Patients Without Erosions (n 20)
Non-RAPatients (n 10)
Patients With Erosions (n 8)
Patients Without Erosions (n 20)
Non-RAPatients (n 10)
P lt0.06, P lt0.003 vs patients with erosions
Fong K, et al. Clin Exp Rheumatol. 19941255-58.