Exam 3 Review Flashcards
Osteoarthritis definition
Degeneration of articular cartilage with hypertrophy of contiguous bone: joint space loss, subchondral cysts, sclerosis, osteophytes
Osteoarthritis joint involvement
DIP (Heberden’s), PIP (Bouchard’s), 1st CMC
Hips and knees
Spine: cervical and lumbar
First MTP
Osteoarthritis predisposing factors
Age, obesity, occupational risks (miners, weavers), trauma
Secondary OA: inflammatory, metabolic (hemochromatosis, Wilson’s disease, ochronosis)
Sports in general present no increased risk; exercise may be protective
Components of cartilage
1) Collagen: predominantly type II
2) Proteoglycans (chondroitin, keratin sulfate) linked to hyaluronic acid
3) Matrix proteins: MMPs (collagenase, gelatinase, stromelysin), TIMPs
4) Chondrocytes
5) Water: 70% by weight
No nerves, blood vessels
Cartilage changes in osteoarthritis
1) Increased chondrocytes
2) Decreased proteoglycan
* 3) Increased metalloproteinases
4) Decreased TIMP
5) Increased water content
6) Lacks systemic features
Synovial fluid in osteoarthritis
Noninflammatory, type I (200-2000 WBC/mm^3)
Cytokines/inflammatory mediators in osteoarthritis
1) IL-1: stimulates MMP production, PGE2, NO, IL-6
2) NO: increases MMP prodution, inhibits proteoglycan synthesis, induces chondrocyte apoptosis
3) Prostaglandins: increase production/activation of MMPs
4) Other cytokines: TNF, IL-6, IL-17, IL-18
5) Complement activated
6) Adipokines
Radiographic findings of osteoarthritis
1) Joint space loss
2) Sclerosis (whitening)
3) Subchondral cysts
4) Osteophytes
Rheumatoid arthritis definition
Systemic, inflammatory, autoimmune disorder of unknown etiology that results in peripheral, symmetric synovitis which can result in cartilage and bone destruction
Rheumatoid arthritis joint involvement
Bilateral, symmetric
Small joints in hands and feet - but sparing the DIPs
Medium and large joints can also be involved
Radiographic findings of rheumatoid arthritis
Marginal joint erosions and deformities
Etiology of rheumatoid arthritis
Unknown beyond arthritogenic peptides in genetically susceptible host
Genetic susceptibility in rheumatoid arthritis
Shared epitope (QKRAA, in antigen-binding groove) In subtypes of HLA-DR4, HLA-DR1
Rheumatoid factor
IgM (sometimes IgG or IgA) antibody directed against Fc portion of IgG Present in 85% of patients with RA Not specific for RA or CTDs Produced locally in synovial tissue *RF-IgG immune complexes are pathogenic
Anti-CCP antibodies
AutoAbs reactive with synthetic peptides containing cirulline (modified arginine residue)
Specifically present in sera of RA patients: 88-99% specificity, 98-100% specific when present with RF
Occur more frequently in individuals with shared epitope - citrullination of peptides enhances binding
Lymphocytes in rheumatoid arthritis synovium
Majority are CD4+ T cells (modulation/amplification of local immune response through Ag recognition) and Th17 cells
IL-1, TNF-a
T cell cytokines (IL-2, IFN-y) are sparse
B cells and plasma cells also present
Extra-articular manifestations of rheumatoid arthritis
RF-IgG immune complex-induced vasculitis
Rheumatoid nodule formation in tissues/organs
Gout definition
Result of tissue deposition of MSU crystals due to hyperuricemia (MSU supersaturation of extracellular fluids)
Joint involvement in gout
1st MTP (podagra) Cool, peripheral joints of lower and upper extremities
2 reasons for hyperuricemia
1) Overproduction of uric acid
* 2) Underexcretion of uric acid (90% of cases)
Uric acid involvement in gout
Product of purine metabolism
Humans lack uricase - oxidizes uric acid into allantoin
Two X-linked defects causing overproduction of uric acid
1) PRPP synthetase overactivity
2) HGPRT deficiency (complete: Lesch-Nyhan)
Crystal arthritis diagnosis
Arthrocentesis
Crystal identification by polarized microscopy: MSU crystals are needle-shaped and negatively birefringent
Mechanism of MSU crystal-induced inflammation
Initial recognition by TLR2/TLR4
Engage caspase-1, activating NLRP3 inflammasome leading to IL-1b production
Self-limiting nature of acute gouty arthritis
1) IgG (not specific anti-crystal antibodies)-coating promotes phagocytosis by PMNs
2) Apolipoprotein B coating inhibits phagocytosis and further inflammatory response
Phagocytosis of crystals decreases concentration
Local heat of inflammation increases MSU solubility
ACTH secretion suppresses inflammation
IL-1 and TNF are modulated by inhibitors
CPDDD definition
Abnormal PPi metabolism (metabolism of NTPs from chondrocytes)
NTPPPH hydrolyzes phosphodiester bond, generating NMP and PPi
Leads to PPi precipitates with calcium forming CPPD crystals in mid-zonal cartilage layers
Crystal release into joint space: shedding phenomenon, enzymatic strip mining
CPDDD genetic mutation
Mutations in ANKH gene
Results in transmembrane PPi transporter protein in chondrocytes
Allows excess intracellular PPi egress from chondrocytes
CPPD crystal identification
Rhomboid, positively birefringent
Ankylosing spondylitis genetic association
HLA-B27
2% chance of developing AS if HLA-B27+
20% chance if HLA-B27+ and have a first-degree relative with AS
Concordance rate in identical twins: 60%
HLA-B27 represents 40% of genetic risk - at least 9 other genes involved (also environment)
Reactive arthritis
Asymmetric, oligoarticular (<5 joints), lower extremity arthritis
Dactylitis (sausage fingers) in 20-50%
Reactive arthritis causes (generally + 4 specific hypotheses)
Bacterial environmental triggers transported to joints inside monocytes (ex. latent Chlamydia)
Hypotheses:
1) Molecular mimicry
2) Arthritogenic peptide hypothesis: unique presentation of processed peptide by HLA-B27
3) HLA-B27 heavy chain theory: NK cell activation
Unfolded protein hypothesis: ER stress response causing inflammation
4) Th2 (IL-4, IL-10) response: ? bacterial persistence
Reiter’s syndrome
Clinical triad of conjunctivitis, urethritis, arthritis
SLE definition
Chronic, systemic autoimmune disease that affects multiple organ systems (skin, joints, serosal surfaces, lungs, kidneys, CNS, hematologic system)
Fundamental defect in SLE
Misdirected recognition of self as foreign, resulting in autoimmune process. T and B cell process
T cell: antibody responses toward autoantigens are antigen-driven, require CD4+ T cells
B cell: loss of T cell tolerance allows autoreactive B cell stimulation
Genetic susceptibility to SLE
Association with HLA-DR3 and C4A null allele (greatest risk)
Concordance among monozygotic twins: 35%
Increased incidence among relatives (RR 2-3)
More common in African Americans, Asians, Hispanic Americans
Environmental triggers of SLE
Sex hormones: female to male ratio 9:1
Increased incidence in women of childbearing age
Sun exposure: exacerbates systemic disease
ANAs
Hallmark of abnormal antibody production in SLE
>95% of patients with SLE have + ANAs
Not specific for SLE, can occur in other CTDs
3 types of ANAs (and common diseases they cause)
1) Anti-dsDNA antibodies: renal disease
2) Anti-histone antibodies: SLE and drug-induced lupus
3) Antibodies to non-DNA, non-histone nuclear antigens - ex. SSA, SSB, Smith, Ribonuclear protein (RNP)
Specific antibody-mediated disease in SLE
Type II immunopathology
Anti-RBC antibodies (hemolytic anemia)
Anti-WBC antibodies, anti-platelet antibodies
Anti-phospholipid antibodies: block prothrombin activation in clotting cascade, associated with increased clotting, but do not cause a vasculitis
Immune complex-mediated disease in SLE
Type III immunopathology
Anti-dsDNA-DNA immune complexes
Glomerulonephritis (lumpy-bumpy immunofluorescence)
Vasculitis definition
Inflammation within or through the vessel wall resulting in damage to vessel integrity/flow
Pathology of vasculitis
Varying degree of infiltrating lymphs, monocytes, histiocytes, eosinophils, and PMNs
Granulomas and/or giant cells in vessel wall in some types of vasculitis (large vessel)
Fibrinoid necrosis of vessel wall secondary to immune complex deposition
Focal and segmental nature of vascular lesions common to all types of vasculitis
Pathophysiology of vasculitis
Immune complexes: inflammation –> PAFs –> increased vascular permeability –> immune complex deposition, palpable purpura
Antineutrophil cytoplasmic antibodies (ANCAs)
Anti-endothelial antibodies
T-cell dependent-mediated endothelial cell injury: HLA-DR4 and giant cell arteritis; suggests antigen-driven vascular inflammation
Infection of vascular endothelial cells
4 sources of antigen for immune complexes
Drugs
Bugs: infectious agents
Connective tissue disease: autoimmune process
Malignancy (leukemias, lymphomas)
Cytoplasmic ANCA (c-ANCA)
Proteinase-3 (PR3) in primary granules of PMNs
Associated with generalized GPA (Wegener’s)
Likely play a role in amplifying the inflammatory vascular response
Perinuclear ANCA (p-ANCA)
Myeloperoxidase (MPO) in primary granules of PMNs
Associated with microscopic polyangiitis (MPA)
Likely play a role in amplifying the inflammatory vascular response
Polymyositis/Dermatomyositis (PM/DM) definition
Inflammatory myopathies, characterized by proximal muscle weakness, low endurance
Usually idiopathic, may occur in association with neoplastic diseases or in overlap with CTD
Typical skin rashes in dermatomyositis
Gottron’s papules: over MCP or IP joints, also elbows and knees
Heliotrope rash: eyelids
V-sign and shawl-sign: on trunk, in photodistributed regions
Mechanic’s hands: fingertips
Periungual changes/erythema: right below nail bed
Anti-synthetase syndrome presentation
PM or DM presenting with:
- 1) Interstitial lung disease (ILD): 60%
2) Fever: 20%
3) Arthritis: 50%
4) Mechanic’s hands: 30%
5) Raynaud’s phenomenon: 40%
Anti-synthetase antibodies
Anti-aminoacyl-tRNA synthetases (cytoplasm)
Anti-Jo-1 = anti-histadyl-tRNA synthetase
Not pathologic or myotoxic antibodies
Polymyositis histological findings
Endomysial distribution of inflammatory cells (CD8+ T cells) surrounding/invading muscle fibers
Dermatomyositis histological findings
Perivascular (CD4+ T cells) and perifascicular inflammatory infiltrate
Etiology of polymyositis/dermatomyositis
Evidence suggests viral etiology:
HIV/influenza can cause myositis
Viral particles by EM and viral RNA detected in muscle from PM/DM patients - no live virus has been cultured from muscle
Juvenile DM: increased antibodies to coxsackie B
Seasonal pattern: anti-Jo-1 antibodies and spring
DM: microarray mRNA profiling with predominance of interferon-responsive pathways suggesting anti-viral response
