• Overview:
  • Chronic multisystem disease
  • ?Unknown cause?
  • Characteristic feature:
    • persistent inflammatory synovitis, usually involving peripheral joints (symmetric distribution)
  • Consequences of synovial inflammation:Disease Hallmarks--
    • cartilage destruction
    • bone erosion
    • joint integrity change
  • Range of Disease Manifestations:
    • mild (brief, oligoarticular illness; minimal joint damage)
    • Substantial (progressive, relentless, polyarthritis ®significant functional impairment)

• Epidemiology
  • Prevalence of rheumatoid arthritis: 0.8%
  • women: affected about 3X more often than men
  • Prevalence increases with age
  • RA:
    • affects all races
    • seen worldwide
    • most frequent onset: age--forties to fifties
• Genetic Predispositions:
  •  severe RA: four times expected rate in first-degree relatives of individuals with disease associated with auto antibody, rheumatoid factor
  • About 10% of patient with RA -- affected first-degree relative
  • Monozygotic twins: at least four times more likely to be concordant for RA than dizygotic twins
  •  About 15% to 20% of monozygotic twins -- concordant for RA suggesting other than genetic factors play an important role

•  Genetic Factors-- RA etiology and other considerations:
  • class II major histocompatibility complex (MHC) gene product HLA-DR4
  • approximately 70% of patients with definitive RA express HLA-DR4 (compared to 28% of controls)
  • Genes outside HLA complex contributes, probably including genes controlling T cell antigen receptor expression and the expression of immunoglobulin heavy and light chains
  • Genetic component associated with drug-induced toxicities -- For example:
    • presence of the HLA-DR3 (DRß1*0301) allele: highly correlated with side effect development to gold therapy including:
      • proteinuria (similar relationship between allele presence and proteinuria associated with D-penicillamine treatment)
      • skin rash
      • thrombocytopenia
• Non-genetic factors:
  • analysis of epidemiologic studies in Africa;indicative of additional factors including
    • climate
    • urbanization
• Pathology & pathogenesis
  • Earliest lesions in rheumatoid synovitis:
    • increased number of synovial lining cells
  • Subsequent changes:
    • increased number of synovial lining cells + mononuclear cell perivascular infiltration
    • synovium: edematous; protruding into the joint cavity
  • Microscopic features:
    • synovial lining cell hyperplasia and hypertrophy
    • focal/segmental vascular change --
      • microvascular injury
      • thrombosis
      • neovascularization
      • edema
      • mononuclear cell infiltration (aggregates around small blood vessels)
    • rheumatoid synovium endothelial cells:
      • resemble high endothelial venules of lymphoid organs
      • altered by cytokine exposure
      • elaboration of adhesion molecules
    • Infiltrating cell types:
      • predominant -- T lymphocytes
        • CD4+ memory T cells more common then CD8+ cells
        • T cell's express early activation antigen CD69
      • Significant B-cell proliferation:
        • local differentiation into antibody-producing plasma cells
        • produce both polyclonal immunoglobulin and autoantibody rheumatoid factor ® local immune complexes formation.
      • HLA-DR+ macrophages
      • dendritic cells
  • synovial fibroblasts are activated producing: collagenase/cathepsins ® articular matrix degradation
    • Activated fiberglass: prominent:
      • lining layer
      • bone/cartilage interface -- osteoclasts prominent
      • at bone erosion sites
  • Rheumatoid synovium:
    • secreted products of activated lymphocytes, macrophages, fibroblasts
    • Local cytokine/chemokine production responsible for many clinical & pathological presentations of rheumatoid arthritis

Effector molecules from T lymphocytes:

IL-2

IFNg

IL-6

IL-10

Effector molecules from activated macrophages:

IL-1	TNFa	IL-6	IL-8	IL-10
GM-CSF	platelet-derived growth factor	macrophage CSF	insulin-like growth factors	TGF-b

Molecules secreted by other cell types(fibroblasts & endothelial cells)

IL-1

IL-6

IL-8

• Progression of rheumatoid arthritis: probably immunologically- mediated; probably T cell driven

Rheumatoid Arthritis: Clinical Manifestations

• Onset:two-thirds of patients -- following symptoms:
  • Fatigue, anorexia, weakness, vague musculoskeletal symptoms
  • Specific symptoms appear gradually:
    • symmetrical effects on joints of the hands, wrists, knees, feet
• Symptoms of Articular disease
  • Most common manifestation of established RA:
    • pain and affected joints
    • worsened by movement
    • morning stiffness
  • Synovial inflammation: swelling, tenderness, motion limitations.
  • With persistent inflammation: characteristic deformities.