The Pathophysiology of Rheumatoid Arthritis - PowerPoint by eib63834

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									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
                                          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-1b and TNF-: Proinflammatory Cytokines
in the Rheumatoid Joint
                                                                                       High endothelial
                                                                                       venule

                                                         Bone
                                              Osteoblasts      Osteoclasts



           Synovial             IL-8                  Cartilage
                                 PGE2
           membrane
                                       IL-6
                                                                         Neutrophils
                                                    TNF-    IL-1b
            Capsule              Synovial
                                 space



                                                                 C hon drocytes

             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.

								
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