Miller-Cartilage and OA Flashcards
what are some physical properties of cartilage?
Viscoelastic: Properties vary according to rate of force application.
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Biphasic—property of liquid and solid
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Cartilage homeostasis disrupted by:
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Direct trauma/excess or inadequate forces
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Loss of underlying bone structure
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Genetic defects in normal structure/function
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Chemical/enzymatic threats
Review the differences between normal aging and osteoarthritis
Water
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Approximately 75% of cartilage
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Highest at surface or superficial layers
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Recurrent low-level forces shifts water in and out of extracellular matrix (ECM)
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Responsible for nutrition and lubrication
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H2O decreases with aging
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H2O increases in osteoarthritis
Review Genetic diseases associated with collagen
TYPE 1- Osteogenesis imperfecta
TYPE1, 3, 5: Ehlers Danlos
TYPE II: Knist, AChondrogenesis, Precocious arthritis, Stickler, SED Congenita
TYPE 9- MED
TYPE 10, Schmids
Review the organic components of cartilage
Type II collagen: 90%–95% of collagen
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Triple helix of α chains (derived from COL2A1 gene)
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Genetic defects of type II cause achondrogenesis (lethal at birth), spondyloepiphyseal dysplasia congenita, precocious arthritis
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Types IX and XI are “linking collagens”
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Type X found only near calcified cartilage, including:
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Calcified zone of articular cartilage’s tidemark
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Hypertrophic zone of the physis (genetic defect of type X leads to Schmid metaphyseal chondrodysplasia)
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Fracture callus and calcifying cartilaginous tumors
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Provides shear and tensile strength
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Contributes to viscoelastic behavior in that it restrains “swelling” of aggrecan
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Proteoglycans
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Make up approximately 10% of wet weight (30% of dry weight) (Fig. 1.28).
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Half-life of 3 months
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Provide compression strength
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Responsible for cartilage’s porous structure
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Trap and hold water
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Produced by chondrocytes
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Most common is aggrecan.
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Large macromolecules shaped like bristle brushes (see Fig. 1.28)
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Composed of repeating disaccharide subunits or glycosaminoglycans attached to protein core
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Repeating carboxyl and sulfate groups which are ionized in solution to COO−and SO3−
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Repel each other but attract positive cations
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Increase osmotic pressure, which traps and holds water and is responsible for ECM’s hydrophilic behavior
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Provides turgor of matrix
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Chondroitin sulfate (most prevalent glycosaminoglycan in cartilage)
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Chondroitin 4-sulfate decreases with age
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Chondroitin 6-sulfate remains constant
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Keratin sulfate
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Increases with age.
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Multiple core proteins in turn attached to hyaluronic acid (through link proteins) producing proteoglycan aggregate
Review chondrocytes
1%–5% of wet weight
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Only cells in cartilage
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Derived from undifferentiated mesenchymal precursors
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BMP-2 and the transcriptional factor SOX-9 important in regulating chondrocyte differentiation and formation
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Mechanotransduction—metabolism modulated via mechanical stimulation
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Cyclical loads of walking stimulate chondrocytes to form matrix
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Low loads (1–5 MPa) at moderate frequency (≈1 Hz)
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Primary cilia are the mechanosensory organ “antennae” for cells.
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Produce the extracellular matrix of collagen and proteoglycans
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Intracellular synthesis of procollagen, link peptide, hyaluronic acid, proteoglycans
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Extracellular assembly of component parts
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Produce proteins and enzymes and maintain matrix
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IL-1β (also from synovium and WBCs): main cartilage destroyer
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Metalloproteinases—break down cartilage matrix
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Collagenase—dissolves collagen (matrix metalloproteinase 13 [MMP-13])
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Aggrecanase—degrades proteoglycans (extracellular protease enzyme ADAMT)
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Enzyme inhibitors—protect cartilage
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Tissue inhibitors of metalloproteinases (TIMPs)
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Plasminogen activator inhibitor-1 (PAI-1)
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Chondrocytes are most dense and most active in the superficial zone.
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Deeper cartilage zone chondrocytes less metabolically active
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Decreased rough endoplasmic reticulum
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Increased intraplasmic filaments (degenerative products)
Review cartilage layers
Zone 1: superficial or tangential zone (10%–20% of thickness)
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Thin lamina splendens
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Flat chondrocytes
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Collagen fibers
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Highest concentration
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Parallel to joint surface strength against shear
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Greatest tensile stiffness
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Lowest concentration of proteoglycans
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Highest concentration of water
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Zone 2: middle or transition zone (40%–60% of thickness)
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Collagen fibers more random and less dense
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High levels of water and proteoglycan
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Zone 3: deep zone (30% of thickness)
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Lower water content
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Highest concentration of proteoglycan
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Chondrocytes and collagen fibers arranged perpendicular to articular surface
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Zone 4: calcified cartilage zone
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Begins at tidemark
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Transitions stiffness from flexible cartilage to rigid subchondral bone
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Low concentration of proteoglycans
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Type X collagen found here
what is lubricin?
Lubricin
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Mucinous glycoprotein that binds to hyaluronic acid
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Also present in lamina splendens
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Contributes to boundary lubrication
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Lubricant is present between two surfaces but its thickness is inadequate to prevent contact throughout the surfaces
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Defect associated with camptodactyly-arthropathy–coxa vara–pericarditis (CACP) syndrome
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Elastohydrodynamic lubrication
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Major mode of lubrication in joints
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Lubricant pressure causes elastic deformation of the opposing surfaces.
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This elastic deformation increases conformity.
what are cartilage changes with arthritis?
Increase in cells early (cloning)
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Loss of smooth lamina leads to fibrillation/fissures.
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Higher coefficient of friction
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Chondrocytes react to IL-1β and TNF and produce nitric oxide
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IL-1 stimulates MMPs, which degrade matrix.
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Collagenases (MMP-13)—first irreversible step
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Aggrecanase—degrade proteoglycans (ADAMTs)
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Stromelysin
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Decreased size and content of proteoglycan molecules
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Decreased keratan SO4− and increased chondroitin/keratan ratio
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Increase in percentage of nonaggregated glycosaminoglycans
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Higher water content and greater permeability initially followed by lower water content in later stages
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Decreased modulus of elasticity (less stiff) and tensile strength
what are cartilage changes with aging?
Decreased number of chondrocytes (but larger in size)
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Increased lysosomal enzymes
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Senescence markers of chondrocytes include telomere erosion, higher β-galactosidase expression, and reduced Wnt2 expression
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Lower response to growth factors (TGF-β)
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Decreased matrix production and matrix maintenance
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Decreased chondroitin SO4− (but increased keratan SO4−)
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Proteoglycan molecules smaller, so less able to hold water (lower water content)
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Increase in advanced glycosylation end products
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Yellows and stiffens cartilage
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Greater stiffness or modulus of elasticity but less tensile strength
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Increased decorin—decorates collagen for cross-links
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Increased collagen cross-links and diameter
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“Dried up old cartilage is yellow, weak, brittle, & stiff”
review growth factors and cartilage injury
IL-1 stimulates MMP, COX-2, and nitric oxide synthetase, which degrades cartilage.
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TGF-β stimulates synthesis of ECM and decreases activity of IL-1 and MMP’s
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Also stimulates chondrogenesis in vitro
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BMP-2, BMP-7, and IGF-1 also stimulate ECM production
what is elastrohydrodynamic lubrication?
Elastohydrodynamic lubrication
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Major mode of lubrication in joints
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Lubricant pressure causes elastic deformation of the opposing surfaces.
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This elastic deformation increases conformity.
review the IL-1 cascade for cartilage degredation:
review the DMARDs for Rheumatoid:
Biologic DMARDs
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Target TNF-α: etanercept, infliximab, adalimumab
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Targets IL-1: anakinra
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Targets CD20: rituximab
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Surgery should be scheduled at end of dosing cycle (e.g., in a patient taking etanercept schedule, surgery should occur the second week after the first withheld dose).
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Risks of opportunistic infection and lymphoma
Intended to address underlying autoimmune response
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Conventional DMARDs take 2–6 months to work
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Methotrexate: folate analogue
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Inhibits purine metabolism and T-cell activation
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Inhibits neovascularization
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Adverse reactions (ADRs): toxic to bone marrow, liver, and lung
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Usually can continue through surgery
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Azathioprine: immunosuppressive agent
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ADR: neutropenia
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Cyclosporine: immunosuppressive agent
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Inhibits activation of CD4+ T cells
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ADRs: nephrotoxicity, neurotoxicity, gingival hyperplasia
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Hydroxychloroquine (Plaquenil)
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Inhibits toll-like receptor 9 (TLR9)
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ADR: retinal toxicity (requires ophthalmology follow-up)
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Usually can continue through surgery
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Sulfasalazine
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Decreases synthesis of inflammatory mediators
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ADRs: granulocytopenia, hemolytic anemia (glucose-6-phosphate dehydrogenase [G6PD])
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Usually can continue through surgery
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Minocycline
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Inhibits MMP collagenase
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ADR: cutaneous hyperpigmentation
How do osteophytes form?
Osteophyte formation due to pathologic activation of endochondral ossification by periarticular chondrocytes through Indian hedgehog (Ihh) mechanism
Review Rheumatoid arthritis
Most common inflammatory arthritis
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Affects 0.5%–1% of population; three times more common in women
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15% concordance rate in monozygotic twins
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Clinical presentation (see Fig. 1.32)
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Insidious subacute onset over 6 weeks
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Fatigue, malaise, anemia
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Morning stiffness and polyarthritis with swelling
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Hand and foot deformities are most common and are discussed in respective subsequent chapters
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Also common in the knees, elbows, shoulders, ankles, and cervical spine
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Subcutaneous rheumatoid nodules (Fig. 1.34)
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Juxtaarticular erosions and periarticular osteopenia on radiographs
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2010 American College of Rheumatology Classification Criteria for RA are summarized in Table 1.21.
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Diagnosis requires score 6 or more
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Criteria include
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Number of joints involved and duration of involvement
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Positive laboratory test results often found
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Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
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Rheumatoid factor (RF) titer
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Antibody (immunoglobulin [Ig] M) against the Fc (crystallizable fragment) portion of IgG
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Positive result in about 80%
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Test for anticyclic citrullinated protein (anti-CCP) antibodies
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Also known as anti-CCP antibodies (ACPAs)
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Most sensitive and specific test (≈90% specific)
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Presence linked to more aggressive disease
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Pathogenesis
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T cell–mediated immune response from an infectious or environmental antigen (smoking is one known trigger) in a genetically susceptible individual (HLA-DR4 and HLA-DW4)
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Mononuclear cells are primary mediator of RA tissue damage
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Initial response in soft tissues—neovascularization and synovitis
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CD4+ T lymphocytes (helper cells) activate synovial cells through direct cell-cell contact
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Synoviocytes produce cytokines
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Macrophages (type A): main source for TNF-α, IL-1
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Fibroblast (type B): main source for MMPs, proteases, and RANKL
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B lymphocytes (plasma cells): make RF, anti-CCP antibodies
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TNF-α, IL-1, IL-6, IL-7 upregulated
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IL-1: Regulator of inflammation and matrix destruction
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TNF-α:
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Upregulates endothelial adhesion molecules and stimulates angiogenesis
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Promotes influx of leukocytes and activates synovial fibroblasts
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Promotes pain receptor pathways
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Drives osteoclastogenesis
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Later response
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Synovial cells invade cartilage “pannus” and release MMPs, causing chondrolysis
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Periarticular bone erosions
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Cytokines stimulate osteoblasts and synovial B cells to make RANKL, which joins with RANK to activate osteoclasts. Responsible for bone destruction.
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Osteoclasts secrete cathepsin K and carbonic anhydrase.
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Systemic manifestations
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Rheumatoid vasculitis
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Distal splinter hemorrhage
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Cutaneous ulcers (pyoderma gangrenosum)
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Visceral arteritis
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Pericarditis and pericardial effusion
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Pulmonary disease including nodules and fibrosis
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Felty syndrome: severe erosive RA with splenomegaly and leukopenia
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Treatments and their perioperative considerations
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Regimen variable and often employs multiple agents
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NSAIDs: help symptoms early—antiinflammatory effects
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Should be held for 7–10 days preoperatively.
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Low-dose steroids
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Decrease prostaglandins and leukotrienes
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Used initially as “bridge therapy” to disease-modifying antirheumatic drugs (DMARDs)
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“Stress dose” steroid should be used perioperatively for patients on long-term steroid therapy
Review Lupus
Chronic inflammatory disease of unknown origin
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90% of cases in women (blacks > whites)
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Initially mediated by tissue-binding autoantibodies and immune complexes (type III hypersensitivity)
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Pathophysiology
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Susceptible genetics stimulated by environment
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Immune system autoregulatory failure
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Sustained production of antibody to self-antigens
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Antinuclear antibodies (ANAs)—best screen; positive in 95%
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Anti-dsDNA, anti-Sm, anti-La (SS-B), antihistone antibodies—drug-induced lupus
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Immune complexes accumulate in various tissues and cause chronic inflammation
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Skin/joints—rash and arthritis
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Heart/kidney—pericarditis/nephritis
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Blood vessels—vasculitis
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Clinical findings
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Bone and joint involvement—most common feature
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Nonerosive polyarthritis affects over 75% (hand and wrist most common).
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Osteonecrosis (especially with steroids)
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Butterfly malar rash—classic feature
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Fever, pancytopenia
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Pharmacologic treatment similar to that for RA.
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Seronegative spondyloarthropathies
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Characterized by negative RF titer result and, often, positive HLA-B27 test result
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Symptoms
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Inflammatory back pain
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Peripheral arthritis
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Enthesitis—heel pain
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Dactylitis—sausage digit
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Eye—uveitis (iritis), conjunctivitis
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Skin, mucosal, GI, urethral
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Similar treatment routines, including NSAIDs, steroids, and DMARDs
Review lupus 2
Systemic lupus erythematosus. (A) Autoantibodies to DNA and DNA-binding proteins form immune complexes that stimulate immune system–directed inflammation throughout the body (type III hypersensitivity reaction). (B) Direct immunofluorescence with anti–immunoglobulin G antibodies shows immune complex deposits at two different places: a bandlike deposit along the epidermal basement membrane—positive result of lupus band test—and within the nuclei of the epidermal cells (ANAs). (C) Most patients have skin and joint involvement. The classic butterfly rash of SLE occurs in 10%–50% of patients with acute SLE. (D) The same immune complexes are seen in the basement membrane of the renal glomerulus. (E) Flea-bitten appearance of kidney specimen, with lupus nephritis causing various degrees of proteinuria, hematuria, and cellular casts.
Gout vs Pseudogout
Pathology from accumulation of crystal formation or deposition in or around joints
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Gout: monosodium urate
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CPDD, also called pseudogout: calcium pyrophosphate
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Tumoral calcinosis: calcium apatite
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Calcium oxalate
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Gout (see Table 1.20)
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Disorder of purine nucleic acid metabolism, causing hyperuricemia
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Deposition of monosodium urate crystals in joints
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Crystals activate inflammatory mediators
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Inflammatory mediators are inhibited by colchicine.
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Attacks precipitated by dehydration, excess alcohol or dietary purines, chemotherapy
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Diagnosis
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Recurrent acute joint pain
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Men aged 40–60 years, postmenopausal women
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Usually lower extremity, great toe (podagra)
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Crystal deposition as tophi when chronic
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Ear helix, eyelid, olecranon, Achilles tendon
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Renal disease or stones—second most common site
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Radiographic findings
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Soft tissue swelling early: edema, tophi
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Punched-out or rat bite periarticular erosions
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Sclerotic overhanging borders
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Synovial fluid findings
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Concomitant septic arthritis must be ruled out
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WBC count: wide range (5,000–80,000 cells/μL; average, 15,000–20,000 cells/μL), mostly PMNs
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Yellow, needle-shaped crystals when parallel to compensator (Fig. 1.38A)
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Strong negative birefringence
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Treatment:
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NSAIDs and colchicine (microtubule inhibitor that inhibits mitosis) for acute attack
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Chronic/maintenance therapy
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Weight loss, low-purine diet, limit of alcohol intake
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Probenecid: uricosuric agent
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Allopurinol: xanthine oxidase inhibitor
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Febuxostat in renally impaired patients
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Pseudogout (see Table 1.20)
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Deposition of calcium pyrophosphate dehydrate (CPPD) crystals in joints
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Associated with lupus, renal dialysis, hemochromatosis, hyperparathyroidism, RA, Wilson disease
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Chondrocalcinosis
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Calcification within hyaline or fibrocartilage or menisci
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Seen in pseudogout but also in other conditions
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Genetic version: ANKH gene mutation
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Increases extracellular pyrophosphate
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Synovial fluid findings
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WBC counts 5000–100,000 cells/μL (average, 24,000 cells/μL)
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Rhomboid-shaped crystals in WBCs
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Weakly positively (blue) birefringent when parallel (see Fig. 1.38B)
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Radiographic findings: fine linear calcification in hyaline cartilage and more diffuse calcification of menisci and other fibrocartilage (triangular fibrocartilage complex, acetabular labrum)
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Treatment with NSAIDs and, potentially, steroid injection
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Calcium hydroxyapatite crystal deposition disease
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Apatite is primary crystal of normal bone.
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Accumulates abnormally in areas of tissue damage or in hypercalcemic or hyperparathyroid states (chronic kidney disease [CKD])
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Associated with
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Acute attacks of bursitis/synovitis
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Severe degenerative joint disease
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Calcific tendinitis of rotator cuff and hip abductors
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Destructive arthropathy can occur in the knee and shoulder.
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Milwaukee shoulder: calcium phosphate deposition with cuff tear arthropathy
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Calcium oxalate deposition
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Primary oxalosis—rare genetic defect of liver enzymes
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Alanine glyoxylate aminotransferase (AGT)
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Glyoxylate reductase (GR)
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Nephrocalcinosis, renal failure, and death by age 20 years
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Treatment: liver/kidney transplantation
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Secondary oxalosis—more common
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Metabolic abnormalities of chronic renal insufficiency
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Associated with calcium oxalate arthritis/periarthritis and nephrolithiasis
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Diagnosis: synovial fluid usually contains fewer than 2000 WBCs/μL.
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Birefringent bipyramidal crystals
Review hemophilic arthropathy
x-linked recessive defect of factor 8 or 9.
Hemophilic arthropathy. (A) Recurrent knee effusions and synovitis. (B) Radiograph of end-stage arthropathy. (C) Synovial proliferation of hemophilic arthropathy demonstrates phagocytic (type A) synovial cells laden with iron pigment but no giant cells, polymorphonuclear leukocytes, and rare lymphocytes. (D) Bloody ankle effusion presentation of teen whose grandfather had a history of bleeding disorder. (E) End-stage hemophilic arthropathy of ankle demonstrates flattening of the talus (arrow).
