Vasculitis

Question 1

Definition/epidemiology

Answer 1

A clinicopathologic process characterized by inflammation of the vessel wall, and associated tissue ischemia and necrosis

The distribution of the antigen responsible for vasculitis determine the pattern (type, size and location) of the blood vessel involved, and produce a group of clinical syndromes with considerable overlap

Vasculitic lesions are focal and segmental – may have skip lesions; important to be aware of this when doing a biopsy

Can be confined to a single organ system, or it may simultaneously involve multiple organ systems – typically will see kidney and lung involvement

Vasculitis in affected organs may be the primary manifestation of a disease process

Vasculitic syndromes are characterized by differences in age of onset, sexual predilection, ethnicity and incidence

Vasculitic syndromes produce a wide spectrum of clinical manifestations that are often serious and sometimes fatal.

Question 2

Pathogenesis - overview

Answer 2

• genetics
• environmental stressors –> particularly infection
• epigenetics
• auto-antibodies
• complement
• neutrophils
• monocytes/macrophages
• T lymphocytes
• B lymphocytes
• endothelial cells
• TLRs

Question 3

Pathogenesis - immune complexes

Answer 3

Immune complexes - complexes deposit in vessel walls formed in the circulation at selective vascular sites. Antigen-antibody complexes produce injury by binding complement and stimulating leukocyte infiltration

• Hypersensitivity vasculitis –> complexes formed to drugs or foreign proteins, i.e., penicillin conjugated serum proteins or streptokinase
• Systemic lupus erythematosus –> DNA-anti-DNA complexes
• Cryoglobulinemia –> IgG, IgM and complement
• Hepatitis B-associated vasculitis –> HBSAg-anti-HBSAg complexes and complement present in vascular lesions

Question 4

Pathogenesis - endothelial cells

Answer 4

• antibodies to endothelial cells can induce the release of cytokines (IL1, IL6, IFN, etc) and promote local inflammatory response
• exposed endothelial cell antigens activate CD4 cells/T cell mediated vasculitis –> may be seen in SLE and Kawasaki disease
• non-endothelial structures of the vessel wall are involved in controlling the inflammatory process

Question 5

Pathogenesis - ANCA

Answer 5

Anti-neutrophil cytoplasmic antibodies –> Autoantibodies directed against cytoplasmic antigens in neutrophils, primarily azurophils or primary granules.
- Can be detected by immuno-fluorescent staining techniques producing 2 main staining patterns:

1. C-ANCA = Cytoplasmic staining of proteinase 3 (PR-3), a neutrophil granule constituent
   - found in granulomatosis and polyangiitis GPA/Wegener’s (~ 90%) –> C-ANCA titers show close association with disease activity and may be important in the pathogenesis of disease
2. P-ANCA = target antigen is perinuclear and specific for myeloperoxidase (MPO).
   - Found primarily in microscopic polyangiitis and Eosinophilic granulomatosis and angiitis (Churg-Strauss Syndrome)

Question 6

Classification of vasculitis

Answer 6

Classically systemic vasculitis disorders are categorized by the size of the predominant blood vessel involved, but there is considerable overlap between these disorders

• large vessel vasculitis –> involves the aorta and its branches
• medium vessel vasculitis –> involves muscular arteries that supply organs
• small vessel vasculitis –> involves arterioles, capillaries and venules

The presence or absence of ANCA is an addition to classification criteria

Question 7

Large vessel vasculites

Answer 7

• giant cell (temporal) arteritis
• takayasu arteritis
• IgG4 related syndrome

Question 8

Medium vessel vasculites

Answer 8

• polyarteritis nodosa
• kawasaki disease
• primary central nervous system vasculitis

Question 9

Small vessel vasculites

Answer 9

• eosinophilic granulomatosis with polyangiitis (churg strauss)
• granulomatosis with polyangiitis (wegeners)
• microscopic polyangiitis
• hypersensitivity vasculitis
• IgA vasculitis - henoch schonelin purpura
• cryoglobulonemic vasculitis
• vasculitis secondary to connective tissue diseases

Question 10

Giant cell arteritis

Answer 10

Chronic vasculitis affecting large and medium sized vessels that originate from the aortic arch including cranial vessels branches –> especially temporal arteries and ophthalmic arteries

• patients will present with onset of blindness
• onset –> most common after age of 50, with a mean age of 72 years.
• greatest risk factors are aging and Scandinavian ethnicity
• often triggered by upper respiratory infection

Question 11

Giant cell arteritis

• manifestations
• treatment
• complications

Answer 11

Manifestations

• Systemic symptoms –> fever, fatigue and weight loss
• Localized headache of new onset
• Jaw claudication
• Visual symptoms
• Tenderness or decreased pulse of the temporal artery
• Polymyalgia rheumatica – syndrome of diffuse stiffness of the upper and lower girdle
• elevated erythrocyte sedimentation rate (ESR) > 50 mm/hr

Biopsy of temporal artery –> necrotizing arteritis with predominance of mononuclear cells or granulomatous process with multinucleated giant cells (segmental disease) – skip lesions, might be missed

Treatment is high dose glucocorticoids (i.e., prednisone 60 mg QD or greater)

Complication of GCA: aneurysm, blindness and stroke –> Important to initiate treatment immediately – within 7 days, because if left untreated the patient will go blind

Question 12

Takayasu arteritis

Answer 12

Chronic vasculitis affecting the aorta and its major branches, resulting in fibrosis of vessels and weakening of pulses (pulseless disease)

• Predominantly young women under 40, particularly common in the Asian populations
• The inflammatory process causes thickening of the wall of the arteries with dilatation, narrowing and obstruction. - Infiltrating cells are mostly gamma delta T lymphocytes
• Initial vascular lesions frequently involves the left middle or proximal subclavian artery

Question 13

Takayasu arteritis

• manifestations
• treatment

Answer 13

Manifestations

• Decrease pulsation of one or both brachial arteries; differences of > 10 mm Hg blood pressure
• Claudication of the extremities
• Bruits over one or both subclavian arteries or abdominal aorta
• Ischemia of cranial vessels:
• arteriography revealing aneurysm formation, occlusion, collateral circulation

Treatment of acute disease with glucocorticoids, and surgical by-pass of occluded vessels
- depend on CT scan for follow up of these patients –> increased linear uptake in the aortic arch helps us know whether or not the disease is active

Question 14

IgG4 related disease

Answer 14

A spectrum of multisystem autoimmune disease that can affect many organs with fibro-inflammatory conditions and has many manifestations –> including pancreatitis, sclerosing cholangiitis and sialadenitis.

Many organs are involved including –> thyroid, lung and pleura, renal, skin, lymph nodes, heart (pericarditis), and CNS (pachymeningitis)

IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia.

IgG4-RD lesions –> infiltrated by T helper cells - cause progressive fibrosis and organ damage.

Although autoreactive IgG4 antibodies are observed against various exocrine gland antigens, there is no evidence that they are directly pathogenic.

Question 15

IgG4 associated vasculitis

Answer 15

IgG4RD has been recognized as one of the causes of non infectious aortitis and periaportitis involving the thoracic and abdominal aorta with lypmhoplasmacytic inflammatory reactions on pathological studies.

IgG4-associated aortitis is recognized at 1.6 % of all thoracic aortic resection in Japan

IgG4 deposition has been reported in cases with churg strauss

Question 16

Polyarteritis nodosa

Answer 16

Systemic necrotizing arteritis of medium and small muscular arteries often involving the kidneys, heart, liver, and GI tract (any organ excluding the lung) –> This is in contrast to Microscopic polyangiitis where smaller vessels are affected,

• Transmural inflammation of vessel wall, fibrinoid necrosis
• Involvement is usually focal and random producing aneurysm formation as well as vascular obstruction/infarction
• not associated with ANCA

Question 17

Polyarteritis nodosa

• manifestations
• diagnosis
• treatment

Answer 17

Adults >40, males more than females

Manifestations

• Constitutional symptoms
• Unexplained weight loss
• Renal involvement with new onset hypertension
• Musculoskeletal, myalgia
• Mononeuritis multiplex,or asymmetric polyneuropathy
• GI tract infarction, mesenteric vasculitis
• Skin: nodules, purpura, Livedo reticularis
• Testicular pain and tenderness

Approximately 30% of PAN patients have Hepatitis B HBV infection

• the hepatitis is silent at onset of PAN, with a mild increase in serum transaminases.
• PAN associated with HBV has a greater likelihood of gastrointestinal involvement

Diagnosis –> arteriography or tissue biopsy of affected organ

Treatment –> high dose glucocorticoids and immunosuppressants, mainly cyclophosphamide

Question 18

Kawasaki disease

Answer 18

Usually young children and infants, esp. in Japan.

• Arteritis involving large, medium and small muscular arteries (often with coronary artery involvement)
• pathology similar to that seen in PAN

Mucocutaneous lymph node syndrome:

• Fever
• Bilateral Conjunctival/ oral erythema,
• Rash of palm and soles with desquamation
• Lymph node involvement/ cervical

Approximately 20% of patients develop CV sequelae –> vasculitis of coronary vessels, ectasia/aneurysm formation, rupture or thrombosis, MI or sudden death

Tx –> high dose IVIG and aspirin are effective in decreasing cardiac manifestations if given early

Question 19

ANCA associated vasculitis

Answer 19

Vasculitis involving the small/ medium vessels clinically manifests in a variety of ways that can include:

• Cutaneous vasculitis,
• Alveolar hemorrhage
• Glomerulonephritis.

Small vessel vasculitis is a prominent feature of 4 important forms of primary systemic vasculitis:

• Granulomatosis with polyangiitis (Wegener’s)
• Microscopic polyangiitis
• Eosinophilic granulomatosis with polyangiitis -Churg-Strauss
• Renal limited vasculitis.
• –> Although these disease entities possess unique features, they are grouped together as they share similar involvement of the small vessels, glomerular histology, and the frequent association with ANCA and absence of immune complexes.

Question 20

Granulomatosis with polyangiitis (Wegners)

Answer 20

Systemic necrotizing granulomatous inflammation of small to medium-sized vessels (arteries, venules and arterioles), most commonly in:

• Nasal or oral inflammation (oral ulcers, bloody discharge)
• Abnormal chest x ray (nodules, fixed infiltrate or cavities)
• Abnormal urinary sediments (microscopic hematuria)

Disease of adults, 40 years and older,
Male > Female

Question 21

Granulomatosis with polyangiitis

• manifestations
• treatment

Answer 21

Manifestations include

• ENT –> Nasal crusting, bloody discharge, sinusitis, oral and/or nasal ulcers, polychodritis/ saddle nose
• Pulmonary –> hoarseness, cough, dyspnea, Persistent pneumonitis, nodular/cavitary infiltrates in the lung parenchyma, fibrosis and pulmonary hypertension
• Renal disease –> Renal failure with hematuria, segmental GN with crescentic formation
• Skin –> leukocytoclastic angiitis
• CNS –> Mononeuropathy or polyneuropathy

c-ANCA [anti-proteinase 3 antibody] is seen in 90%

Treatment with prednisone and cyclophosphamide or rituximab

Question 22

Eosinophilic granulomatosis and polyangiitis (churg strauss)

Answer 22

Seen in individuals (mean age 40 years) with underlying asthma and allergic rhinitis

• Pathology similar to that seen with PAN, but rich eosinophilic infiltration;
• Blood eosinophilia > 10 % of WBC
• Several asthma medication has been associated with churg strauss, including leukotriene modifying agents, that may be most likely due to unmasking of underlying disease
• Genetic factors such as HLA class and certain interleukin- 10 polymorphism may play a role in pathogenesis

Question 23

Eosinophlic granulomatosis and polyangiitis

• manifestations
• treatment

Answer 23

Clinical manifestations similar to poly-arteritis nodosa (PAN) - mononeuropathy

• transient pulmonary opacity
• paranasal sinus abnormality
• lung involvement is common.
• necrotizing crescentic glomerulonephritis is frequent
• skin with leukocytoclastic vasculitis

Associated with p-ANCA directed against myeloperioxidase

Cardiac complication accounts to one-half of deaths related to heart failure and arrhythmia

Treatment - corticosteroids + cyclophosphamide

Question 24

Microscopic polyangiitis

Answer 24

Usually affects arterioles, capillaries, and venules, all lesions to be of same age and p-ANCA usually present (> 80%)

• Arteries usually not involved
• distinguished from GPA and churg strauss by the absence of granuloma formation and the presence of necrotizing vasculitis
• closely related to wegners affecting skin, mucous membranes, lungs, brain, heart, GI tract, kidneys (crescentric glomerulonephritis) and muscle –> nasopharyngeal involvement is absent

Question 25

Hypersensitivity vasculitis - general - manifestations - treatment

Answer 25

Small sized vessel vasculitis - isolated vasculitis limited to skin, and sometimes glomerulonephritis - small vessels, particularly post-capillary venules - predominantly leukocytes infiltration with fragmentation and microthrombi --> leukocytoclasia/leukocytoclastic vasculitis Immune complex mediated secondary to colagen vascular disorders, drug, or isolated disease without clear etiology (most often) Manifestations - palpable purpura - kidney involvement Prognosis and tx depend on etiology

Question 26

Henoch schonlein purpura - IgA vasculitis

Answer 26

Small vessel vasculitis with IgA-immune deposits in vessel walls - Skin: Palpable purpura - GI tract: Bowel angina, GI bleeding - Glomeruli: Gross hematuria and / or proteinuria - Musculoskeletal system: arthralgia and myalgia - Usually attacks children, young adults < 20 Serologic studies document elevated levels of IgA and activation of the alternate pathway of the complement system. Characteristic histopathologic finding of HSP --> leukocytoclastic vasculitis (neutrophilic / monocytic) with IgA deposits within the affected vessels/post capillary venules

Question 27

Cryoglobulinemic vasculitis

Answer 27

Cryoglobulins --> typically composed of a mixture of immunoglobulins and complements components that deposits in the walls of small vessels, capillaries, venules or arterioles Often associated with cryoglobulins in serum --> immunoglobulins that precipitate in the cold composed principally of IgG-IgM complexes Cryoglobulins may be seen related to Hepatitis C virus infection or lymphoproliferative malignancy

Question 28

Cryoglobulinaemia - type 1 - type 2 - type 3

Answer 28

TYPE I = monoclonal/ IgM or IgG - Waldenström - Myeloma - Lymphoma TYPE II = monoclonal IgM + polyclonal IgG - HCV - Myeloma - Lymphoma - Autoimmune diseases TYPE III = polyclonal IgM + polyclonal IgG - Autoimmune diseases - Chronic Inflammatorydiseases

Question 29

Cryoglobulinemic vasculitis - clinical characteristics

Answer 29

HYPER VISCOSITY Raynaud’s Digital ischemia Hyperviscosity syndrome CRYOGLOBULINAEMIC VASCULITIS - Purpura - Arthritis - Raynaud’s - Renal disease - Neuropathy Low complement levels, and circulating cryoglobulins Abnormal Rheumatoid factor may be present

Question 30

Vasculitis mimics

Answer 30

``` Fibromuscular dysplasia Cholesterol emboli Atrial myxoma Infective endocarditis Atherosclerosis Radiation Fibrosis Thrombocytopenia purpura Malignancy Rickettsial infection Amyloidosis Cocaine use – induces vasospasm that can mimic vasculitis Ergotism Vasospasm Hypercoagulable state ```

Question 31

Drug induced vasculitis

Answer 31

- anti-TNF therapy - propylthiouracil - levamisole contaminated cocaine - the new small molecules including: - --> gefitinib = EGFR AB - --> masitinib = TK blocker

Question 32

Thromboangiitis obliterans - buergers disease

Answer 32

Distinctive entity occurring exclusively in heavy smoking men > women Peak incidence in 30’s – 40’s Segmental, thrombosing, acute and chronic inflammation of medium-sized and small arteries; microabscesses characteristic, as well as, spread to veins. - There is no evidence of atherosclerosis - Affects primarily vessels of the extremities, esp. tibial and radial arteries - Endothelial dysfunction --> direct endothelial cell toxicity induced by some tobacco product - Genetic predilection with HLA antigens (HLA-A9, B5); more common in Israel, Japan and India

Question 33

Thromboangiitis obliterans - manifestations - treatment

Answer 33

Manifestations - nodular phlebitis - raynauds - claudiciation - severe pain at rest (neuropathy) - chronic ulcerations/gangrene Treatment - abstinence from tobacco

Question 34

Clinical features suggestive of vasculitis

Answer 34

Mononeuritis multiplex or asymetric polyneuropathy --> highly suggestive of vasculitis - polyarteritis nodosa in particular Palpable purpura --> likely seen in patients with hypersensitivity vasculitis - if the purpura is present with systemic organ involvement then such patient may have HSP (IgA vasculitis), microscopic polyangitis/ arteritis or cryoglobulinemic vasculitis Pulmonary renal involvement --> The combination of hemoptysis and renal involvement suggestive of glomerulonephritis suggest the diagnosis of Wegners or microscopic polyangiitis - anti-glomerular basement membrane (anti-GBM) antibody disease, SLE and infections may cause similar presentation and have similar findings.