Connective Tissue and Joints

Question 1

Central Tolerance

Answer 1

• process by which B and T cells that recognize self antigens are either killed or rendered harmless.
• autoreactive T cells can become regulatory T cells.
• developing B cells that react to self antigen undergo Ig rearrangement = receptor editing.

Question 2

AIRE

Answer 2

• autoimmune regulator.
• induces self antigen expression.
  
  • mutation ⇒ autoimmune polyendocrinopathy.

Question 3

Peripheral Tolerance

Answer 3

• via anergy, suppression by regulatory T cells, deletion by activation-induced cell death, or antigen sequestration.

Question 4

Anergy

Answer 4

• type of peripheral tolerance.
• irrversible functional inactivation when T cells don’t receive co-stimulatory signals.
• APC can inhibit T cells through T cell CTLA-4 or PD-1 receptors.
• B cells lose capacity for antigenic stimulation with lack of T cell help.

Question 5

Suppression by Regulatory T cells

Answer 5

• type of peripheral tolerance.
• regulatory T cells: CD4+, CD25, Foxp3 transcription factor ⇒ inhibit lymphocyte activation and function by secreting IL-10 and TGF-beta.
• mutation in Foxp3 ⇒ severe autoimmune diseases = immune disregulation, polyendocrinopathy, enteropathy, X-linked (IPEX).

Question 6

Deletion by Activation-Induced Cell Death

Answer 6

• type of peripheral tolerance
• persistent activation of self reactive T cells ⇒ increased expression of pro-apoptotic molecules or increased expression of FasL.
• ↑ FasL ⇒apoptosis of T cells by engaging Fas.
• B cells deleted by FasL positive T cells.
• mutation in FAS ⇒ autoimmune lymphoproliferative syndrome.

Question 7

Antigen Sequestration

Answer 7

• immune-privileged sites that have an impermanent blood-tissue barrier.
  
  • ex. eye, testis, brain.

Question 8

PTPN-22

Answer 8

• encodes a tyrosine phosphatase.
• mutation ⇒ doesn’t counter activity of lymphocyte tyrosine kinases ⇒ excessive activation of lymphocyte tyrosine kinases.
• implicatd in type I diabetes and rheumatoid arthritis.

Question 9

NOD-2

Answer 9

• part of sensing mechanism for intracellular microbes.
• mutation ⇒ exaggerated inflammation in resonse to normal GI flora.
• implicated in inflammatory bowel disease.

Question 10

IL-2 and IL-7 Receptor

Answer 10

• mutation ⇒ affects regulatory T cell development and maintenance.
• in multiple sclerosis.

Question 11

Molecular Mimicry

Answer 11

• microbe sharing epitopes with self antigens could cross-react ⇒ damage normal tissues.

Question 12

Role of Infection in Autoimmune Disorders

Answer 12

• through molecular mimicry
• tissue injury ⇒ structurally alter self antigens or release normal self antigens ⇒ activate T cells.

Question 13

Epitope Spreading

Answer 13

• cryptic epitopes = epitopes within self antigens that aren’t normally presented to T cells.
  
  • have no tolerance since never see the immune system.
  • when become exposed can ⇒ persistent autoimmunity.

Question 14

T_H1 Responses

Answer 14

• macrophage rich inflammation and substantial Ab-mediated elements.

Question 15

T_H17 Response

Answer 15

• neutrophil-mediated injury.

Question 16

Systemic Lupus Erythematosus (SLE)

Answer 16

• autoimmune disorder. 9:1 females:male.
• Abs: ANA, anti-dsDNA, and anti-Smith.
  
  • 40-50% have antiphospholipid Abs.
  • may bind to cardiolipin ⇒ false positive for syphilis.
  • lupus anticoagulants = anticoagulant in vitro but procoagulant in vivo ⇒ vascular thromboses, miscarriages, and cerebral ischemia (secondary antiphospholipid Ab syndrome).
• genetic predisposition
• defective elimination of self reactive B cells and ineffective peripheral tolerance.
• inappropriate B cell activation by nuclear RNA or DNA TLR
• environmental factors: UV light exacerbates SLE, estrogen, procainamide
• pathogenesis: cell injury ⇒ apoptosis and ↑ burden nuclear antigens.
  
  • defective B and T cell tolerance ⇒ autoantibodies to nuclear antigens ⇒ immune complexes in B cells and dendritic cells.
  • TLR engagement ⇒ cellular activation, cytokine production, augmented autoantibody synthesis ⇒ cell injury = self-amplifying loop.
• tissue damage via immune complexes (type III hypersensitivity) or via Ab-mediated injury to blood cells (type II hypersensitivity).
• morphology: involvement of skin, blood vessels, kidneys, CT.
  
  • see alterations in: kidney, skin, joints, CNS, pericarditis, cardiovascular system, spleen, and lungs.
• presentation: systemic, chronic, recurrent, febrile illness particularly involving the skin, kidney, serosal membranes, and joints.
  
  • can have thrombocytopenia, leukopenia, and anemia.
  • characterized by recurrent flares and remissions.
• tx: immunosuppression.
• death usually from renal failure or intercurrent infection.

Question 17

Lupus Kidney

Answer 17

• almost always involved.
• injury from immune complex deposition.
• 5 patterns of lupus nephritis with increasing degrees of cellular infiltration, microvascular thrombosis, and vascular wall deposition.
• ⇒ varying degrees of hematuria, proteinuria, HTN, and renal insufficiency.

Question 18

Lupus Vessels

Answer 18

• type III hypersensitivity with acute necrotizing vasculitis and fibrinoid deposits involving small arteries and arterioles.
• Ig, dsDNA, C3 in vessel walls. perivascular lymphocytic infiltrate.
• chronic = fibrous thickening and lumenal narrowing.

Question 19

Lupus Skin

Answer 19

• classic = malar erythema.
• exacerbated by sunlight.
• basal layer degeneration with dermal-epidermal junction Ig and complement deposits.
• dermis has variable fibrosis, perivascular mononuclear cell infiltrates, and vascular fibrinoid change.

Question 20

Lupus Joints

Answer 20

• nonspecific, nonerosive synovitis with minimal joint deformity.

Question 21

Lupus CNS

Answer 21

• neuropscyh manifestations from damage to endothelium and antiphospholipid antibodies or impaired neural function from autoantibodies to synovial membrane antigen.

Question 22

Lupus Serositis

Answer 22

• ex. pericarditis.
• initially fibrinous with focal vasculitis, fibrinoid necrosis, and edema ⇒ adhesions obliterating serosal cavities.

Question 23

Lupus Cardiovascular System

Answer 23

• pericarditis, myocarditis.
• classic = nonbacterial verrucous (Libman-Sacks) endocarditis.
  
  • small warty vegetations on inflow/outflow of mitral/tricuspid valves.
  • can have diffuse leaflet thickening of mitral/aortic valves ⇒ functional stenosis or insufficiency.
• ↑ incidence of accelerated coronary atherosclerosis from exacerbated risk factors (HTN, hypercholesterolemia) and antiphospholipid Ab-mediated vascular damage.

Question 24

Lupus Spleen

Answer 24

• splenomegaly with capsular thickening and follicular hyperplasia.
• penicilliary artery perivascular fibrosis ⇒ onion-skin appearance.

Question 25

Lupus Lungs

Answer 25

• pleuritis and/or effusions in 50%.
• chronic interstitial fibrosis and 2° pulmonary HTN.

Question 26

Chronic DIscoid Lupus Erythematosus

Answer 26

• cutaneous lesions that mimic SLE
• 35% have positive ANA
• deposition of Ig and C3 at dermal-epidermal junction
• 5-10% develop systemic manifestations.

Question 27

Sjögren Syndrome

Answer 27

• characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) from immune-mediated lacrimal and salivary gland destruction.
• mostly women btw 35-45yrs.
• 40% are primary syndrome, rest are in association with autoimmune disease (RA most common but also SLE and scleroderma)
• can have RF, ANAs to ribonucleoproteins SS-A and SS-B
• injury started by CD4+ T cells to unknown self antigen.
• EBV and Hep C may be involved as well as HTLV-1
• morphology: initially periductal lymphocytic infliltrate with ductal epithelial hyperplasia and luminal obstruction.
  
  • then acinar atrophy, fibrosis, and fatty replacement. lymphoid infiltrate can make lymphoid follicles and germinal centers.
  • can have corneal inflammation, erosion, and ulceration.
  • atrophy of oral mucosa with inflammatory fissuring and ulceration
  • have nasal drying and crusting, potentially septal perforation.
  • _respiratory involvement _⇒ laryngitis, bronchitis, or pneumonitis.
• presentation: difficulty swallowing food, vision changes.
  
  • 1/3 have synovitis, pulmonary fibrosis, peripheral neuropathy.
  • renal tubular acidosis and phosphaturia with tubulointerstitial nephritis.
  • adenopathy with pleomorphic lymph node infiltrate ⇒ ↑ risk B-cell lymphoma.
• dx: lip biopsy

Question 28

Mikulicz Syndrome

Answer 28

• lacrimal and salivary gland enlargement from any cause.

Question 29

Scleroderma

Answer 29

• characterized by widespread vascular injury and progressive perivascular/interstitial fibrosis in multiple organs. skin, GI, kidneys, heart liver, lung.
• 3:1 f:m ratio, peak ages 50-70yrs.
• diffuse scleroderma = widespread skin involvement, rapid progression, early visceral involvement.
• limited scleroderma = limited cutaneous involvement, late visceral involvement, benign course.
  
  • can develop calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia, or CREST syndrome.
• CD4+ T cells respond to unknown antigens and release TGF-beta and IL-13 to activate inflammatory cells and fibroblasts.
  
  • markers: antitopoisomerase I (in scleroderma and pulm fibrosis); anticentromere (CREST syndrome)
• hallmark = microvascular injury from direct autoimmune attack or by-product of chronic perivascular inflammation
  
  • cycles of endovascular injury with platelet aggregation ⇒ vascular smooth muscle and fibroblast proliferation, matrix synthesis ⇒ narrowing
• fibrosis from ischemic scarring and fibrogenic cytokine elaboration and hyperresponsiveness of fibroblasts to growth factors.
• morphology: affects skin, alimentary tract, musculoskeletal system, kidneys, lungs, heart.
• presentation: cutaneous fibrosis, Raynaud’s phenomenon, dysphagia, malabsorption/intestinal pain/obstruction, pulmonary fibrosis ⇒ respiratory or right-sided heart failure, arrhythmias, malignant HTN ⇒ renal failure.

Question 30

Scleroderma Skin

Answer 30

• diffuse sclerosis with atrophy
• initially edematous with doughy consistency
• face = drawn mask
• fingers = fibrotic, tapered and clawlike with diminished motility.
• focal vascular obliteration ⇒ ulceration.
• fingertips may auto-amputate.

Question 31

Scleroderma Alimentary Tract

Answer 31

• progressive atrophy and fibrosis of muscularis
  
  • esophagus = rubber-hose consistency.
• mucosal thinning, ulceration, scarring.

Question 32

Scleroderma Musculoskeletal System

Answer 32

• inflammatory synovitis ⇒ fibrosis.
• muscle involvement begins proximally with edema and mononuclear perivascular infiltrates ⇒ interstitial fibrosis with myofiber degeneration

Question 33

Scleroderma Kidney

Answer 33

• affected in 2/3 pts.
• 50% of deaths from renal failure.
• intimal proliferation and deposition of mucinous or collagenous material in vessel walls.
• HTN ⇒ fibrinoid necrosis with thrombosis and necrosis.

Question 34

Scleroderma Lungs

Answer 34

• variable fibrosis of small pulmonary vessels with diffuse interstitial and alveolar fibrosis ⇒ honeycombing

Question 35

Scleroderma Heart

Answer 35

• perivascular infiltrates with interstitial fibrosis ⇒ restrictive cardiomyopathy or arrhythmias

Question 36

Mixed Connective Tissue Diseases

Answer 36

• subgroup of autoimmune diseases.
• can evolve into SLE or scleroderma.
• characterized by:
  
  • high Ab titers to U1 ribonucleoprotein
  • modest initial renal involvement
  • good initial response to steroids
  • complications = pulmonary HTN, progressive renal disease.

Question 37

Direct Pathway of Allograft HLA Recognition by Host T cells

Answer 37

• host T cells recognize donor HLA on donor derived APC, usually donor dendritic cells.
• CD8+ cells recognize HLA type I ⇒ CTL
• CD4+ cells recognize HLA type II ⇒ T_H1 and T_H17.

Question 38

Indirect Pathway of Allograft HLA Recognition by Host T cells

Answer 38

• host T cells recognize donor HLA through host APC.
• ⇒ DTH mediated by CD4+ cells.

Question 39

Hyperacute Rejection

Answer 39

• recipient previously sensitized to graft antigens (blood transfusion or pregnancy).
• circulating Ab binds graft HLA ⇒ immediate complement and antibody dependent cell-mediated cytotoxicity injury.
  
  • occurs within minutes to days.
• organ looks cyanotic, mottled, and flaccid.
• resembles immune-complex mediated disease: complement and Ig in vessel walls ⇒ endothelial injury, fibrin-platelet microthrombi, neutrophil infliltrates, and arteriolar fibrinoid necrosis ⇒ distal parenchymal infarction.

Question 40

Acute Rejection

Answer 40

• days to months after transplantation or cessation of immunosuppressive therapy.
• acute cellular rejection = interstitial mononuclear cell infiltrate (macrophages, CD4+, CD8+)
• acute humoral rejection = rejection vasculitis. newly made anti-donor Ab ⇒ necrotizing vasculitis with thrombosis
  
  • complement C4D deposition in vascular beds = diagnostic feature.
  • subacute vasculitis = intimal thickening from proliferating fibroblasts, smooth muscle cells, and macrophages** ⇒ vascular narrowing and infarction.**

Question 41

Chronic Rejection

Answer 41

• months to years.
• progressive organ dysfunction.
• dense obliterative intimal fibrosis ⇒ allograft ischemia.

Question 42

Means to Increase Graft Survival

Answer 42

• HLA matching
• immunosuppressive therapy blocking T cell activation or co-stimulation, IL-2 production, signaling, T cell proliferation, and inflammation.
• T cell destruction
• Plasmapheresis or anti-B cell therapy

Question 43

Hematopoietic Cell Transplants

Answer 43

• for hematologic malignancies, aplastic anemia, or immunodeficiency states.
• complications = recipient NK cells or radiation resistant T cells, Graft versus Host Disease.

Question 44

Graft Versus Host Disease (GVHD)

Answer 44

• donor lymphocytes recognize host cells as foreign ⇒ CD4+ and CD8+ mediated injury.
• mostly affects host immune cells (immunosuppression), biliary epithelium (jaundice), skin (desquamative rash), and GI mucosa (bloody diarrhea)

Question 45

Noninfectious Inflammatory Myopathies

Answer 45

• immune mediated disorders characterized by skeletal muscle inflammation and injury.
  
  • dermatomyositis
  • polymyositis
  • inclusion body myositis

Question 46

Dermatomyositis

Answer 46

• skin and muscle.
• targets capillaries.
• lilac discoloration of upper eyelids and periorbital edema with weakness
• scaling, erythematous patches over knuckles, elbows, and knees (Grotton lesions).
• weakness in proximal muscles first, bilaterally symmetric.
• dysphagia in 1/3 pts.
• can have interstitial lung disease, vasculitis, and myocarditis.
• 1/4 adults with this have cancer.
• kids have GI symptoms, 1/3 have calcinosis.
• morphology: perivascular inflammatory infiltrates with scattered necrotic muscle fibers muscle fiber atrophy = perifascicular atrophy
• tx: immunosuppression

Question 47

Polymyositis

Answer 47

• mostly in adults.
• bilateral muscle weakness starting in proximal muscles.
• cytotoxic T-cell driven myocyte damage
• auto-Ab against tRNA synthetases.
• morphology: endomysial inflammation, scattered necrotic muscle fibers, no vascular injury
• tx: immunosuppressive therapy

Question 48

Inclusion Body Myositis

Answer 48

• begins with distal muscle involvement (extensors of knee, flexors of wrist).
• can be asymmetric
• insidious onset, age >50yrs.
• frequently have intracellular deposits of beta-amyloid and hyperphosphorylated tau proteins = abnormal protein folding.
• not helped by immunosuppression.
• morphology: endomysial inflammatory infiltrates are rimmed vacuoles = clear cytoplasmic vacuoles in myocytes surrounded by thin rim of basophilic material.
  
  • may have amyloid deposits on Congo red stain.

Question 49

Immune-Complex Associated Vasculitis

Answer 49

• deposition of circulating antigen-Ab complexes ⇒ complement activation and recruitment of Fc receptor-bearing cells.
• see with drug hypersensitivity, viral infections.

Question 50

MPO-ANCA

Answer 50

• aka p-ANCA.
• Ab against MPO.
• see in microscopic polyangiitis and Churg-Strauss syndrome

Question 51

PR3-ANCA

Answer 51

• aka c-ANCA.
• against a neutrophil azurophilic granule constituent.
• in Wegener granulomatosis

Question 52

Anti-Endothelial Cell Ab

Answer 52

• see in Kawasaki disease

Question 53

Giant Cell (Temporal) Arteritis

Answer 53

• most common vasculitis in USA
• focal granulomatous inflammation of med and small arteries
  
  • temporal arteries
  • involve aorta = giant cell aortitis
• T cell mediated immune response to vessel wall antigens.
• morphology: granulomatous vasculitis with elastic tissue fragmentation, multinucleated giant cells, intimal fibrosis with medial scarring and luminal narrowing.
• presentation: headache and facial pain. may have flu-like symptoms with fever, fatigue, weight loss.
  
  • ophthalmic artery involved ⇒ visual problems and potential blindness.
• tx: steroids

Question 54

Takayasu Arteritis

Answer 54

• aka pulseless disease.
• granulomatous vasculitis of med and large arteries
• transmural fibrous thickening of aortic arch and obliteration of great vessel branches.
• morphology: irregular aortic thickening with intimal hyperplasia.
  
  • adventitial perivascular mononuclear cell infiltrates ⇒ medial fibrosis, granulomas, acellular intimal thickening.
  • indistinguishable from giant cell arteritis.
• presentation: eye and neuro disturbances, weakening of upper extremity perfusion pressures (weak or absent pulses).
  
  • involves pulmonary artery 50% of time.
  • also in coronary arteries and renal arteries.
  • HTN 2° to renal artery disease.
  • pt <50yrs.

Question 55

Polyarteritis Nodosa

Answer 55

• necrotizing vasculitis of **small to med arteries. **
• involves kidney, heart, liver, and GI.
• 1/3 cases have immune complex deposition.
• morphology: sharply demarcated lesions.
  
  • induce thrombus ⇒ distal ischemic area
  • temporal heterogeneity.
  • acute lesion = sharply circumscribed arterial fibrinoid necrosis (hyaline in vessel wall) with neutrophilic infiltrates into adventitia.
  • healed lesion = marked fibrotic thickening of artery with elastic lamina fragmentation and aneurysmal dilation.
• presentation: young adult with nonspecific systemic symptoms (fever, malaise, weight loss) and presentation of symptoms from organ involved.
• tx: 90% remission with immunosuppressive therapy.

Question 56

Kawasaki Disease

Answer 56

• acute, febrile, self-limited illness of infants and kids. associated with med to large vessel arteritis.
• T cell hypersensitivity.
• morphology: sharply demarcated lesions ⇒ thrombosis ⇒ distal ischemic injury.
  
  • acute lesions = arterial fibrinoid necrosis with neurophilic infiltrates.
  • healed lesions = fibrotic thickening of artery with elastic lamina fragmentation and some aneurysmal dilation.
• presentation: fever, lymphadenopathy, skin rash, and oral/conjunctival erythema.
  
  • 20% ⇒ coronary arteritis if untreated = aneurysms that rupture or thrombose ⇒ MI.
• tx: aspirin and IV gamma globulin to reduce incidence of coronary arteritis.

Question 57

Microscopic Polyangiitis

Answer 57

• necrotizing vasculitis of vessels smaller than PAN (arterioles, venules, and capillaries).
• temporal homogeneity.
• most lesions pauci-immune. p-ANCA indicated.
• morphology: fibrinoid necrosis but vessel may show leukocytoclastic vasculitis (fragmented neutrophilic nuclei around vessels).
  
  • necrotizing glomerulonephritis and pulmonary capillaritis common.
  • Ig deposition rare.
• presentation: symptoms depend on vascular bed. include hemoptysis, hematuria and proteinuria, purpura, or bowel pain and bleeding.
• tx: cyclosporine and steroids.

Question 58

Churg-Strauss Syndrome

Answer 58

• aka allergic granulomatosis and angiitis.
• small vessel necrotizing vasculitis associated with asthma, allergic rhinitis, peripheral eosinophilia, and extravascular necrotizing granulomas.
• ANCAs in <50%.
• lesions resemble PAN but have eosinophils and granulomas.
• 60% develop cardiomyopathy from eosinophils. causes mortality in 50%.

Question 59

Wegener Granulomatosis

Answer 59

• triad of:
  
  • necrotizing or granulomatous vasculitis of small to med sized vessels in lungs and upper airway
  • necrotizing granulomas of upper and lower respiratory tract
  • glomerulonephritis
• c-ANCA in 95%; T cell hypersensitivity
• morphology: granulomas with geographic necrosis and vasculitis;
  
  • granulomas coalesce ⇒ nodules that cavitate
  • renal lesions vary from focal and segmental necrosis to proliferative GN.
• presentation: men >40yrs.
  
  • 80% 1yr mortality without tx.
• tx: cyclophosphamide, steroids, TNF antagonist.

Question 60

Thromboangiitis Obliterans

Answer 60

• aka Buerger Disease
• in heavy smokers <35yrs old.
• segmental, thrombosing, acute, and chronic inflammation of **intermediate and small arteries and veins in extremities. **
• T cell hypersensitivity
• morphology: acute lesions = neutrophilic infiltrates with mural thrombi with microabscesses. giant cell formation and involvement of adjacent vein and nerve.
  
  • late lesions organized and recanalized.
• presentation: consequences = nodular phlebitis, Raynaud’s, leg claudication.
  
  • vascular insufficiency ⇒ pain at rest, skin ulcers, and gangrene.

Question 61

Osteoarthritis

Answer 61

• aka Degenerative Joint Disease
• progressive erosion of articular cartilage.
• primary DJD = insidious onset as age, in a few joints.
  
  • knees and hands in women; hips in men
• secondary DJD = at any age in previously damaged joint or pts with diabetes, ochronosis, or hemachromatosis
• pathogenesis: polymorphisms in PG synthesis and WNT signaling. affected by aging, obesity, muscle strenght, joint architecture.
• phases:
  
  • chondrocyte injury from age, trauma, biochemical/genetic influence.
  • chondrocyte proliferation and secretion of matrix and inflammatory mediators ⇒ cartilage remodeling and changes in synovium/subchondral bone.
  • chondrocyte dropout and cartilage loss from repetitive injury and chronic inflammation.
• morphology: articular surface soft with fragments of cartilage and subchondral bone (joint mice)
  
  • bone eburnation and sclerotic cancellous bone underneath
  • cystic spaces filled with synovial fluid
  • osteophytes capped by cartilage on edge of articular cartilage.
  • Heberden nodes = osteophytes of distal interphalangeal joints. mostly in women.
  • chondrocyte proliferation, ↑ matrix water, ↓ PG content ⇒ fibrillation and cracking of matrix
  • synovium congested with scattered chronic inflammation
• presentation: insidious and slowly progressive. deep achy joint pain, worse with use, morning stiffness, crepitus, limited ROM.
  
  • osteophyte can ⇒ radicular pain, muscle spasm or atrophy, and neurologic deficits.
• no tx.

Question 62

Rheumatoid Arthritis

Answer 62

• chronic systemic inflammatory disease of joints ⇒ non-suppurative proliferative synovitis ⇒ joint destruction and ankylosis
• can impact blood vessels, skin, heart, lungs, and muscles.
• f:m 3-5:1. peak ages 40-70 yrs
• morphology: affects joints, skin, and blood vessels.
  
  • joint: pannus encroaches on hyaline cartilage ⇒ destruction. bridge btw bones ⇒ fibrous ankylosis.
    
    • hemosiderin deposits and aggregates of fibrin.
    • bone erosion, osteoporosis, subchondral cysts.
  • skin: rheumatoid nodules found in knees, heart valves, lungs, spleen, aorta, and other viscera.
    
    • fibrinoid necrosis with activated macrophages.
  • blood vessels: high RF titers ⇒ small to med vessel vasculitis.
• pathogenesis: exposure to arthritogenic antigen ⇒ loss of self-tolerance and chronic autoimmune response.
  
  • genetic: HLA-DRB1; PTPN22 - tyrosine phosphatase regulating T cell activation.
  • environmental: microbes (EBV, retroviruses, mycobacteria, Borrelia, Mycoplasma); modified host proteins.
  • autoimmunity to type II collagen and glycosaminoglycans with T_H1 and T_H17 proliferation.
    
    • auto-Ab to citrulline-modified proteins
    • auto-Ab to Fc of IgG (rheumatoid factor)
  • damage from IFN-gamma and IL-17 by producing IL-1, IL-6, IL-23, TGFbeta, PDE₂ and TNF.
• presentation: non-specific malaise, fatigue, generalized pain ⇒ insidious onset localized joint involvement.
  
  • small joints first (digits to wrist to ankles to elbows to knees).
  • bilaterally symmetric
  • joints swollen, warm, painful.
  • greatest damage happens in first 5 years.
  • destruction of tendons, ligaments, and joint capsules ⇒ radial deviation of wrist, ulnar deviation of fingers, flexion-hyperextension abnormalities of digits
  • loss of joint stability and ROM.
  • joint effusions, juxta-articular osteopenia, narrowing of joint space.
• tx: corticosteroids, methotrexate, TNF antagonists

Question 63

RA Joint Morphology

Answer 63

• synovium edematous and hyperplastic with delicate and bulbous fronds
• pannus of proliferative synovium, inflammatory cells, and fibroblasts encroach on hyaline cartilage ⇒ destruction
  
  • bridges bones ⇒ fibrous ankylosis that can ossify
• lesions have dense perivascular mononuclear infiltrate with focal lymphoid aggregates.
• neutrophils on synovial surface and in synovial fluid.
• vasodilation and ↑ vascular permeability with hemosiderin deposits and aggregates of fibrin
• osteoclast activation with bone erosion, osteoporosis, and subchondral cysts

Question 64

RA Skin Morphology

Answer 64

• rheumatoid nodules: firm, non-tender in subcutaneous tissues of areas under recurrent pressure. (elbow)
• in lungs, spleen, heart valves, aorta, other viscera.
• central zone of fibrinoid necrosis with palisade of activated macrophages.

Question 65

RA Blood Vessel Morphology

Answer 65

• severe disease and high RF titers ⇒ small to med sized vessel vasculitis

Question 66

Juvenile Idiopathic Arthritis

Answer 66

• 7 subsets of arthritis in kids under 16yrs. persist at least 6 weeks.
• differs from RA by:
  
  • oligoarthritis more common, systemic disease more common, large joints affected, ANA positive, rheumatoid nodules not present.
• 10% ⇒ functional disability.

Question 67

Ankylosing Spondyloarthritis

Answer 67

• aka Marie-Strümpell disease
• chronic ankylosing synovitis of vertebrae and sacroiliac joints.
• m:f 2-3:1 with onset 20-30yrs.
• progressive course involving **hips, knees, and shoulders. **
• complications = uveitis, aortitis, and amyloidosis
• 90% are HLA-B27 positive
• also associated with IL23 receptor and ARTS1 (codes a peptidase that trims peptides for HLA class I)

Question 68

Reiter Syndrome

Answer 68

• triad of arthritis, nongonoccocal urethritis or cervicitis, and conjunctivitis.
• typically a 20-30yr old man.
• 80% have HLA-B27
• triggered by prior GI or GU infection. symptoms begin several weeks after urethritis or diarrheal illness.
• asymmetric distribution btw ankles, knees, and feet.
• chronic disease involves spine.
• extraarticular manifestations = conjunctivitis, cardiac conduction abnormalities, aortic regurg.
• some have recurrent arthritis, tendinitis, and fasciitis with significant impairment.

Question 69

Enteritis-Associated Arthritis

Answer 69

• from GI infections with Yersinia, Salmonella, Shigella, or Campylobacter.
• arthritis appears suddenly in knees and ankles.
• remits after 1 yr.

Question 70

Psoriatic Arthritis

Answer 70

• in 10% ppl with psoriasis.
• affects small hand and foot joints but can involve knees, ankles, hips, and wrists.
• spinal disease in 20-40%.
• less joint destruction than RA.

Question 71

Bacterial Arthritis

Answer 71

• by gonococcus, staph, strep, H influenzae (kids <2yrs), gram (-) rods.
• Salmonella in sickle cell pts.
• single joint affected, usually knee.
• predisposing conditions: immune deficiency, debilitating illness, joint trauma, chronic arthritis, and IV drug use.

Question 72

Tuberculous Arthritis

Answer 72

• insidious chronic arthritis from hematogenous spread or nearby TB osteomyelitis.
• involves hips, knees, and ankles.
• chronic disease ⇒ severe destruction with fibrous ankylosis.

Question 73

Lyme Arthritis

Answer 73

• in 60-80% untreated ppl after weeks to 2 yrs after initial infection by B. burgdorferi.
• oligoarticular, remitting, and migratory arthritis of large joints (knees, shoulders, elbows, ankles).
• clears spontaneously or with antibiotics.
• 10% ⇒ permanent deformities.

Question 74

Viral Arthritis

Answer 74

• may be from direct infection or from autoimmune response to viral infection.
• HIV-related seems to be autoimmune

Question 75

Gout

Answer 75

• transient attacks of acute arthritis from crystallization of urates around joints ⇒ chronic gouty arthritis and tophi (large aggregates of urate crystals and inflammation).
• caused by hyperuricemia (>6.8). Only 0.5% of hyperuricemics get gout.
• pathogenesis: hyperuricemia from overproduction or reduced renal excretion (lack uricase).
  
  • ↑ risk with **obesity and alcohol. **
  • thiazides ⇒ ↓ urate excretion.
  • also caused by lead toxicity.
  • overproduction: 10% of cases. from ↑ nucleic acid turnover (cancer, psoriasis, tumor lysis). HGPRT deficiency (lack = Lesch-Nylan Syndrome).
  • ↓ renal excretion: 90% cases. ↓ filtration and underexcretion of uric acid. ** URAT1** imporant for reabsorption.
  • deposition of MSU (monosodium urate) affected by temp and intra-articular concentrations of urates and cations. phagocytosed by macrophages ⇒ release IL-1beta ⇒ recruit and activate neutrophils ⇒ acute arthritis.
    
    • recurrent rounds ⇒ chronic arthritis and tophus formation, cartilage damage, joint compromise.
• morphology: acute arthritis = dense neutrophilic infiltrate in synovium and synovial fluid. slender, birefringent MSU crystals in edematous and congested synovium and in neutrophils. scattered chronic inflammation.
  
  • chronic tophaceous arthritis = urates encrust articular surface ⇒ synovial deposits. synovium hyperplastic and fibrotic, ↑ inflammatory infiltrates. ** pannus extends to juxta-articular bone ⇒ erosions, fibrosis, bony ankylosis**.
  • tophi = pathologic lesions. masses of urates, crystalline or amorphous with intense mononuclear inflammation and foreign body giant cells. occur on ear, olecranon, patellar bursae, periarticular ligaments and CT.
  • gouty nephropathy = renal medullary MSU deposition and uric acid stones. obstruction ⇒ 2° pyelonephritis.
• presentation: yrs of asymptomatic hyperuricemia followed by excruciating joint pain with hyperemia and warmth. usually monoarticular and on big toe, then involves insteps, ankles, or heels/knees.
  
  • resolves ⇒ asymptomatic intercritical period. usually recur with ↑ frequency and become polyarticular with joint effacement.
  • see with atherosclerosis and HTN. 20% get gouty nephropathy

Question 76

Calcium Pyrophosphate Crystal Deposition Disease (Pseudo-Gout)

Answer 76

• aka chondrocalcinosis
• age >50yrs; 30=60% >85yrs
• autosomal dominant = mutated ANKH encoding pyrophosphate transport channel.
• 2° form associated with trauma, hyperparathyroidism, hemachromatosis, and diabetes.
  
  • altered matrix synthesis and pyrophosphate degradation
• similar to gout: crystals formed in cartilage, seed the joint where macrophages engulf them, activate inflammasomes ⇒ IL-1beta.
  
  • neutrophil recruitment and recurrence ⇒ joint damage.
• affects knees, wrists, elbows, shoulders, and ankles.
• morphology: crystals = chalky, white, friable deposits. rarely make tophus. oval blue-purple aggregates, weakly birefringent, geometric shapes.
  
  • chronic lesions have mononuclear cell infiltrates and fibrosis.

Question 77

Ganglion Cysts

Answer 77

• small, multiloculated cystic lesions of CT near joint capsules or tendon sheaths (wrist).
• from myxoid degeneration and softening of CT.
• NOT lined by epithelium. DO NOT communicate with joint space.

Question 78

Synovial Cysts

Answer 78

• herniations of synovium through joint capsule.
• synovial lining can be hyperplastic with scattered inflammation.
• Baker’s cyst = in popliteal fossa.

Question 79

Tenosynovial Giant-Cell Tumor

Answer 79

• benign neoplasms involving synovial membranes, tendon sheaths, and bursae.
• t(1;2) chromosomal translocation fuses CSF1 to promoter for alpha3 chain of collagen type IV ⇒ **overexpress CSF1 **⇒ accumulation of swarms of macrophages.
• diffuse type = pigmented villonodular tenosynovitis
  
  • present with knee pain (80%), locking and swelling, ↓ ROM, aggressive ⇒ bone and soft tissue erosion.
• localized type = giant cell tumor of tendon sheath.
  
  • solitary painless mass in tendon sheaths of wrist and fingers. 15% have cortical bone erosion.
• morphology: red-brown to mottled orange lesions.
  
  • diffuse = synovium is tangled mat of red-brown folds, nodules, and finger projections along articular surface into subsynovial tissue.
  • localized = well-circumscribed nodular tumors that may be attached to synovium by pedicle.
  • neoplastic cells are polyhedral and look like synoviocytes. many macrophages with hemosiderin, multinucleated giant cells.

Question 80

Lipoma

Answer 80

• most common benign soft tissue tumor in adults.
• soft, mobile, and painless (except angiolipomas).
• morphology: well-encapsulated tumor of mature adipocyte.
  
  • rarely large, intramuscular, poorly circumscribed.
• tx: excision = cure

Question 81

Liposarcoma

Answer 81

• common adult sarcoma.
• appear age 40-70yrs.
• large masses in deep soft tissues of proximal extremities and retroperitoneum.
• three types:
  
  • well-differentiated = indolent.
  • pleomorphic = very aggressive.
  • myxoid/round cell = intermediate
    
    • t(12;16) translocation. ** CHOP/TLS fusion gene**.
• morphology: cells show **fatty differentiation. **
  
  • lipoblasts mimic fetal fat cells with clear cytoplasmic lipid droplets scalloping the nucleus.

Question 82

Nodular Fasciitis

Answer 82

• aka pseudosarcomatous fasciitis
• morphology: large, nodular, with ill-defined margins.
  
  • lesions cellular and highly mitotic with plump, reactive, immature-appearing fibroblasts or myofibroblasts arranged randomly or in intersecting fascicles.
  • myxoid stroma and scattered lymphocytes.
• presentation: several week history of solitary, rapidly growing, maybe painful mass on volar forearm, chest, or back.
  
  • rarely recur after excision.

Question 83

Myositis Ossificans

Answer 83

• reactive fibroblastic proliferation with metaplastic bone.
• morphology: initially looks like nodular fasciitis, then zone of osteoblasts ⇒ deposits of ill-defined trabeculae of woven bone ⇒ well-formed cancellous bone. after ossification, intratrabecular areas have marrow.
• presentation: after trauma in adolescents and young adults.
  
  • initially painful ⇒ painless, hard, well-demarcated mass
• tx: excision

Question 84

Palmar Fibromatosis

Answer 84

• aka Dupuytren contracture.
• superficial fibromatosis = benign fibroproliferative lesion with abundant dense collagen.
• M>F.
• irregular thickening of palmar fascia, bilateral in 50%.
• attachment to overlying skin ⇒ skin puckering ⇒ slowly progressive flexion contracture of 4th and 5th fingers.
• morphology: 1-15cm gray-white, rubbery, poorly demarcated mass made of banal fibroblasts in broad sweeping fascicles infiltrating neighboring tissues.

Question 85

Deep-Seated Fibromatosis

Answer 85

• locally aggressive, recurrent neoplasm with little potential for metastasis.
• mutations = APC or beta-catenin
• 3 types: extra-abdominal, abdominal, intra-abdominal.
  
  • extra-abdominal: M=W; in musculature of shoulder, chest wall, back, and thigh.
  • abdominal: in anterior abdominal wall in women during or after pregnancy.
  • intra-abdominal: in mesentary or pelvic walls.
    
    • particularly in Gardner syndrome.
• morphology: 1-15cm gray-white, rubbery, poorly demarcated lesion made of banal fibroblasts in broad sweeping fasciles that infiltrate neighboring tissues.
• tx: surgery, tamoxifen, chemo, radiation.

Question 86

Fibrosarcoma

Answer 86

• in deep soft tissue, usually in extremities.
• >50% recur, 25% metastasize.
• morphology: unencapsulated, infiltrative, soft (fish-flesh consistency) masses with focal hemorrhage and necrosis.
  
  • all degrees of differention: cellular fibromatosis to highly cellular anaplastic appearance.

Question 87

Malignant Fibrous Histiocytoma

Answer 87

• fibrosarcoma variant with extensive pleomorphism and storiform architecture.

Question 88

Rhabdomyosarcoma

Answer 88

• most common soft tissue sarcoma of kids.
• in head and neck or GU tract.
• aggressive neoplasms.
• three types: embryonal, alveolar, pleomorphic.
  
  • embryonal: (60%) most common. kids <10yrs. ** nasal cavity, orbit, middle ear, prostate, and paratesticular** region.
    
    • parental isodisomy of 11p15 ⇒ overexpression of IGFII.
    • botryoidessubtype in walls of hollow, mucosa-lined structures = better prognosis
  • alveolar: (20%) middle adolescence in deep musculature of extremities.
    
    • t[2,13] fuses PAX3 to FOXO1a and t[1,13] fuses PAX7 to FOXO1a
  • Pleomorphic: rare. In deep soft tissue of adults.
• morphology: rhabdomyoblast round or elongated with sarcomeres and myogenic markers.
  
  • embryonal: soft, gray, infiltrative masses. sheets of round and spindled cells in myxoid stroma.
    
    • botryoid subtype looks like cluster of grapes.
  • alveolar: **network of fibrous septae **⇒ clusters that look like alveoli. mod sized tumor cells, little cytoplasm.
  • pleomorphic: resemble pleomorphic sarcomas.
• tx: surgery, radiation, chemo.

Question 89

Leiomyomas

Answer 89

• benign smooth muscle tumors typically in uterus
• mass<1-2cm, made of fascicles of bland appearing smooth muscle cells, few mitoses.
• **autosomal dominant disorder **when: multiple cutaneous leiomyomas from arrector pili muscles, with uterine leiomyomas, and renal cell carcinomas.
  
  • loss of function of fumarate hydratase gene.

Question 90

Leiomyosarcomas

Answer 90

• 10-20% of soft tissue sarcomas.
• F>M.
• in skin and deep soft tissues of extremities and retroperitoneum.
• superficial = small and good prognosis.
• retroperitoneal = larger, non-resectable ⇒ death by local extension and metastasis.
• morphology: painless, firm mass.
  
  • malignant spindle cells in interweaving fascicles; bundles of muscle filaments ultrastructurally and on immunohistochemistry.

Question 91

Synovial Sarcoma

Answer 91

• unknown origin.
• btw age 20-50yrs.
• in deep soft tissues of lower extremity (knee and thigh).
• t[x;18] ⇒ chimeric transcription factor
• morphology: biphasic = cuboidal epithelial and spindled mesenchymal differentiation.
  
  • monophasic = mesenchymal.
  • may have calcified concretions.
• tx: surgery, chemo.
• good 5yr survival, poor 10yr survival.

Question 92

Plantar Fibromatosis

Answer 92

• superficial fibromatosis = benign fibroproliferative lesion with abundant dense collagen.
• M>F.
• irregular thickening of plantar fascia of foot.
• rare to be bilateral or have contractures.
• morphology: 1-15cm gray-white, rubbery poorly demarcated mass made of banal fibroblasts in broad sweeping fascicles that infiltrate neighboring tissues.

Question 93

Penile Fibromatosis

Answer 93

• aka Peyronie disease.
• superficial fibromatosis = benign fibropriliferative lesion with abundant dense collagen.
• M.
• on dorsolateral penis ⇒ abnormal curvature and/or urethral obstruction.
• morphology: 1-15cm gray-white, rubbery, poorly demarcated lesion made of banal fibroblasts in broad sweeping fascicles that infiltrate neighboring tissues.

Question 94

Benign Fibrous Histiocytoma

Answer 94

• aka Dermatofibroma
• common painless, slow growing lesion of dermis and subcutis.