Vasculitis, Noninfectious Vasculitis

Question 1

What is vasculitis? What are the clinical SX?

Answer 1

Inflammation of vessels
Clinical symptomology depends on vascular bed affected (CNS VS. heart etc.)

Constitutional SX = fever, malaise, arthralgias, myalgias

Question 2

In vasculitis, are more vessels more commonly affected than others?

Answer 2

Any type may be affected - more often arterioles, capillaries, & venules

Question 3

What are the 2 types of vasculitis? Describe them.

Answer 3

Non-infectious vs. infectious - can be immune mediated inflammation vs. direct invasion by infectious pathogens (can provide immunosuppressive TX for immune-mediated)

Infections can also INDIRECTLY induce a noninfectious vasculitis (generating immune complexes or triggering cross-reactive immune response)

Physical & Chemical injury can also cause vasculitis ( irritation, mechanical trauma, toxins)

Question 4

What is the major cause of noninfectious vasculitis? What are some examples?

Answer 4

Immune response - local or systemic

Giant cell (Temporal) arteritis 
Polyarteritis Nodosa (PAN) 
Granulomatosis with Polyangiitis 
Thromboangiitis Obliterans (Buerger Dz)

Question 5

What are the characteristics of Giant Cell (temporal) Arteritis? Include sites of involvement, inflammatory cells present, and clinical Hx.

Answer 5

Sites = AORTA, medium sized arteries

Inflamm. cells = Lymphocytes, Macrophages (neutrophils/eosinophils rare)

Features:
Granulomas, Thrombosis , Giant cells (often, not required)
May present with constitutional Sx = fever, fatigue, weight loss
Facial Pain, Headache

Clinical Hx = >40 yo +- polymyalgia rheumatica

Question 6

What are the characteristics of Churg-Strauss syndrome (allergic granulomatosis and angiitis? Include sites of involvement, inflammatory cells present, and clinical Hx.

Answer 6

Sites = Medium and Small sized arteries (small vessel necrotizing vasculitis) assoc with:
Clinical Hx = Asthma, allergic rhinitis, hypereosiniphilia

Inflamm cells = EOSINOPHILS required
+ Lymphocytes, Macrophages, Neutrophils

May resemble PAN/microscopic polyangiitis w/ addition of eosinophils and granulomas

Features:
Granulomas, thrombosis, Serum ANCA positivity (<1/2, mostly MPO)
Many organ systems involved = palpable purpura, GI tract bleeding, renal disease (focal/segmental glomerulosclerosis)
Myocardial involvement –> cardiomyopathy (60%, half deaths)

Question 7

What are the characteristics of Leukocytoclastic vasculitis? Include sites of involvement and inflammatory cells present.

Answer 7

Sites = Small sized arteries, capillaries, veins

Inflamm cells = Lymphocytes, macrophages, neutrophils, eosinophils (all +-)

Features:
Thrombosis

Question 8

What are the characteristics of Buerger Dz (thromboangiitis obliterans)? Include sites of involvement, inflammatory cells present, and clinical Hx.

Answer 8

Sites = Medium/small sized arteries, veins

• Segmental, thrombosing
• Tibial and Radial arteries
• Occ secondary extension to veins and nerves of extremities (pain!)

May lead to vascular insufficiency of extremities
Chronic ulcerations –> may lead to gangrene

Inflamm cells = Lymphocytes, macrophages, neutrophils, eosinophils

Features:
THROMBOSIS Required

Clinical HX:
Young male smoker, <35 yo
Hypersensitivity to intradermally injected tobacco
Assoc. with HLA haplotypes of certain ethnic groups: Israeli, Indian, Japanese

Question 9

What is immune complex vasculitis?

Answer 9

Autoantibody production and formation of immune complexes
Deposition of antigen-antibody complexes in vascular wall
-incites inflammatory reaction within the wall
-Ag is often unidentified

Question 10

In what conditions may you see immune complex vasculitis?

Answer 10

Systemic immunologic diseases (ex: SLE)
Drug hypersensitivity
Secondary to exposure to infectious agent

Question 11

Describe drug hypersensitivity in relation to immune complex vasculitis (ex: PCN). What may you see clinically? What happens if you stop the drug?

Answer 11

PCN acts as hapten binding to serum proteins of vessel walls
-Streptokinase acts as foreign protein

Clinically = mild to fatal; SKIN LESIONS most common

Always consider drug hypersensitivity. Stop drug –> resolution of vasculitis

Question 12

How can you get immune complex vasculitis secondary to an infectious agent?

Answer 12

Ab to microbial constituents form immune complexes that deposit in vascular lesions

Polyarteritis nodosa = 30% associated with HBsAg and anti-HBsAg

Question 13

What is Antineutrophil cytoplasmic antibodies (ANCA)?

Answer 13

A heterogenous group of antibodies reactant with cytoplasmic enzymes found in neutrophil granules, monocytes, and endothelial cells

Question 14

What are the antibodies associated with ANCA?

Answer 14

Anti-proteinase-3 –> seen with PR3-ANCA

Anti-myeloperoxidase –> seen with MPO-ANCA

Question 15

What dz is PR3-ANCA associated with?

Answer 15

Polyangiitis

Question 16

What dz is MPO-ANCA associated with?

Answer 16

Microscopic polyangiitis and Churg-Strauss syndrome

Induced by RX: propylthiouracil

Question 17

What do ANCA TITERS primary detect?

Answer 17

Disease SEVERITY

Question 18

ANCA is pauci-immune. What does that mean?

Answer 18

ANCA Ab directed at cellular constituents and do not form circulating immune complexes.

You will not see a lot of immune cells

Vascular lesions do NOT typically contain Ab and complement

Question 19

Describe the pathogenesis behind Giant cell (temporal) arteritis & aortitis.

Answer 19

Chronic (T-cell mediated, CD4>CD8) inflammation of arteries in the head, especially temporal arteries

Medial granulomatous inflammation, often with multinucleated giant cells
Fragmentation of the elastic lamina and intimal thickening
Site of involvement within an artery may be patchy and focal
Healed sites of inflammation show scarring of the media and intimal thickening
Double vision - involvement of ophthalmic artery may lead to vision loss

Question 20

What do you see with Takayasu arteritis? Location? Sx?

Answer 20

Characterized by ocular disturbances and marked weakening of pulses of the UPPER extermities

Sx: weak pulse and low BP in UE

Granulomatous vasculitis of medium and larger arteries

Question 21

Takayasu Arteritis is similar histologically to?

Answer 21

Giant cell arteritis

Question 22

How would you differentiate Takayasu arteritis with Giant cell arteritis?

Answer 22

Takayasu involves:

• Aortic arch (aortitis) and major branch vessels - causes dilation and aortic valve insufficiency
• Pulmonary artery (1/2 of cases), coronary & renal arteries
• Younger age (<50), historically Japanese, now global

Question 23

What Symptoms do you see with Takayasu arteritis? Initially vs. later? Distally on the aorta? Quiescent stage sx?

Answer 23

Initially nonspecific - fatigue, wt loss, fever

Later - Vasc sx dominate = decreased BP, weak carotid and UE pulses, visual deficits, retinal hemorrhage, total blindness, neuro deficit

Distal aorta Sx = claudication of legs, pulm artery = pulm HTN, coronary artery = MI, renal artery = systemic HTN

Quiescent stage after few yrs permits long-term survival with visual and neuro deficits

Question 24

What are the most common causes of aortitis?

Answer 24

Giant cell arteritis and Takayasu arteritis

Question 25

Clinically, how would you diagnose GCA and Takayasu?

Answer 25

GCA = best is to do a biopsy at multiple places (b/c doesn't occur everywhere) of the temporal artery, look to see if cells are abnormally large Takayasu = Check BP in involved arteries arising form aorta, pulses + BP low/impossible to fine; generally brisk pulses in leg, bruits may be at narrowed arteries

Question 26

What vessels does polyarteritis nodose involve? (In decreasing order of frequency)

Answer 26

Renal vessels Heart Liver GI tract Pulm vessels spared

Question 27

What demographic does Polyarteritis Nodosa affect?

Answer 27

May affect any age group, but classically young adults

Question 28

What are some characteristics seen with Polyarteritis nodosa?

Answer 28

1/3 of pts have CHRONIC HEP-B = HBsAg-Ab complexes found in involved vessels Immunosuppressive therapy usually effective Segmental transmural necrotizing inflammation (neutrophils, eosinophils, lymphocytes, macrophages); predilection for branch points Ulcerations, infarcts, ischemic atrophy or hemorrhage may be first sign of Dz Sites of inflammation are typically not circumferential

Question 29

With Polyarteritis Nodosa, inflamed vessels are susceptible to?

Answer 29

Thrombus formation/occlusion Aneurysm Rupture

Question 30

What are the Sx seen with polyarteritis nodosa?

Answer 30

Result form ischemia and infarction of affected tissue REMITTING AND EPISODIC with long Sx-free intervals, variable Classic presentation: - rapidly accelerating HTN = renal artery involvement - abd pain and bloody stools = vascular gastrointestinal lesions - diffuse myalgias and peripheral neuritis - predom affecting motor nerves - Renal involvement prominent and major cause of mortality - Immunosuppression can help

Question 31

What is Kawasaki disease?

Answer 31

Acute arteritis of infants and small children (80% < 4 yrs) Often involves coronary arteries -Affected sites may form aneurysms --> thrombosis or rupture --> acute MI Usually self-limited, but IVIg and aspirin are indicated to lower risk of coronary event

Question 32

How does Kawasaki Dz present? What are the Sx?

Answer 32

Sx: Conjunctival and oral erythema and blistering Edema of hands and feet Erythema of palms and soles Desquamative rash Cervical lymph node enlargement - "Mucocutaneous lymph node syndrome" 20% of untreated pts develop cardiovasc sequelae, ranging from asymptomatic coronary arteritis --> ectasia --> aneurysms --> rupture/thrombosis, MI, death

Question 33

What is Microscopic Polyangiitis?

Answer 33

Necrotizing vasculitis involving arterioles, capillaries, and venules Unlike polyarteritis nodosa, all lesions tend to be same age and distributed more widely -Henoch-Schonlein pupura, essential mixed cyroglobinemia, vasculitis assoc with CT DOs Affects vessels of many organ systems -Renal glomeruli and lung capillaries most common (90% necrotizing glomerulonephritis) Leukocytoclastic vasculitis or hypersensitivity vasculitis - immunosuppression helps

Question 34

What biomarker is Microscopic Polyangiitis associated with ?

Answer 34

MPO-ANCA

Question 35

What Sx will you observe with Microscopic Polyangiitis?

Answer 35

Segmental necrotizing inflammation with fibroid necrosis = Mainly apoptotic NEUTROPHILS (fragmented PMN - polymorphonuclear neutrophils) ``` Hemoptysis Hematuria & proteinuria Bowel pain or bleeding Muscle pain or weakness Palpable cutaneous purpura ```

Question 36

What are the characteristics of Bechet Dz? Include sites of involvement, inflammatory cells present, and clinical Hx.

Answer 36

Sites = Medium and small sized arteries, capillaries, veins Inflamm cells = NEUTROPHILS required, lymphocytes, neutrophils, macrophages Neutrophilic and morphologically nonspecific, may involve visceral organ systems with subsequent aneurysm formation Features: Thrombosis Clinical Hx: Orogenital Ulcers

Question 37

Bechet Dz has a classic triad of Sx. Name them.

Answer 37

Aphthous ulcers of oral cavity Genital ulcers Uveitis (also GI and Pulm manifestations)

Question 38

What gene is Bechet Dz associated with?

Answer 38

HLA-B51

Question 39

In Bechet Dz, mortality is related to ___. What Tx may be beneficial?

Answer 39

Neurologic involvement or rupture of aneurysm | Immunosuppression with steroid or TNF-antagonist tx is effective

Question 40

What are the characteristics of Granulomatosis with Polyangiitis? Include sites of involvement and inflammatory cells present.

Answer 40

Sites = Medium and Small sized arteries Necrotizing vasculitis featuring: -Necrotizing granulomas = upper/lower resp tracts -Necrotizing or granulomatous vasculitis = resp tract -Focal necrotizing, often Crescentric, glomerulonephritis Inflamm cells = Lymphocytes, Macrophages, Neutrophils, and Eosinophils Features: GRANULOMAS required Giant cells, Thrombosis, Serum ANCA positivity

Question 41

What biomarker is Granulomatosis w/ polyangiitis associated with?

Answer 41

PR3-ANCA (95% of cases)

Question 42

What reaction is occurring with Granulomatosis w/ polyangiitis?

Answer 42

T-cell mediated hypersensitivity response to normally "innocuous" inhaled microbial or other environmental agents

Question 43

What are the clinical features of Granulomatosis w/ polyangiitis?

Answer 43

``` M > F, Avg age 40 Sx: Persistent pneumonitis & sinusitis Renal dz Nasopharyngeal ulceration Rashes, myalgias, articular involvement, neural inflammation and fever ```

Question 44

What happens if Granulomatosis w/ polyangiitis is untreated? What is the Tx?

Answer 44

Left untreated, rapidly fatal, 80% mortality at one year Tx: steroids, cyclophosphamide, TNF antagonists Once fatal, now chronic relapsing and remitting

Question 45

What is the morphology of Granulomatosis w/ polyangiitis at the upper and lower respiratory tracts?

Answer 45

Upper resp tract = sinonasal and pharyngral inflammation with granulomas & vasculitis -Granulomas w/ geographic patterns of central necrosis and accompanying vasculitis Lower resp tract = multiple necrotizing granulomas, which may coalesce and cavitate

Question 46

What are the Sx of Buerger Dz (thromboangitis obliterans?

Answer 46

Acute/chronic inflammation + luminal thrombosis Thrombus = small microabscesses composed of neutrophils surrounded by granulomatous inflammation Cold-induced Raynaud phenomenon Intermittent claudication - leg pain induced by exercise, relieved on rest Instep claudication Superficial nodular phlebitis - venous inflammation Sever pain - even at rest Chronic extremity ulcerations - lead to frank gangrene