Vasculitis

Question 1

Vasculitis

Answer 1

General term for inflammation of blood vessel wall

Question 2

Vasculitis Clinical Features

Answer 2

1. Varied, depend on size and location of vessel targeted
2. In addition to localized effects, vasculitis may frequently include systemic symptoms (fatigue, myalgias, arthralgias, malaise)

Question 3

Vasculitis Classification Schemes

Answer 3

1. Forms of vasculitis grouped according to:
   1) size/diameter of vessel involved
   2) role of immune complexes
   3) presence of specific autoantibodies
   4) presence/absence of granuloma formation
   5) organ specificity
   6) patient population most affected
2. Clinical and pathologic features of various entities can overlap

Question 4

Vasculitis Main Pathological Mechanisms

Answer 4

1. Immune-mediated inflammation (non-infectious)
2. Direct invasion of blood vessel by infectious pathogens

Question 5

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Question 6

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Question 7

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Question 8

Answer 8

Question 9

Non Infectious Vasculitis

Answer 9

•Immunologic injury to blood vessels may be due to:

1. Immune complex deposition
2. Anti-neutrophil cytoplasmic antibodies (ANCA)
3. Anti-endothelial cell antibodies
4. Autoreactive T-cells

•Treatment generally involves various forms of immunosuppression: Corticosteroids, cyclophosphamide, anti-TNF agents, intravenous immunoglobulin (IVIg)

Question 10

Non Infectious Vasculitis - Immune Complex-Associated Vasculitis

Answer 10

1. Usually seen in systemic disorders, associated with autoantibody formation
   a. SLE
   b. Serum sickness
   c. Arthus reaction
2. Also seen in:
   a. Drug hypersensitivity vasculitis
   i. Antibodies form against drug-modified self-proteins or against foreign molecules from drug
   b. Immunologic vasculitis secondary to infection (not direct invasion of organism into vessel)
   i. Antibodies form to circulating antigens related to microbes and subsequent complexes form and deposit in vessels, causing vasculitis

Question 11

Non Infectious Vasculitis - Immune Complex-Associated Vasculitis Morphologc Features

Answer 11

a. Acute inflammation of vessels with associated immune complexes
i. If due to SLE – will have “full house” staining on immunofluorescence
b. Affected vessels may have fibrinoid necrosis
c. Renal manifestations of SLE vary by class

Question 12

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis

Answer 12

1. ANCA = group of antibodies that react with neutrophil cytoplasmic antigens
   a. Detection of ANCA very useful for diagnosis
   b. Titer of ANCA usually correlates with disease severity, recurrence
2. Two types a. Anti-proteinase 3 (PR3) – i.e. c-ANCA (c = cytoplasmic staining pattern on immunofluorescence)
   b. Anti-myeloperoxidase (MPO) – i.e. p-ANCA (p = perinuclear staining pattern on immunofluorescence)
3. ANCA’s thought to be implicated directly in pathogenesis of the vasculitis
   a. ANCA can activate PMN’s, stimulate release of reactive oxygen species and proteolytic enzymes, and induce inflammation
4. ANCA’s are directed against cellular antigens and cause local injury (type II hypersensitivity) but do not form circulating immune complexes to any significant degree
   a. Vascular lesions do not contain discrete immune complexes when visualized under immunofluorescence, therefore they are “pauci-immune”
5. ANCA-associated vasculitis tends to predominantly affect lung and kidney (“pulmonary renal syndrome”), although other organs can be involved

Question 13

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Granulomatosis with Polyangiitis

Answer 13

• Previously called “Wegener granulomatosis”
• Associated with cANCA (PR3)
• Males > Females affected, average age 40 yrs
• Rapidly fatal if untreated (80% mortality in 1 year)

Question 14

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Granulomatosis with Polyangiitis Classic Triad

Answer 14

• Necrotizing and/or granulomatous inflammation of upper respiratory tract, lung and kidney

Question 15

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Granulomatosis with Polyangiitis Morphologic Features

Answer 15

• Morphologic features
• Lung: Granulomas with necrosis, acute inflammation of alveolar capillaries with hemorrhage
• Renal: Pauci-immune necrotizing and crescentic glomerulonephritis
• General: No immune complexes (pauci-immune)

Question 16

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Microscopic Polyangiitis

Answer 16

• Associated with pANCA (MPO)
• Can triggered by drugs, infections, tumor proteins
• Necrotizing vasculitis of capillaries, small arterioles and venules
• Renal (90%) and lung
• May involve skin, mucous membranes, brain, heart, GI tract and muscle

Question 17

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Microscopic Polyangiitis Morphologic Features

Answer 17

• Renal: Necrotizing and crescentic glomerulonephritis
• Lung: Acute inflammation of pulmonary capillaries
• General:
• Fibrinoid necrosis of vessel walls, infiltrating PMN’s
• No granulomas or immune complexes (pauci-immune)

Question 18

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Churg Strauss Syndrome

Answer 18

• Also known as “allergic angiitis and granulomatosis”
• ANCA present in 50% (usually anti-MPO/pANCA)
• Small vessel necrotizing vasculitis with:
• Asthma
• Allergic rhinitis
• Skin rash/purpura
• Lung infiltrates with eosinophils, granulomas
• Blood eosinophilia
• Necrotizing granulomas of various organs
• Myocarditis, cardiomyopathy (60% of patients)

Question 19

Non Infectious Vasculitis - Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis - Churg Strauss Syndrome Morphologic Features

Answer 19

• Vessel inflammation and necrosis similar to microscopic polyangiitis and polyarteritis nodosa
• More involvement of eosinophils
• Granulomas usually present

Question 20

Non Infectious Vasculitis - Giant Cell (Temporal) Arteritis

Answer 20

• Large to small size arteries in the head
• Temporal, vertebral and ophthalmic arteries
• Older patients (usually >50 years)
• Fatigue, fever, facial pain, headache, vision abnormalities
• Prompt therapy needed to prevent blindness
• Diagnosis:
• Vessel biopsy (at least 1 cm segment) to confirm vasculitis
• Granulomatous inflammation of vessel media with giant cells, disruption of internal elastic lamina

*Features may be difficult to identify in small biopsy specimen

Question 21

Non Infectious Vasculitis - Giant Cell (Temporal) Arteritis Morphologic Features

Answer 21

i. Granulomatous inflammation of the vessel media and disruption of the internal elastic lamina
1. Multinucleated giant cells and granulomas may be difficult to find in small biopsies
ii. Healed vasculitis – intimal thickening, thinned media, fibrosis

Question 22

Non Infectious Vasculitis - Takayasu Arteritis

Answer 22

• Granulomatous vasculitis of medium to larger sized arteries

-Aortic arch, great vessels off the aorta

• Older adults
• Etiology thought to be autoimmune
• Clinical signs/symptoms
• Vision changes, weakened pulse in upper extremities
• Pulmonary hypertension
• Myocardial infarction
• Renal artery stenosis with secondary hypertension

Question 23

Non Infectious Vasculitis - Takayasu Arteritis Morphologic Features

Answer 23

• Similar to giant cell arteritis
• Irregular thickening of vessel with intimal hyperplasia
• Mononuclear inflammation of vessel; may see granulomas/giant cells
• Late: Fibrosis of vessel with dilation of lumen

Question 24

Non Infectious Vasculitis - Polyarteritis Nodosa (PAN)

Answer 24

• Systemic vasculitis of small to medium sized muscular arteries
• Kidney > heart > liver > GI tract > nerves
• Ischemic injury: ulceration, infarcts, hemorrhage, atrophy (late)
• Clinical presentation:

*Hypertension, abdominal pain with bloody stool, diffuse myalgias, peripheral neuralgias, skin/soft tissue nodules

• No association with ANCA
• 30% patients have Hepatitis B virus
• Antibodies form to circulating viral antigens, form complexes and deposit in vessels (Type III hypersensitivity)

Question 26

Non Infectious Vasculitis - Polyarteritis Nodosa (PAN) - Morphologic Features

Answer 26

• Acute: Segmental transmural inflammation and fibrinoid necrosis - Weak vessels may have aneurysms and rupture ---\> hemorrhage - Luminal thrombosis * Chronic: Fibrosis with thickening of wall * Often find lesions of varying ages and stages of involvement

Question 27

Non Infectious Vasculitis - Behcet Disease

Answer 27

* Small to medium sized vessels * Recurrent oral ulcers, genital ulcers and uveitis/retinitis -May have GI and pulmonary involvement • Associated with certain HLA haplotypes -HLA-B51

Question 28

Non Infectious Vasculitis - Thromboangiitis Obliterans

Answer 28

* Previously known as “Buerger disease” * Segmental, thrombosing acute and chronic inflammation of medium and small arteries - Tibial, radial arteries - May extend into veins and nerves of extremities: VERY painful * Young adults (\<35 years) * Associated with heavy SMOKING -Immune response (hypersensitivity) to components of tobacco -\> endothelial injury • Raynaud phenomenon, leg and/or foot pain (often exercise induced), nodular phlebitis (venous inflammation)

Question 29

Non Infectious Vasculitis - Thromboangiitis Obliterans Morphologic Features

Answer 29

* Early: Acute and chronic inflammation, luminal thrombi * Late: Luminal fibrosis (organization of thrombi) * Treatment involves smoking cessation if early in disease

Question 30

Non Infectious Vasculitis - Kawasaki Disease

Answer 30

1. Acute febrile illness of infancy and childhood, usually self-limited 2. Clinical features: a. Arteritis primarily affecting large to medium sized vessels i. Coronary artery involvement (20% of untreated patients) may cause aneurysm with thrombosis or rupture, leading to myocardial infarction and/or sudden death b. Non-vasculitis manifestations: Conjunctival and oral erythema/blistering, erythema of hands and feet, rash, cervical lymph node enlargement 3. Pathogenesis is uncertain; injury primarily mediated by activated T cells and macrophages

Question 31

Non Infectious Vasculitis - Kawasaki Disease Morphologic Features

Answer 31

a. Similar to polyarteritis nodosa (PAN) b. Dense transmural inflammation i. Fibrinoid necrosis is less prominent vs PAN c. Intimal thickening in healed lesions (may obstruct the lumen)

Question 32

Non Infectious Vasculitis - Kawasaki Disease Treatment

Answer 32

a. Intravenous immunoglobulin, aspirin (to prevent coronary thrombosis)

Question 33

Infectious Vasculitis

Answer 33

Inflammation of vessel associated with direct invasion of infectious agent. May be part of localized tissue infection or from hematogenous spread of organism from distant site.

Question 34

Infectious Vasculitis Most Common Pathogens

Answer 34

Most common pathogens: 1. Bacteria - Pseudomonas 2. Fungi – Aspergillus, Mucor species a. Often associated with immunosuppressed patients b. May be life threatening if vessels leading to brain are involved

Question 35

Infectious Vasculitis Mechanism of Tissue Injury

Answer 35

1. Weakening of arterial wall with aneurysm formation, rupture and hemorrhage 2. Thrombosis with infarction 3. Inflammatory response from the infection leads to further vessel injury

Question 36

Infectious Vasculitis Morphologic Features

Answer 36

1. Acute inflammation and fibrinoid necrosis of vessels 2. Hemorrhage and infarction of adjacent tissue 3. Organisms present within vessel lumen and infiltrating through vessel wall a. Special stains (GMS, PAS) may be helpful to identify organisms in tissue.

Question 37

Infectious Vasculitis - Pseudomonas

Answer 37

Question 38

Infectious Vasculitis - Mucor

Answer 38