Rheumatoid Arthritis(RA)
  • 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:
    • 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
GM-CSF (granulocyte macrophage colony stimulating factor) TNFa (tumor necrosis factor alpha) TGF-b (transforming growth factors beta)

 

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

 

GM-CSF macrophage CSF

 

Chemokine & Cytokine factors account for many rheumatoid synovitis characteristics
synovial tissue inflammation synovial fluid inflammation synovial proliferation cartilage and bone damage
Systemic Effects of Rheumatoid Arthritis
  • 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.
Katzung, B. G. and Furst, D. E. Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 578-602.
Primary Reference:Lipsky, P.E. Rheumatoid Arthritis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1880-1888.
Agudelo, C.A. Gout in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton & Lange, 1996, pp 223-226.