THE VASCULITIS SYNDROMES
 Sandra 3D 
Vasculitis
 Clinicopatho process char. by inflammation of & damage to
blood vessels
 Vessel lumen  compromised; assoc. w/ ischemia of tissues
supplied by involved vessel
 Any type, size & location of blood vessel
 Primary manifestation of a disease or secondary component of
another disease
 Single organ or several organ systems
Vasculitis syndromes
 Great deal of heterogeneity but also considerable overlap
between the syndromes
Pathophysio & Pathogenesis
 Hypothesis: most are assumed to be mediated in part by
immunopathogenic mech. that occur in response to certain
antigenic stimuli
 But it is unknown why some develop vasculitis in response to
certain antigenic stimuli while others do not
 It is likely that a number of factors are involved
 Genetic predisposition
 Environmental exposures
 Regulatory mech. assoc. w/ immune response to certain
antigens
Potential Mechanisms of Vessel Damage in Vasculitis Syndromes
1. Pathogenic Immune-Complex Formation &/or Deposition
 Deposition of immune complexes in vessel walls
 Most widely accepted pathogenic mech. but causal role
has not been clearly established in most syndromes
 Diseases
 Henoch-Schonlein purpura
 Vasculitis assoc. w/ collagen vascular diseases
 Serum sickness & cutaneous vasculitis syndromes
 HepaC - associated essential mixed cryoglobulinemia
 HepaB – associated Polyarteritis nodosa
 Mechanism of tissue damage (resembles mech. for serum
sickness)
1. Ag-Ab complex formation in antigen excess
2. Complex deposition in vessel walls whose
permeability is ↑ by vasoactive amines (from
platelets & mast cells) due to IgE-triggered mech.
3. Activation of complement components, esp. C5a
(strongly chemotactic for neutrophils)
4. Infiltration of vessel wall by neutrophils,
phagocytosis of immune complexes, release of
intracytoplasmic enzymes  vessel wall damage
5. Infiltration of vessel wall by mononuclear cells
(subacute or chronic process)
6. Compromise of vessel lumen w/ ischemic changes in
tissues supplied by the vessel
 Variables w/c explain why only certain types of immune
complexes cause vasculitis & why only certain vessels are
affected
 Ability of reticuloendothelial system to clear
circulating complexes from blood
 Size & physicochemical properties of immune
complexes
 Relative degree of turbulence of blood flow
 Intravascular hydrostatic pressure in different vessels
 Preexisting integrity of vessel endothelium
2. Antineutrophil Cytoplasmic Antibodies (ANCA)
 Ab directed against certain proteins in cytoplasmic
granules of neutrophils and monocytes
 In high % of px w/ certain systemic vasculitis syndromes
(Wegener's granulomatosis, microscopic polyangiitis, px
w/ necrotizing & crescentic GN)
 2 major categories based on different targets:
 Cytoplasmic ANCA (c-ANCA)
 diffuse, granular cytoplasmic staining pattern
observed by immunofluorescence microscopy
when serum Ab bind to indicator neutrophils
 Major target for c-ANCA (or major c-ANCA
antigen): Proteinase-3
 Perinuclear ANCA (p-ANCA)
 More localized perinuclear or nuclear staining
pattern of indicator neutrophils
 Major target for p-ANCA: myeloperoxidase
(assoc. w/ vasculitis)
 p-ANCA to myeloperoxidase in px w/
microscopic polyangiitis, Churg-Strauss
syndrome, crescentic GN, Goodpasture's
syndrome & Wegener's granulomatosis
 Other targets (assoc. w/ non-vasculitic
entities): elastase, cathepsin G, lactoferrin,
lysozyme, & bactericidal or permeability-
increasing protein
 Possible mechanisms how these Ab contribute to
pathogenesis of the vasculitis syndromes
 Proteinase-3 & myeloperoxidase reside in
azurophilic granules & lysosomes of resting
neutrophils & monocytes – inaccessible to serum
Ab
 But both translocate to the cell membrane when
neutrophils/monocytes are primed by TNFa or IL1,
& interact w/ extracellular ANCA
 Neutrophils then
• Degranulate & produce ROS w/c can cause
tissue damage
• Can adhere to & kill endothelial cells in vitro
• Induce release of proinflam cytokines (IL-1 &
IL-8), also by monocytes
 But role of these autoAb in patho of systemic vasculitis
remains unclear
 Px may have active Wegener’s w/o ANCA
 Px w/ Wegener’s in remission may continue to
have high c-ANCA for years
3. Pathogenic T Lymphocyte Responses and Granuloma
Formation
 Histopatho feature of granulomatous vasculitis shows:
delayed hypersensitivity & cell-mediated immune
injury
 But immune complexes may also induce granulomatous
responses
 Vascular endothelial cells
 Can express HLA class II molecules after cytokine
activation – allows participation in immunologic
reactions such as interaction with CD4+ T
lymphocytes
 Can secrete IL-1 - may activate T lymphocytes &
initiate/propagate in situ immunologic processes
w/in blood vessel
 IL-1 & TNF-a – potent inducers of endothelial-
leukocyte adhesion molecule 1 (ELAM-1) &
vascular cell adhesion molecule 1 (VCAM-1), which
may enhance adhesion of leukocytes to blood
vessel endothelial cells
 Other mechanisms are also suggested, but lacking
convincing evidence (direct cellular cytotoxicity,
antibody directed against vessel components or
antibody-dependent cellular cytotoxicity)
APPROACH TO THE PATIENT
 Consider diagnosis in any px w/ unexplained systemic illness
 Clinical abnormalities (alone or in combination) w/c suggest
diagnosis
 Palpable purpura
 Pulmonary infiltrates & microscopic hematuria
 Chronic inflammatory sinusitis
 Mononeuritis multiplex
 Unexplained ischemic events
 Glomerulonephritis w/ evidence of multisystem disease
 But some nonvasculitic diseases may also produce these
 First step: exclude other diseases w/ clinical manifestations
mimicking vasculitis (esp. infxs diseases)
 Next step: establish diagnosis & determine the category of
the syndrome (impt. because most require aggressive
therapy, but some require only symptomatic treatment)
 Definitive diagnosis: biopsy of involved tissue (avoid ‘blind’
biopsies of organs w/ no subj. or obj. evidence of
involvement)
 Angiogram of organs w/ suspected involvement
 PAN, Takayasu’s arteritis, isolated CNS vasculitis
 Don’t perform if px w/ localized cutaneous vasculitis
has no clinical indication of visceral involvement

 Clinical + Laboratory + Biopsy + Radiographic findings 
Treatment
 Treatment
o Removal of offending antigen (if recognized)
o Treatment of underlying disease (infection,
neoplasm, CT disease)
o If still doesn’t resolve or there is no recognizable
underlying disease, initiate treatment accdng. to
category of syndrome
WEGENER’S GRANULOMATOSIS
 Definition
 Granulomatous vasculitis of upper & lower respi. tracts +
glomerulonephritis
 Variable degrees of disseminated vasculitis (both small
arteries & veins) may occur
 Incidence & Prevalence
 Uncommon (3/100,000)
 M=F
 Any age
 15% <19 y.o.
 rare before adolescence
 mean age of onset: 40 y.o.
 Pathology & Pathogenesis
 Necrotizing vasculitis of small arteries & veins +
granuloma formation (intra or extravascular) – histopatho
hallmark
 Classic triad: upper & lower respi. tracts & kidney
 But any organ can be involved w/ vasculitis, granuloma or
both
 Lungs
 Multiple, bilateral, nodular cavitary infiltrates
 Diagnosis
 Biopsy reveals granulomatous vasculitis
 Upper airway (esp. sinuses & nasopharynx): inflam,
necrosis, granuloma formation w/ or w/o vasculitis
 Renal
 Focal & segmental glomerulitis (early)  rapidly
progressive crescentic glomerulonephritis
 Biopsy rarely show granuloma formation
 Evidence of immune complex deposition is not found
in renal lesions
 Immunopathogenesis
 Unclear; suggested aberrant cell-mediated immune
response to exogenous or endogenous antigen (upper
airway & lung involvement)
 Chronic nasal carriage of S.aureus – assoc. w/ higher
relapse rate; but NO role in pathogenesis of disease
 Peripheral blood mononuclear cells
  IFN, CD4+ T cells, TNF-a, IL-12
 Indicate unbalanced TH1-type T-cell cytokine pattern
 Development of ANCA in high % of px
 Clinical & Laboratory Manifestations
 Upper airway (95% of px)
 Often w/ severe upper respi. tract findings
 Paranasal sinus pain & drainage & purulent or bloody
nasal discharge, w/ or w/o nasal mucosal ulceration
 Nasal septal perforation may follow  saddle nose
deformity
 Serous otitis media may occur (result of eustachian
tube blockage)
 Subglottic tracheal stenosis (result of active disease
or scarring): 16% of px  severe airway obstruction
 Pulmonary involvement (85-90%)
 Asymptomatic infiltrates or
 Cough, hemoptysis, dyspnea & chest discomfort
 Endobronchial disease (active form or result of
fibrous scarring)  obstruction w/ atelectasis
 Eye involvement (52%)
 From mild conjunctivitis to dacryocystitis,
episcleritis, scleritis, granulomatous sclerouveitis,
ciliary vessel vasculitis, & retroorbital mass lesions
leading to proptosis.
 Skin lesions (46%)
 Papules, vesicles, palpable purpura, ulcers, or
subcutaneous nodules
 Biopsy: vasculitis, granuloma or both
 Cardiac involvement (8%)
 Pericarditis, coronary vasculitis, or rarely,
cardiomyopathy
 Nervous system manifestations (23%)
 Cranial neuritis, mononeuritis multiplex, or rarely,
cerebral vasculitis &/or granuloma.
 Renal disease (77%)
 Generally dominates the clinical picture
 Left untreated, accounts for most of mortality
 May smolder in some cases as mild glomerulitis
w/ proteinuria, hematuria, & RBC casts
 Once clinically detectable renal functional
impairment occurs, rapidly progressive renal
failure usually ensues unless treated appropriately
 Nonspecific ssx (while disease is active)
 Malaise, weakness, arthralgias, anorexia, & weight
loss
 Fever - may indicate activity of underlying disease
but more often reflects secondary infection
(usually upper airway)
 Characteristic lab findings
 Markedly elevated ESR
 Mild anemia and leukocytosis
 Mild hypergammaglobulinemia (particularly IgA)
 Mildly elevated RF
 Thrombocytosis (as acute-phase reactant)
 Positive antiproteinase-3 ANCA (90% of px w/
active disease)
 Antimyeloperoxidase rather than antiproteinase-3
antibodies (small % of px)
 Necrotizing granulomatous vasculitis on tissue biopsy in
px w/ compatible clinical features
 Tissue biopsy
 Pulmonary tissue: highest diagnostic yield; shows
granulomatous vasculitis
 Upper airway tissue: granulomatous inflammation
w/ necrosis; may not show vasculitis
 Renal biopsy can confirm presence of pauci-
immune glomerulonephritis
 Antiproteinase-3 ANCA
 Very high specificity, esp. in present active
glomerulonephritis
 But presence should be adjunctive
 Not substitute for tissue diagnoses, except in rare
cases
 False-positive ANCA titers: certain infectious &
neoplastic diseases
 If all typical features not present at once, need to
differentiate from
 Other vasculitides
 Goodpasture's syndrome
 Tumors of upper airway or lung
 Infectious diseases such as histoplasmosis,
mucocutaneous leishmaniasis, & rhinoscleroma
 Noninfectious granulomatous diseases
 Need to differentiate from midline granuloma and
upper airway neoplasms
 Lead to extreme tissue destruction & mutilation
localized to midline upper airway structures
including the sinuses
 Erosion through skin of face commonly occurs
(extremely rare in Wegener's)
 Blood vessels may be involved in intense
inflammatory reaction & necrosis but primary
vasculitis is seen rarely
 Usually declares itself as neoplastic process (in
systemic involvement)
 Idiopathic midline granuloma – when extensive
diagnostic workup failed to reveal anything other
than inflam. & necrosis
 Local irradiation with 50 Gy (5000 rad)
 Upper airway lesions should NEVER be irradiated in
Wegener's
 Need to differentiate lymphomatoid granulomatosis
 EBV B cell proliferation assoc. w/ exuberant T cell
reaction
 Char. by lung, skin, CNS & kidney involvement
 Atypical lymphocytoid & plasmacytoid cells
infiltrate nonlymphoid tissue in angioinvasive
manner
 NOT an inflammatory vasculitis but an infiltration
of vessels with atypical mononuclear cells
  Granuloma may be present in involved tissues
 Up to 50% of px may develop true malignant
lymphoma
 Treatment
 Glucocorticoids alone – some symptomatic improvement,
w/ little effect on ultimate disease course
 Oral cyclophosphamide (2 mg/kg/day) + glucocorticoids –
most effective therapy
 Induce & maintain clinical remission w/o causing severe
leukopenia & assoc. risk of infection by
 Adjust cyclophosphamide dosage to maintain
leukocyte count above 3000/uL during therapy
 This maintains neutrophil count at 1500/uL
 Cyclophosphamide continued for 1yr following
induction of complete remission then gradually taper
& discontinue
 Glucocorticoids
 Prednisone (1 mg/kg/day) for 1st month
 Gradual conversion to alternate-day schedule
 Taper & discontinue after 6 months
 Excellent prognosis w/ appropriate treatment
 Marked improvement in >90% of px
 Complete remissions in 75% of px
 Some px w/ irreversible renal failure but achieved
subsequent remission on have undergone successful
renal transplant
 Long-term follow-up
 50% of remissions are later assoc. w/ 1 or more
relapses
 Reinduction of remission almost always achieved
 But high % of px have some degree of morbidity from
irreversible features (renal insufficiency, hearing
loss, tracheal stenosis, saddle nose deformity, &
chronically impaired sinus function)
 Determination of relapse
• Based on obj. evidence of disease activity
• Rule out features w/ similar appearance
(infection, medication toxicity or chronic
disease sequelae)
• ANCA titer can be misleading
• Many px w/ remission have elevated titers for
years
• Patients may relapse many mos. or yrs after rise
in ANCA
• Rise in titer by itself is not a harbinger of
immediate disease relapse & should NOT lead to
reinstitution or increase in therapy
• But examine px carefully for any obj. evidence
of active disease & monitor closely
 Toxic side effects of treatment
 Glucocorticoid – DM, cataracts, life-threatening
infectious disease complications, serious
osteoporosis, & severe cushingoid features
 Reduce alternate-day glucocorticoid regimen
 Cyclophosphamide - more frequent & severe
• Cystitis: 30% of px
• Bladder cancer: 6%
• Myelodysplasia: 2%
• High risk of permanent infertility in men &
women
 Intermittent bolus of IV cyclophosphamide
(1g/m2/month)
 Therapeutic success w/ less frequent & severe toxic
side effects
 But increased rate of relapse
 Therefore use daily oral therapy
 Px w/ immediately life-threatening disease (e.g. RPGN)
 Daily cyclophosphamide & glucocorticoids - TOC to
induce remission
 Consider stopping cyclophosphamide & begin w/
methotrexate or azathioprine after remission
• Maintain remission
• Lessen toxicity of chronic cyclophosphamide
• Methotrexate
 Oral at 0.3 mg/kg, single weekly dose,
don’t exceed 15 mg/week
 If well tolerated after 1-2 wks, increase
dosage by 2.5 mg weekly up to 20-25
mg/week & maintain
 Given for 2 yrs past remission
 Then taper by 2.5 mg each month until
discontinuation
 Give w/ folic acid (1mg daily) or folinic
acid (5-10mg 1/week 24h after
methotrexate) to lessen toxicity
 Can’t be given to px w/ renal
insufficiency or chronic liver disease
• Azathioprine (2mg/kg/day) – for maintaining
remission
 Px w/ disease NOT immediately life threatening or px
w/ previous history of significant cyclophosphamide
toxicity
 Methotrexate + glucocorticoids considered as
alternative for initial therapy
 Trimethoprim-sulfamethoxazole (TMP-SMX)
 Decreased relapses shown only w/ regard to upper
airway disease
 Alone should NEVER be used to treat active
Wegener's outside of upper airway disease
 Not all manifestations require or respond to cytotoxic
therapy
 For managing non-major organ disease (isolated to
sinus, joints, or skin), risks of treatment vs.
benefits
 Effective treatment w/o cytotoxic therapy, but
must be monitored closely for development of
disease activity in lungs, kidneys or other major
organs
 Treatment w/ cyclophosphamide is rarely justified
for isolated sinus disease due to toxicity
 Examples of disease manifestation not responsive
to systemic immunosuppressive treatment:
subglottic tracheal stenosis & endobronchial
stenosis
CHURG-STRAUSS SYNDROME
 Definition
 AKA allergic angiitis & granulomatosis
 Asthma, peripheral & tissue eosinophilia, extravascular
granuloma formation, & vasculitis of multiple organ
systems
 Incidence & Prevalence
 Uncommon: 1-3 per million
 Any age w/ exception of infants
 Mean age of onset: 48 y.o.
 Female-to-male ratio – 1.2:1
 Pathology & Pathogenesis
 Necrotizing vasculitis involving small & medium-sized
muscular arteries, capillaries, veins, & venules
 Granulomatous reactions in tissues or w/in walls of
vessels
 Characteristic histopatho feature
 Usually assoc. w/ infiltration of tissues w/
eosinophils
 Can occur in any organ
 Predominant lung involvement
 Skin, CV system, kidney, PNS & GIT also commonly
involved
 Precise pathogenesis uncertain
 Strong assoc. w/ asthma & its clinicopatho
manifestations (eosinophilia, granuloma, & vasculitis)
 aberrant immunologic phenomena.
 Clinical & Laboratory Manifestations
 Often nonspecific manifestations (charac. Of
multisystem disease) – fever, malaise, anorexia, &
weight loss
 Pulmonary findings dominate the clinical picture
 Severe asthmatic attacks
 Presence of pulmonary infiltrates
 Mononeuritis multiplex – 2nd most common
manifestation; up to 72% of px

 Allergic rhinitis & sinusitis – early in disease; up to 61% of
px
 Clinically recognizable heart disease – impt. cause of
mortality; 14% of px
 Skin lesions – purpura in addition to cutaneous &
subcutaneous nodules; 51% of px
 Renal disease - less common, generally less severe than
Wegener's & microscopic polyangiitis
 Characteristic laboratory finding
 Striking eosinophilia: >1000 cells/uL in >80% of px
 Evidence of inflammation: elevated ESR, fibrinogen,
or a2-globulins in 81% of px
 Involvement of other organ systems
 Circulating ANCA (usually antimyeloperoxidase): 48%
of px
 Diagnosis
 Biopsy in px w/ characteristic clinical manifestations
 Histo confirmation – challenging; pathognomonic features
often do not occur simultaneously
 Px should have evidence of asthma, peripheral blood
eosinophilia, & clinical features consistent w/ vasculitis
 Treatment
 Poor prognosis of untreated disease (5-year survival of
25%)
 Favorable prognosis w/ treatment
 Myocardial involvement – most frequent cause of death;
39% of patient mortality
 Glucocorticoids – effective in many px
 Low-dose prednisone – px w/ persistent asthma due to
limited dosage tapering w/ glucocorticoids
 Daily cyclophosphamide + prednisone – treatment in cases
of glucocorticoid failure or px presenting w/ fulminant
multisystem disease
POLYARTERITIS NODOSA (PAN)
 Definition
 Also referred to as classic PAN
 Multisystem, necrotizing vasculitis of small & medium-
sized muscular arteries w/ characteristic involvement of
renal & visceral arteries
 Does NOT involve pulmonary arteries, but bronchial
vessels may be involved
 Granulomas, significant eosinophilia, & allergic diathesis
NOT observed
 Incidence & Prevalence: very uncommon
 Pathology & Pathogenesis
 Necrotizing inflammation of small & medium-sized
muscular arteries
 Segmental lesions, tend to involve bifurcations &
branchings
 May spread circumferentially to involve adjacent veins
 However, involvement of venules is NOT seen
 Acute stages of disease
 PMN neutrophils infiltrate all layers of vessel wall &
perivascular areas
 Results in intimal proliferation & degeneration of the
vessel wall
 Subacute to chronic stages
 Mononuclear cells infiltrate the area
 Fibrinoid necrosis of vessels w/ compromise of
lumen, thrombosis, infarction of tissues supplied by
vessel, & in some cases, hemorrhage
 As lesions heal, collagen deposition leading to
further occlusion of lumen
 Aneurysmal dilatations up to 1 cm along involved
arteries – characteristic of PAN
 Granulomas and substantial eosinophilia with
eosinophilic tissue infiltrations NOT found
 Involvement of multiple organ systems
 Clinicopatho findings reflect degree & location of
vessel involvement & resulting ischemic changes
 Pulmo. arteries NOT involved
 Bronchial artery involvement uncommon
 Kidney patho. in classic PAN: arteritis w/o GN
 Px w/ significant hypertension, typical pathologic
features of glomerulosclerosis w/ or w/o lesions of
GN + patho. sequelae of hypertension elsewhere in
body
 Hepatitis B antigenemia
 10-30% of px w/ systemic vasculitis, particularly
PAN type
 Isolation of circulating immune complexes
composed of hepa B antigen & Ig
 Demo. by immunofluorescence of hepa B antigen,
IgM, & complement in blood vessel walls
 Suggest role of immunologic phenomena in
pathogenesis of disease
 Hairy cell leukemia can be assoc. w/ PAN, but patho.
mech. are unclear
 Clinical & Laboratory Manifestations
 Nonspecific signs & symptoms – hallmarks of PAN
 Fever, weight loss & malaise (> ½ of px)
 Usually present w/ vague symptoms (weakness,
malaise, headache, abdominal pain & myalgias)
that can rapidly progress to fulminant illness
 Also specific complaints related to vascular
involvement within a particular organ system
 Renal involvement most commonly manifests as
HPN, renal insufficiency, or hemorrhage due to
microaneurysms
 No diagnostic serologic tests
 >75% of px: elevated leukocyte count (neutrophil
predominance)
 Almost always present: elevated ESR
 Other common lab findings: reflect organ involved
 Up to 30% of px: (+) hepaB surface antigen
 May be seen: anemia of chronic disease,
hypergammaglobulinemia
 Rarely found: Eosinophilia (at high levels, suggests
Churg-Strauss), Ab against myeloperoxidase or
proteinase-3 (ANCA)
 Diagnosis
 Based on biopsy of involved organs
 Vasculitis findings
 Highest yields in nodular skin lesions, painful
testes & nerve/muscle
 Angiography of involved vessels (in absence of
accessible tissue for biopsy)
 Aneurysms of small & medium-sized arteries in
renal, hepatic & visceral vasculature (NOT
pathognomonic), or
 Stenotic segments & obliteration of vessels
 Treatment
 Extremely poor prognosis for untreated PAN
 5-yr survival rate: 10-20%
 Death usually from GI complications (bowel
infarcts & perforation) & CV causes
 Intractable hypertension often compounds
dysfunction in other organ systems (kidneys,
heart, & CNS) – additional morbidity & mortality
 Prednisone + cyclophosphamide
 Less severe cases: glucocorticoids alone
 PAN related to hepaB: IFN-a + glucocorticoids + plasma
exchange
 Careful attention to treatment of HPN can lessen acute
& late morbidity & mortality assoc. w/ renal, cardiac &
CNS complications
 Relapse of PAN: 10% of px
MICROSCOPIC POLYANGIITIS
 Definition
 Microscopic polyarteritis – presence of
glomerulonephritis in px w/ PAN (1948, Davson)
 Microscopic polyangiitis – necrotizing vasculitis w/ few
or no immune complexes affecting small vessels
(capillaries, venules or arterioles), (1992,
Nomenclature of Systemic Vasculitis)
 GN very common
 Pulmonary capillaritis often occurs
 NO granulomatous inflammation
 Incidence & Prevalence
 Incidence not yet reliably established
  Mean age of onset: 57 y.o.
 Males slightly more frequently affected than females
 Pathophysio. findings in organs result from ischemia
related to involved vessels
 Pathology & Pathogenesis  Immunopathogenic mechanisms
 Vascular lesion histologically similar to PAN
 But has predilection to involve capillaries & venules in  Distinct cytokine patterns & T lymphocytes
addition to small & medium-sized arteries expressing specific antigen receptors
 Immunohistochemical staining  IL-6 & IL-1ß detected in majority of circulating
 Paucity of immunoglobulin deposition monocytes
 Suggest that immune complex formation does not
play a role in the pathogenesis  T cells recruited to vasculitic lesions produce
 Renal lesion predominantly IL-2 and IFN (suggested involved in
 Identical to Wegener's granulomatosis progression to overt arteritis)
 Highly assoc. w/ (+) ANCA  Sequence analysis of T cell receptor indicates
 Clinical & Laboratory Manifestations restricted clonal expansion (an antigen in the
arterial wall is recognized by some T cells)
 Clinical features shared w/ Wegener’s due to predilection
 Clinical & Laboratory Manifestations
to involve small vessels
 Complex of fever, anemia, high ESR & headaches in px
over 50 y.o.
 Onset  Other manifestations: malaise, fatigue, anorexia,
 Often acute weight loss, sweats & arthralgias
 May be gradual  Polymyalgia rheumatica syndrome: stiffness, aching &
 Initial sx of fever, weight loss & musculoskeletal pain pain in muscles of neck, shoulders, lower back, hips &
thighs.
 GN (at least 79% of px), can be rapidly progressive,
 In temporal artery involvement
leading to renal failure
 Headache
 Hemoptysis (12% of px) - 1st sx of alveolar hemorrhage • Predominant symptom
 Other manifestations • May be assoc. w/ tender, thickened or
 Mononeuritis multiplex nodular artery, which may pulsate early in
 GI tract & cutaneous vasculitis the disease but may become occluded later
 NOT typically found  Scalp pain & claudication of jaw & tongue may
 Upper airways disease & pulmonary nodules occur.
 Suggest Wegener's  Ischemic optic neuropathy
 Features of inflammation • Dreaded complication, esp. in untreated px
 Elevated ESR • May lead to serious visual symptoms, even
sudden blindness
 Anemia, leukocytosis, thrombocytosis
 ANCA (75% of px): predominance of
• But most patients have complaints relating to
head or eyes before visual loss
antimyeloperoxidase Ab
 Diagnosis • Attention to such symptoms + appropriate
 Histo evidence of vasculitis or pauci-mmune GN in px w/ therapy to avoid this
compatible clinical features of multisystem disease
 Treatment
 Claudication of ext., strokes, MI & infarctions of
visceral organs
 5-yr survival rate for treated px: 74%
 Disease-related mortality from alveolar hemorrhage or GI,  Increased risk of aortic aneurysm – usually late
cardiac or renal disease complication, may lead to dissection & death
 Therapeutic approach similar to Wegener's  Lab findings
 Immediately life-threatening disease
 Prednisone + daily cyclophosphamide  Elevated ESR
 Disease relapse  Normochromic or slightly hypochromic anemia
 At least 34% of px  Liver function abnormalities common (esp.  ALP)
 Tx similar to that used at initial presentation &  Increased IgG levels & complement
based on site & severity
 Diagnosis
 Based on clinical manifestations: fever, anemia & high
GIANT CELL ARTERITIS
ESR w/ or w/o sx of polymyalgia rheumatica in px >50
 Definition
years
 AKA cranial arteritis or temporal arteritis  Confirmation by biopsy of temporal artery
 Inflammation of medium- & large-sized arteries  3-5 cm segment + serial sectioning of specimens
 1/more branches of carotid artery, esp. temporal artery
 Obtain as quickly as possible in setting of ocular
 But is a systemic disease, can involve arteries in multiple ssx & don’t delay therapy (even on pending
locations biopsy)
 Incidence & Prevalence
 May show vasculitis even after >14 days of
 Almost exclusively in >50 y.o. glucocorticoid therapy
 More common in women  Ultrasonography of temporal artery – helpful
 High incidence: Scandinavia & regions of US w/ large  Dramatic clinical response to glucocorticoid therapy
Scandinavian pop. further supports diagnosis
 Treatment
 Familial aggregation: association w/ HLA-DR4
 Disease-related mortality very uncommon
 Genetic linkage studies: assoc. of temporal arteritis with  Fatalities from cerebrovascular events, MI & aortic
alleles at the HLA-DRB1 locus aneurysms
 Goals of treatment: reduce symptoms & prevent visual
 Closely associated w/ polymyalgia rheumatica (more
loss (important)
common)
 Sensitive to glucocorticoid therapy
 Pathology & Pathogenesis
 Prednisone (40-60 mg/d) for 1 month
 Temporal artery – most frequently involved
 Gradual tapering
 Also systemic vasculitis of multiple medium- & large-sized
 Can be adjusted to control ocular ssx
arteries (may go undetected)
 Histopatho  Most require tx for 2 yrs
 Panarteritis w/ inflam. mononuclear cell infiltrates  ESR
w/in vessel wall w/ frequent giant cell formation
 Proliferation of intima & fragmentation of internal
 Useful indicator of inflame.disease activity in
monitoring & tapering therapy
elastic lamina

 Can be used to judge pace of tapering schedule
 But minor increases can occur as glucocorticoids are
being tapered (do not necessarily reflect
exacerbation of arteritis, esp. if px remains
symptom-free); continue tapering w/ caution
 Glucocorticoid toxicity (35-65% of px) – impt. cause of px
morbidity
TAKAYASU'S ARTERITIS
 Definition
 AKA aortic arch syndrome
 Inflam. & stenotic disease of medium- & large-sized
arteries, w/ strong predilection for aortic arch &
branches
 Incidence & Prevalence
 Uncommon disease
 Most prevalent in adolescent girls & young women
 More common in Asia, but neither racially nor
geographically restricted
 Pathology & Pathogenesis
 Involves medium- & large-sized arteries, w/ strong
predilection for aortic arch & branches (more marked at
origin than distally)
 Pulmonary artery may also be involved
 A panarteritis w/ inflam. mononuclear cell infiltrates &
occasional giant cells
 Marked intimal proliferation & fibrosis, scarring &
vascularization of media, & disruption & degeneration of
elastic lamina
 Narrowing of lumen occurs w/ or w/o thrombosis
 Vasa vasorum frequently involved
 Pathologic changes in various organs reflect the
compromise of blood flow through the involved vessels.
 Immunopathogenic mechanisms, the precise nature of
which is uncertain, are suspected in this disease. As with
several of the vasculitis syndromes, circulating immune
complexes have been demonstrated, but their pathogenic
significance is unclear.
 Clinical & Laboratory Manifestations
 Generalized sx
 Malaise, fever, night sweats, arthralgias, anorexia &
weight loss
 May occur mos. before apparent vessel involvement
 May merge into sx related to vascular compromise &
organ ischemia
 Vascular sx
 Pulses commonly absent in involved vessels, esp.
subclavian artery
 Arteriographic abnormalities
 HPN in 32-93% of px, contributes to renal, cardiac &
cerebral injury
 Lab findings: elevated ESR & Ig levels, mild anemia
 Diagnosis
 Young woman w/ decrease/absence of peripheral pulses,
discrepancies in BP & arterial bruits
 Confirmed by arteriography
 Irregular vessel walls, stenosis, poststenotic
dilatation, aneurysm formation, occlusion, &
evidence of increased collateral circulation
 Complete aortic arteriography should be obtained,
unless this is renally contraindicated
 Histopatho. of inflamed vessels adds confirmatory data,
but tissue is rarely available
 Treatment
 Disease-related mortality
 From congestive heart failure, cerebrovascular
events, MI, aneurysm rupture or renal failure
 Can be assoc. w/ significant morbidity even in absence of
life-threatening disease
 Most often chronic & relapsing
 Glucocorticoid therapy may alleviate sx, but doesn’t
increase survival
 Glucocorticoid therapy (for acute ssx) + aggressive
surgical &/or angioplastic approach to stenosed vessels
 Lessens risk of stroke
 Corrects HPN due to renal artery stenosis
 Improves blood flow to ischemic viscera & limbs
 Unless urgently required, surgical correction should be
undertaken only when vascular inflam. process is well
controlled w/ medical therapy
 Methotrexate (up to 25mg/wk) in px w/ refractory to
or unable to taper glucocorticoids
HENOCH- SCHONLEIN PURPURA
 Definition
 AKA anaphylactoid purpura
 Small-vessel systemic vasculitis charac. by palpable
purpura (most commonly buttocks & LE), arthralgias, GI
ssx & GN
 Incidence & Prevalence
 Usually in children (4-7 y.o.)
 Also in infants & adults
 Not rare
 Male-to-female ratio 1.5:1.
 Seasonal variation: peak in spring
 Pathology & Pathogenesis
 Immune-complex deposition - presumptive pathogenic
mechanism
 Suggested antigens: URT infections, various drugs,
foods, insect bites & immunizations
 IgA – most often seen in immune complexes &
demonstrated in renal biopsies
 Clinical & Laboratory Manifestations
 Pedia px
 Palpable purpura (all px)
 Polyathralgias in absence of frank arthritis (most)
 GI (70%)
• Colicky abdominal pain
• Nausea, vomiting, diarrhea or constipation
• Frequently passage of blood & mucus
• Bowel intussusception may occur
 Renal involvement (10-50% )
• Usually mild GN leading to proteinuria &
microscopic hematuria, w/ RBC casts (in
majority)
• Usually resolves spontaneously w/o therapy
• Rarely develops into progressive GN
 Adult px
 Presentin sx most frequently related to skin &
joints (related to gut less common)
 Course of renal disease may be more insidious,
requires close follow-up
 Myocardial involvement can occur (rare in
children)
 Lab
 Mild leukocytosis
 Occasional eosinophilia
 Elevated IgA levels (1/2 of px)
 Normal platelet count & serum complement
components
 Diagnosis
 Based on clinical ssx
 Confirmatory: skin biopsy specimen w/ IgA & C3
deposition by immunofluorescence
 Renal biopsy rarely need but may provide prognostic
information
 Treatment
 Excellent prognosis
 Rare mortality (1-5% of children progress to end-stage
renal disease)
 Most recover completely, some don’t require therapy
 Tx similar for adults & children
 In required glucocorticoid therapy
 Prednisone (1 mg/kg/day & tapered)
 Useful in decreasing tissue edema, arthralgias &
abdominal discomfort
 But not beneficial in treatment of skin or renal
disease
 Doesn’t shorten duration of active disease or
lessen chance of recurrence
 Px w/ RPGN
 Intensive plasma exchange + cytotoxic drugs
 Recurrence in 10-40% of px
IDIOPATHIC CUTANEOUS VASCULITIS
 Definition
  Cutaneous vasculitis – inflammation of blood vessels of  Cryoglobulins – cold-precipitable monoclonal or
the dermis; not one specific disease, but a manifestation polyclonal Ig
that can be seen in a variety of settings  Cryoglobulinemia may be assoc. w/ a systemic
 >70% of cases: either as part of primary systemic vasculitis charac. by
vasculitis or as secondary vasculitis related to an inciting  Palpable purpura
agent or underlying disease  Arthralgias
 Remaining 30% of cases: idiopathic  Weakness
 Incidence & Prevalence  Neuropathy
 Exact incidence not yet determined  GN
 But cutaneous vasculitis is the most commonly  Essential mixed cryoglobulinemia
encountered vasculitis in clinical practice  Apparent absence of underlying disease (multiple
 Pathology & Pathogenesis myeloma, lymphoproliferative disorders, CT
 Vasculitis of small vessels diseases, infection, & liver disease), and
 Postcapillary venules – most commonly involved  presence of cryoprecipitate containing
 Capillaries & arterioles less frequently oligoclonal/polyclonal Ig
 Char. by leukocytoclasis (nuclear debris remaining from  In majority of px, it is related to aberrant immune
neutrophils that infiltrated in & around vessels during response to chronic hepaC infection
acute stages)  Incidence & Prevalence
 Subacute or chronic stages  Develop in 5% of px w/ chronic hepaC
 Pathology & Pathogenesis
 Mononuclear cells predominate  Skin biopsy
 Eosinophilic infiltration (certain subgroups)  Inflam. infiltrate surrounding & involving blood
vessel walls
 Erythrocytes often extravasate from involved  W/ fibrinoid necrosis, endothelial cell hyperplasia
vessels, leading to palpable purpura & hemorrhage
 Deposition of Ig & complement is common
 Abnormalities of uninvolved skin
 Clinical & Laboratory Manifestations  Basement membrane alterations
 Hallmark: predominance of skin involvement  Deposits in vessel walls
 Skin lesions  Membranoproliferative glomerulonephritis – responsible
 Typically palpable purpura for 80% of all renal lesions
 Others: macules, papules, vesicles, bullae,  Association w/ hepaC
subcutaneous nodules, ulcers, & recurrent/chronic  HepaC RNA & anti-hepaC Ab in serum
urticaria cryoprecipitates
 May be pruritic or even quite painful (burning or  HepaC antigens in vasculitic skin lesions
stinging)  Effective antiviral therapy
 Most commonly in LE (ambulatory px) or sacral area  In majority of cases, occurs when aberrant
(bedridden px) due to effects of hydrostatic forces immune response to hepaC infection leads to
on postcapillary venules formation of immune complexes, w/c deposits in
 Edema may accompany lesions blood vessel walls & triggers an inflam. cascade
 Hyperpigmentation often in areas of recurrent or  Immune complexes: hepatitis C antigens +
chronic lesions polyclonal hepatitis C-specific IgG + monoclonal
 No specific diagnostic lab tests IgM rheumatoid factor
 Mild leukocytosis w/ or w/o eosinophilia  Clinical & Laboratory Manifestations
 Elevated ESR  Most common: cutaneous vasculitis, arthritis,
 Diagnosis peripheral neuropathy, & GN
 Demonstration of vasculitis on biopsy  Renal disease: 10-30% of px
 Important: search for the etiology (exogenous or  Infrequently: Life-threatening rapidly progressive GN or
endogenous) of the vasculitis vasculitis of CNS, GIT or heart
 Careful PE & lab exam to rule out features suggesting  Fundamental finding: (+) circulating cryoprecipitates
underlying disease or systemic vasculitis  Other frequent findings
 From least invasive to approach to more invasive only if  Rheumatoid factor – useful clue when
clinically indicated cryoglobulins not detected
 Treatment  Hypocomplementemia: 90% of px
 Remove antigenic stimulus when recognized  Elevated ESR & anemia
(antimicrobial therapy if microbe)  HepaC infection must be sought in all patients by
testing for Ab & RNA
 If w/ associated underlying disease, treat the underlying  Treatment
disease (often leads to resolution of vasculitis)  Acute mortality uncommon
 In apparently self-limited disease – no therapy,  Presence of GN
symptomatic therapy if indicated
 Poor prognostic sign for overall outcome
 In persistent cutaneous vasculitis or no evidence of
 15% progress to end-stage renal disease
inciting agent, assoc. disease or underlying systemic
 40% later experiencing fatal CV disease, infection
vasculitis – weigh degree of symptoms vs. risk of
or liver failure
treatment
 In assoc. w/ hepaC infection
 Some cases resolve spontaneously
 Tx w/ IFN-a + ribavirin
 Others remit & relapse
 Clinical improvement dependent on virologic
 For persistent vasculitis
response
 Lack of consistent response to therapy usually
doesn’t lead to life-threatening situation (since  Cleared hepaC from blood – improvement in
generally limited to skin) vasculitis & reductions in levels of circulating
 Glucocorticoids: prednisone (1mg/kg/day w/ rapid cryoglobulins, IgM & RF
tapering)
 If refractory: use cytotoxic agent, but ONLY as a last
 But some px w/ hepaC don’t have sustained
virologic response to therapy, vasculitis relapses
resort (since vasculitis isolated to cutaneous venules
with return of viremia
rarely respond dramatically to any regimen)
 Cyclophosphamide, though most effective therapy  Transient improvement w/ glucocorticoids,
for systemic vasculitides, should ALMOST NEVER be complete response in only 7% of px
used for this disease (potential toxicity)
 Other agents that have been used: Methotrexate, BEHCET’S SYNDROME
azathioprine, dapsone, colchicine & NSAIDS  Recurrent episodes of oral & genital ulcers, iritis, &
cutaneous lesions
ESSENTIAL MIXED CRYOGLOBULINEMIA
 Definition
 Pathologic process: leukocytoclastic venulitis
 Although vessels of any size & in any organ can be involved
ISOLATED VASCULITIS OF THE CENTRAL NERVOUS SYSTEM
 Uncommon
 Vasculitis restricted to vessels of CNS w/o other apparent
systemic vasculitis
 Most commonly affected: arteriole
 Inflammatory process: mononuclear cell infiltrates w/ or w/o
granuloma formation
 Severe headaches, altered mental fxn, focal neurologic
defects
 Systemic sx generally absent
 Devastating neuro abnormalities depend on extent of vessel
involvement
 Diagnosis: characteristic vessel abnormalities on angiography +
confirmation by biopsy of brain parenchyma & leptomeninges
 Differential dx: infection, atherosclerosis, emboli, CT disease,
sarcoidosis, malignancy, vasospasm, drug-associated causes
 Poor prognosis
 Glucocorticoid therapy w/ or w/o cyclophosphamide 
sustained clinical remissions in small # of px
COGAN’S SYNDROME
 Interstitial keratitis + vestibuloauditory sx
 May be assoc. w/ systemic vasculitis, particularly aortitis w/
aortic valve involvement
 Glucocorticoids: mainstay of treatment
 Initiate treatment ASAP after onset of hearing loss to improve
outcome
KAWASAKI DISEASE
 AKA mucocutaneous lymph node syndrome
 Acute, febrile, multisystem disease of children
 80% before 5 y.o. (peak at 2 y.o.)
 Nonsuppurative cervical adenitis & changes in skin & mucous
membranes (edema; congested conjunctivae; erythema of oral
cavity, lips & palms; desquamation of skin of fingertips)
 Generally benign & self-limited
 But assoc. w/ coronary artery aneurysms
 25% of cases
 Overall case-fatality rate: 0.5-2.8%
 Occurs at 3-4 wk (convalescent stage)
 Vasculitis of the coronary arteries
 Typical intimal prolif. & infiltration of vessel wall w/
mononuclear cells
 Beadlike aneurysms & thromboses along artery
 Other manifestations: pericarditis, myocarditis, myocardial
ischemia & infarction, cardiomegaly
 Excellent prognosis (except for those w/ fatal complications)
 High-dose IV globulin (2 g/kg as single infusion over 10h) +
aspirin (100 mg/kg/day for 14 days, then 3-5 mg/kg/day for
several wks)  to prevent coronary artery abnormalities
POLYANGIITIS OVERLAP SYNDROMES
 Clinicopatho characteristics not fitting to any specific disease,
but w/ overlapping features of diff. vasculitides
 Same potential for causing irreversible organ system damage
 treat as described under Wegener’s granulomatosis
 Diagnostic & therapeutic considerations & prognosis depend on
sites & severity of active vasculitis
SECONDARY VASCULITIS
 Drug-Induced Vasculitis
 Usually present w/ palpable purpura, generalized or
limited to LE or other dependent areas
 Urticarial lesions, ulcers, hemorrhagic blisters may occur
 Skin: predominant organ involved
 But systemic vasculitis may also occur (fever, malaise,
polyarthralgias)
 Drugs implicated in vasculitis: allopurinol, thiazides,
gold, sulfonamides, phenytoin, penicillin
 ANCA-positive drug-induced vasculitis: hydralazine,
propylthiouracil (clinical manifestations: from cutaneous
lesions to glomerulonephritis & pulmo hemorrhage)
 Treatment: discontinue drug; glucocorticoids &
cyclophosphamide (for immediately life-threatening
small-vessel vasculitis)
 Serum Sickness & Serum Sickness-Like Reactions
 Fever, urticaria, polyarthralgias & lymphadenopathy
 7-10 days after primary exposure, and
 2-4 days after secondary exposure to a
heterologous protein (Classic Serum Sickness) or a
nonprotein drug such as penicillin or sulfa (Serum
Sickness-Like Reaction)
 Most manifestations NOT due to vasculitis
 Occasionally, typical cutaneous venulitis (may progress
rarely to systemic vasculitis)
 Vasculitis Associated with Other Underlying Primary
Diseases
 Infections may directly trigger an inflam. vasculitic
process
 Rickettsias - vasculitis due to invasion &
proliferation in endothelial cells of small blood
vessels
 Systemic fungal diseases (e.g. histoplasmosis) –
inflam. response around blood vessels may mimic
primary vasculitic process
 Other infxns (e.g. subacute bacterial
endocarditis, EBV, HIV) – leukocytoclastic
vasculitis predominantly involving skin w/
occasional involvement of other organ systems
 Malignancies, particularly lymphoid or
reticuloendothelial neoplasms
 Leukocytoclastic venulitis confined to skin – most
common finding
 Widespread systemic vasculitis may occur
 Association of hairy cell leukemia w/ PAN
 Connective Tissue Diseases
 Vasculitis as secondary manifestation of underlying
primary process
 SLE, RA, inflammatory myositis, relapsing
polychondritis, Sjogren’s syndrome
 Small-vessel venulitis isolated to skin: most
common form of vasculitis
 Fulminant systemic necrotizing vasculitis – some
px
 Other Diseases
 Ulcerative colitis
 Congenital deficiencies of various complement
components
 Retroperitoneal fibrosis
 Primary biliary cirrhosis
 a1-antitrypsin deficiency
 Intestinal bypass surgery
PRINCIPLES OF TREATMENT
 Weigh carefully the risk vs. benefit ratio
 General principles
o Glucocorticoids &/or cytotoxic therapy instituted
immediately in diseases w/ irreversible organ system
dysfunction & established high morbidity/mortality
(prototype: Wegener's granulomatosis)
o Only symptomatic treatment for vasculitic
manifestations rarely resulting in irreversible organ
system dysfunction & usually not responding to
aggressive therapy (e.g. idiopathic cutaneous
vasculitis)
o Glucocorticoids for those that cannot be specifically
categorized or no established std therapy
o Cytotoxic therapy added only if no adequate response
or if remission can only be achieved & maintained with
unacceptable toxic regimen of glucocorticoids
o Upon remission, taper glucocorticoids to alternate-day
regimen & discontinue when possible
o In using cytotoxic regimens, base choice of agent on
available therapeutic data supporting efficacy, site &
severity of organ involvement & toxicity profile
 Be aware of toxic side effects
o Decrease freq. & duration on alternate-day regimens
o Chronic cyclophosphamide
 Cystitis, bladder CA, etc. (see Wegener’s)
 Monitor for bladder CA indefinitely because can
occur years after discontinuation of drug
  To reduce risk of bladder injury: take
cyclophosphamide all at once in morning + large
amount of fluid throughout day to maintain dilute
urine
 Chronic low-dose regimen: significant alopecia
(unusual)
 Permanent infertility in men & women
 Bone marrow suppression – observe during tapering
of glucocorticoid or after periods of stable
measurements
 Cytopenias – prevent by CBC monitoring every 1-2
wks during therapy
o Life-threatening opportunistic infections
 Low at WBC >3000/uL & px not receiving daily
glucocorticoids
 But WBC count not an accurate predictor of risk
 Pneumocystis carinii infection & certain fungi in face
of px w/ WBCs w/in normal limits, esp those
receiving glucocorticoids
 Prophylaxis against P.carinii: TMP-SMX added to
regimen (if px is NOT allergic to sulfa)
 Individualize therapy