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Rheumatoid-Arthritis

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					Rheumatoid Arthritis
  1. Chronic systemic inflammatory disease of unknown cause. Persistent symmetric
     polyarthritis that affects the hands and feet, but can affect any synovial joint. Extra-
     articular involvement of skin, heart, lungs and eyes can be significant.
  2. Epidemiology: 3/10,000 ww, ~2.1mill ppl. Peaks in ages 35-50yo, mostly females (2-3X
     > males)
  3. Etiology:
         a. Genetic factors: certain histocompatibility genes make ppl more prone to get RA.
             HLA DR allels (DR4,1,10,14) are often increased in RA patients. HLA-DR4/1
             are present in 90% of cases, 40% of normal ppl.
         b. Humoral immunity: lymphocytes and plasma cells accumulate in synovium and
             make antibodies (IgG). Immune-complexes also deposit in joint. 80% of patients
             with classic RA are + for rheumatoid factor (RF) which is mostly IgM but can
             be IgG/A that is directed against the Fc fragemetn of IgG. RF is also found in
             patients with collagen vascular disease (systemic lupus erythematous, progressive
             systemic sclerosis, dermatomyositis). It is also present in many other disease.
         c. Cellular immunity: abundant T-cells in rheumatoid synovium are frequently Ia
             positive (activated) and are usually Thelper cells. Usually in close contact with
             HLA-DR-+ cells (macP or dendritic cells. T cells usually in contact with macP
             and dendritic cells through cytokines, usually TNF and IL-1
         d. Infectious agents: not detected in joints of ppl with RA. Most patients with RA
             make antibodies agasint nuclear antigen in B cells infected with Epstein-Barr
             virus (EBV) (RA-associated nuclear antigen (RANA), also EBV makes B cells
             make RF
         e. Local factors: synovial cells from RA patient’s joints have decreased response to
             glucocorticoids and increased production of hyaluronate, release peptide
             (connective tissue-activating peptide) that causes increased amounts of
             prostaglandins (particularly PGE2)
  4. Pathogenesis:
         a. Genetically susceptible person gets a joint infected (with maybe EBV) or some
             other tissue and causes antibody formation
         b. Antibodies act as new antigens triggering production of antiidiotype antibodies
             (RF)
         c. Immune complexes form with RF and deposit in joints activating complement
             increasing vascular permeability and uptake of immune complexes by leukocytes
             which release lysosomal enzymes and ROS and other damaging products
         d. Activated macP in joint present to T cells stimulating production of cytokines
             which amplify inflammation and injury
  5. Pathology:
      a. Early synovial changes: edema, accumulation of plasma cells, lymphocytes and
          macP. Vascularity increases with exudation of fibrin into joint which may result
          in small fibrin nodules that float in joint (rice bodies)
      b. Pannus formation: synovial lining increases from 1-3 layers to 8-10 layers, may
          form multinucleated giant cells. Synovial mem is heavily infiltrated by chronic
          inflamm cells (lymphocytes and plasma cells). Lymphocytes get together and
          eventually develop follicular centers (Allison-Ghormely Bodies= inflammatory
          synovium creeps over surface of articular cartilage transforming into pannus
          (cloak) which is a sheet of inflamm granulation tissue that spreads from synovial
          mem into joint. Pannus able to destroy both articular cartilage and bone.). pannus
          covers the articular cartilage, isolating it, it then erodes articular cartilage using
          collagenase . osteoclasts are made in the mutated synovium (stim by PGE2 and
          IL-1 and mediate marginal bone erosion in the areas that don’t have articular
          cartilage over them cause of the pannus. Pannus also destroys cartilage by
          depriving it from nutrients, stim T-cells to secrete something causing the release
          of lysosomal enzymes. Once entire cartilage destroyed joint goes through fibrous
          fusion called ankylosis
      c. Changes in synovial fluid: massive increase in volume, turbidity, decreased
          viscosity, increased protein content and inflamm cells
      d. Rheumatoid nodules: found in extra-articular location, has central core of
          fibrinoid necrosis (mix of fibrin and other proteins). Surrounding rim of macP
          arranged in radial fashion, outside of which are lymphocytes, plasma cells and
          other mononuclear cells. Resembles granuloma surrounding fibrinoid necrosis
          core. Found in areas of pressure, movable, firm, rubbery, tender. Often reoccur.
          May also be seen in lupus erythematous and rheumatic fever. Sometimes found in
          organs (heart lungs GI)
      e. Rheumatoid vasculitis: RA may also be joined with acute necrotizing vasculitis
          of small vessels, affecting any organ. Probably due to immune complexes
6. Clinical features:
      a. Joint involvement: mostly small joints of hands and feet, symmetric distribution.
          Most common joints are MCP, wrist, PIP, knee, MTP, shoulder, ankle, C-
          spine, hip, elbow and temporomandibular
      b. Systemic manifestations of RA:
               i. Skin: subcutaneous nodules (rheumatoid nodules) present over pressure
                  points. Vasculitic lesions of skin may occur as palpable purpura or skin
                  ulceration
              ii. Rheumatoid heart disease: myocardial infarction, myocardial
                  dysfunction, asymptomatic pericardial effusions are common
             iii. Rheumatoid lung disease: pleural effusions, interstitial fibrosis,
                  rheumatoid nodules with lung parenchyma (caplan syndrome), and
                  bronchiolitis obliterans-organizing pneumonia
              iv. GI: secondary to associated processes such as medication effects,
                  inflammation and other diseases. Liver is most often affected in patietns
                  with felty syndrome = triad of seropositive rheumatoid arthritis,
                  splenomegaly, and granulocytopenia (1-3% of patients). Clinically
                  characterized by severe joint destruction, high frequency of rheumatoid
                  nodules, lymphadenopathy, hepatopathy, vasculitis, leg ulcers, skin
                  pigmentation.
               v. Renal: kidneys (like GI) are usually affected through secondary
                  involvement due to medicaitons (NSAIDs, gold, cyclosporine) , chronic
                  inflammation, and disease
              vi. Vascular: vasculitic lesions in skin most common (palpable purpura,
                  ulcers or digitial infarcts)
             vii. Hematologic: anemia of chronic disease
            viii. Neurologic: entrapment of nerves common (median in carpel tunnel)
              ix. Ocular: keratoconjuctivitis sicca is common. Eye may also have
                  episcleritis, uveitis, and nodular sceritis
7. Common deformities from RA
      a. Ulnar deviation of fingers: due to swelling of MCP get displaced toward little
          finger
      b. Swan neck deformity: hyperextension of PIP and flexion of DIP
      c. Rheumatoid nodules: subcutaneous nodule in 20-30% of cases just outside joint
          on pressure points due to increased intra-articular pressure causing outpouches of
          synovium
      d. Boutonniere deformity: hyperflexion of PIP and hyperextension of DIP
8. Pathophysiology of joint deformities
      a. Early articular stage: mostly small joints. Early on synovitis of MCP and PIP
          are the main Sx. Symmetrical pattern. Inflamm chronically damages joints,
          marginal erosion develops, articular cartilage destroyed, articular space
          disappears, joint capsule becomes fibrotic and shrinks, fibrous or bony ankylosis
          develops
      b. Later periarticular stage: joint effusions lead to stretching of tendons and
          ligaments which can lead to scarring and shortening and deformities
      c. Established deformities: all the previous stuff leads to this. Capsular contraction
          and tendon shortening leads to joint subluxation and malalignment.
9. Differences btw RA and Osteoarthritis (OA)
        a. RA: not a condition of wear and tear, its autoimmune disease. Causes bilateral
           symmetrical pain and stiffness lasting 30+min in morning or long rest. affects
           smaller joints. RA likes PIP and MCP of the hand
        b. OA: not autoimmune, condition of wear and tear associated with aging and
           injury. OA stiffness gets worse with use. Sx are joint stiffness, pain, enlarged
           joints, often asymmetrical, affects larger joints. OA prefers the DIP and CMC
           joint of thumb
10. DX: requires presence of four of the following.
        a. Morning stiffness
        b. Arthritis in 3 or more joints
        c. Arthritis of typical hand joints
        d. Symmetric
        e. Rheumatoid nodules
        f. Serum rheumatoid factor
        g. Typical radiographic changes: juxtaarticular osteopenia and bone erosions with
           narrowing of joint spaces, destruction of tendons, ligaments, joint capsules
           leading to deformities.
11. Lab studies:
        a. Erythrocyte sedimentation rate and C-reactive protein: both increased
        b. CBC: demonstrates anemia of chronic diease
        c. Antinuclear antibody (ANA): present in 40% of patients. Titers of 1:40 or lower
           are negative
        d. Rheumatoid factor (RF): present in 60-80% of those with RH, fewer than 40%
           of those with early RA. RF not specific for RA
        e. Anti-citrullinated protein antibodies (ACPAs): higher sensitivity and
           specificity than RF and increased + for early RA. Precens of ACPAs is specific
           for RA and indicates worse prognosis
12. Prognosis: 40% of patients become disabled after 10 yrs. Cardiovascular morbidity and
    mortality increased, mortality of those with RA is 2.5X > regular pop mostly b/c of
    cardiovascular disease, infection, respiratory disease, vasculitis, and malignancies
    (Hodgkin lymphoma).

				
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posted:10/23/2012
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