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The Pathophysiology of

Rheumatoid Arthritis

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RA Is Characterised by Synovitis andJoint Destruction

NORMAL RASynovial

membrane

Cartilage

CapsuleSynovialfluid

Inflamedsynovial

membrane

Pannus

Major cell types:

• T lymphocytes• macrophages

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

Major cell type:• neutrophils

Adapted from Feldmann M, et al. Annu Rev Immunol . 1996;14:397-440.

Cartilage thinning

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Numerous Cellular Interactions Drivethe RA Process

B cell

T cell

Antigen-presenting

cells

B cell or macrophage

SynoviocytesPannus

Articular cartilage

Production of collagenase and other neutral proteases

IL-1 andTNF- α Chondrocytes

Rheumatoidfactors

Soluble factorsand directcell–cellcontact

Immune complexesBacterial productsIL-1, TNF- α , etc

Macrophage

IL-1

H LA - D R

Arend W. Semin Arthritis Rheum. 2001;30(suppl 2):1-6.

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IL-1β and TNF- α : ProinflammatoryCytokines in the Rheumatoid Joint

Neu t roph i l s

Os t eoc l a s t s

Bone

Cartilage

Osteob la s t s

C h o n d r o c y t e s

Bone

TNF-α IL -1βSynovialspace

IL-6PGE 2

IL-8

High endothelialvenule

Synovialmembrane

Capsule

PannusOsteoblasts Osteoclasts

PGE 2 = prostaglandin-E 2

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.

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

COX-2 = cyclo-oxygenase type 2; PGE 2 = prostaglandin-E 2; NO = nitric oxide

↑COX-2↑PGE 2

↑NO↑Adhesion molecules

↑Chemokines

↑Collagenases↑IL-6

Proinflammatoryeffects of IL-1

Proinflammatoryeffects of TNF- α

↑TNF- α↑Osteoclast

activation ↑Angiogenic

factors

↑IL-1 ↑cell death

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Activatesmonocytes/

macrophages

Activateschondrocytes

Induces fibroblastproliferation

Activatesosteoclasts

Inflammation Synovial pannusformation

Cartilagebreakdown

Boneresorption

IL-1

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

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Patients With Erosive RA Have Higher Levels of IL-1 Than Patients WithoutErosions

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

0100

200

300

400500

600

700

PatientsWith Erosions

(n = 8)

Mean Cytokine Concentrations in Synovial Fluid

IL-1(pg/mL

)

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

PatientsWithout Erosions

(n = 20)

Non-RAPatients(n = 10)

0100

200

300

400500

600

700

PatientsWith Erosions

(n = 8)

TNF- α

(pg/mL)

PatientsWithout Erosions

(n = 20)

Non-RAPatients(n = 10)

** *