The Pathophysiology of

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

Major cell types:

• T lymphocytes
• macrophages
Pannus
Cartilage Minor cell types:
• fibroblasts
• plasma cells
• endothelium
• dendritic cells

Synovial Major cell type:

Capsule fluid • neutrophils

Cartilage thinning
Adapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.
Numerous Cellular Interactions Drive
the RA Process
Rheumatoid Immune complexes
B cell factors Bacterial products
IL-1, TNF-, etc
IL-1
Soluble factors
T cell and direct
cell–cell
HLA -DR contact
Antigen-
presenting Macrophage
cells
B cell or
macrophage IL-1 and
Synoviocytes TNF- Chondrocytes
Pannus

Articular Production of collagenase and

cartilage other neutral proteases
Arend W. Semin Arthritis Rheum. 2001;30(suppl 2):1-6.
IL-1 and TNF-: Proinflammatory Cytokines
in the Rheumatoid Joint
High endothelial
venule

Bone
O steoblasts O steoclasts

Synovial IL-8 Cartilage

membrane PGE2
IL-6
N eutrophils
TNF-  IL-1
Capsule Synovial
space

C h o nd ro cytes

Pannus
Osteoblasts Osteoclasts

Bone

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.
IL-1 and TNF- Have a Number of
Overlapping Proinflammatory Effects

Proinflammatory Proinflammatory
effects of IL-1 effects of TNF-

COX-2
TNF- PGE2
Osteoclast NO IL-1
activation Adhesion molecules cell death
Angiogenic Chemokines
factors Collagenases
IL-6

COX-2 = cyclo-oxygenase type 2; PGE2 = prostaglandin-E2; NO = nitric oxide

IL-1 Plays a Pivotal Role in the Inflammatory
and Destructive Processes of RA

IL-1

Activates
monocytes/ Induces fibroblast Activates Activates
macrophages proliferation chondrocytes osteoclasts

Inflammation Synovial pannus Cartilage Bone

formation breakdown resorption
Patients With Erosive RA Have Higher
Levels of IL-1 Than Patients Without
Erosions
Mean Cytokine Concentrations in Synovial Fluid

700 700
600 600

TNF- (pg/mL)
IL-1 (pg/mL)

500 500
400 400
300 300
** *
200 200
100 100
0 Patients Patients Non-RA 0 Patients Patients Non-RA
With Erosions Without Erosions Patients With Erosions Without Erosions Patients
(n = 8) (n = 20) (n = 10) (n = 8) (n = 20) (n = 10)

*P <0.06, **P <0.003 vs patients with erosions

Fong K, et al. Clin Exp Rheumatol. 1994;12:55-58.