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Daily cyclophosphamide + prednisone – treatment in cases May be seen: anemia of chronic disease,
of glucocorticoid failure or px presenting w/ fulminant hypergammaglobulinemia
multisystem disease Rarely found: Eosinophilia (at high levels, suggests
Churg-Strauss), Ab against myeloperoxidase or
POLYARTERITIS NODOSA (PAN) proteinase-3 (ANCA)
Definition Diagnosis
Also referred to as classic PAN Based on biopsy of involved organs
Multisystem, necrotizing vasculitis of small & medium- Vasculitis findings
sized muscular arteries w/ characteristic involvement of
Highest yields in nodular skin lesions, painful
renal & visceral arteries
testes & nerve/muscle
Does NOT involve pulmonary arteries, but bronchial
vessels may be involved Angiography of involved vessels (in absence of
Granulomas, significant eosinophilia, & allergic diathesis accessible tissue for biopsy)
NOT observed
Aneurysms of small & medium-sized arteries in
Incidence & Prevalence: very uncommon renal, hepatic & visceral vasculature (NOT
Pathology & Pathogenesis pathognomonic), or
Necrotizing inflammation of small & medium-sized Stenotic segments & obliteration of vessels
muscular arteries Treatment
Segmental lesions, tend to involve bifurcations & Extremely poor prognosis for untreated PAN
branchings 5-yr survival rate: 10-20%
May spread circumferentially to involve adjacent veins Death usually from GI complications (bowel
infarcts & perforation) & CV causes
However, involvement of venules is NOT seen
Acute stages of disease
Intractable hypertension often compounds
dysfunction in other organ systems (kidneys,
PMN neutrophils infiltrate all layers of vessel wall & heart, & CNS) – additional morbidity & mortality
perivascular areas Prednisone + cyclophosphamide
Results in intimal proliferation & degeneration of the
vessel wall Less severe cases: glucocorticoids alone
Subacute to chronic stages PAN related to hepaB: IFN-a + glucocorticoids + plasma
Mononuclear cells infiltrate the area exchange
Fibrinoid necrosis of vessels w/ compromise of
lumen, thrombosis, infarction of tissues supplied by Careful attention to treatment of HPN can lessen acute
vessel, & in some cases, hemorrhage & late morbidity & mortality assoc. w/ renal, cardiac &
As lesions heal, collagen deposition leading to CNS complications
further occlusion of lumen Relapse of PAN: 10% of px
Aneurysmal dilatations up to 1 cm along involved
arteries – characteristic of PAN MICROSCOPIC POLYANGIITIS
Granulomas and substantial eosinophilia with Definition
eosinophilic tissue infiltrations NOT found Microscopic polyarteritis – presence of
Involvement of multiple organ systems glomerulonephritis in px w/ PAN (1948, Davson)
Clinicopatho findings reflect degree & location of Microscopic polyangiitis – necrotizing vasculitis w/ few
vessel involvement & resulting ischemic changes or no immune complexes affecting small vessels
Pulmo. arteries NOT involved (capillaries, venules or arterioles), (1992,
Bronchial artery involvement uncommon Nomenclature of Systemic Vasculitis)
Kidney patho. in classic PAN: arteritis w/o GN GN very common
Px w/ significant hypertension, typical pathologic Pulmonary capillaritis often occurs
features of glomerulosclerosis w/ or w/o lesions of NO granulomatous inflammation
GN + patho. sequelae of hypertension elsewhere in Incidence & Prevalence
body 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
Unless urgently required, surgical correction should be
Can be used to judge pace of tapering schedule
undertaken only when vascular inflam. process is well
But minor increases can occur as glucocorticoids are controlled w/ medical therapy
being tapered (do not necessarily reflect Methotrexate (up to 25mg/wk) in px w/ refractory to
exacerbation of arteritis, esp. if px remains or unable to taper glucocorticoids
symptom-free); continue tapering w/ caution
HENOCH- SCHONLEIN PURPURA
Glucocorticoid toxicity (35-65% of px) – impt. cause of px
Definition
morbidity
AKA anaphylactoid purpura
TAKAYASU'S ARTERITIS Small-vessel systemic vasculitis charac. by palpable
Definition purpura (most commonly buttocks & LE), arthralgias, GI
AKA aortic arch syndrome ssx & GN
Inflam. & stenotic disease of medium- & large-sized Incidence & Prevalence
arteries, w/ strong predilection for aortic arch & Usually in children (4-7 y.o.)
branches Also in infants & adults
Incidence & Prevalence Not rare
Uncommon disease Male-to-female ratio 1.5:1.
Most prevalent in adolescent girls & young women Seasonal variation: peak in spring
More common in Asia, but neither racially nor Pathology & Pathogenesis
geographically restricted Immune-complex deposition - presumptive pathogenic
Pathology & Pathogenesis mechanism
Involves medium- & large-sized arteries, w/ strong Suggested antigens: URT infections, various drugs,
predilection for aortic arch & branches (more marked at foods, insect bites & immunizations
origin than distally) IgA – most often seen in immune complexes &
demonstrated in renal biopsies
Pulmonary artery may also be involved
A panarteritis w/ inflam. mononuclear cell infiltrates & Clinical & Laboratory Manifestations
occasional giant cells Pedia px
Palpable purpura (all px)
Marked intimal proliferation & fibrosis, scarring & Polyathralgias in absence of frank arthritis (most)
vascularization of media, & disruption & degeneration of GI (70%)
elastic lamina • Colicky abdominal pain
Narrowing of lumen occurs w/ or w/o thrombosis • Nausea, vomiting, diarrhea or constipation
• Frequently passage of blood & mucus
Vasa vasorum frequently involved
• Bowel intussusception may occur
Pathologic changes in various organs reflect the
compromise of blood flow through the involved vessels. Renal involvement (10-50% )
Immunopathogenic mechanisms, the precise nature of • Usually mild GN leading to proteinuria &
which is uncertain, are suspected in this disease. As with microscopic hematuria, w/ RBC casts (in
several of the vasculitis syndromes, circulating immune majority)
complexes have been demonstrated, but their pathogenic • Usually resolves spontaneously w/o therapy
significance is unclear. • Rarely develops into progressive GN
Clinical & Laboratory Manifestations Adult px
Generalized sx Presentin sx most frequently related to skin &
Malaise, fever, night sweats, arthralgias, anorexia & joints (related to gut less common)
weight loss Course of renal disease may be more insidious,
May occur mos. before apparent vessel involvement requires close follow-up
May merge into sx related to vascular compromise & Myocardial involvement can occur (rare in
organ ischemia children)
Vascular sx Lab
Pulses commonly absent in involved vessels, esp. Mild leukocytosis
subclavian artery Occasional eosinophilia
Arteriographic abnormalities Elevated IgA levels (1/2 of px)
HPN in 32-93% of px, contributes to renal, cardiac & Normal platelet count & serum complement
cerebral injury components
Lab findings: elevated ESR & Ig levels, mild anemia Diagnosis
Diagnosis Based on clinical ssx
Young woman w/ decrease/absence of peripheral pulses, Confirmatory: skin biopsy specimen w/ IgA & C3
discrepancies in BP & arterial bruits deposition by immunofluorescence
Confirmed by arteriography Renal biopsy rarely need but may provide prognostic
Irregular vessel walls, stenosis, poststenotic information
dilatation, aneurysm formation, occlusion, & Treatment
evidence of increased collateral circulation Excellent prognosis
Complete aortic arteriography should be obtained, Rare mortality (1-5% of children progress to end-stage
unless this is renally contraindicated renal disease)
Histopatho. of inflamed vessels adds confirmatory data, Most recover completely, some don’t require therapy
but tissue is rarely available Tx similar for adults & children
Treatment In required glucocorticoid therapy
Prednisone (1 mg/kg/day & tapered)
Disease-related mortality Useful in decreasing tissue edema, arthralgias &
From congestive heart failure, cerebrovascular abdominal discomfort
events, MI, aneurysm rupture or renal failure But not beneficial in treatment of skin or renal
Can be assoc. w/ significant morbidity even in absence of disease
life-threatening disease Doesn’t shorten duration of active disease or
Most often chronic & relapsing lessen chance of recurrence
Glucocorticoid therapy may alleviate sx, but doesn’t Px w/ RPGN
increase survival Intensive plasma exchange + cytotoxic drugs
Glucocorticoid therapy (for acute ssx) + aggressive Recurrence in 10-40% of px
surgical &/or angioplastic approach to stenosed vessels
Lessens risk of stroke IDIOPATHIC CUTANEOUS VASCULITIS
Corrects HPN due to renal artery stenosis Definition
Improves blood flow to ischemic viscera & limbs
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
Treatment: discontinue drug; glucocorticoids &
cyclophosphamide (for immediately life-threatening
Uncommon
small-vessel vasculitis)
Vasculitis restricted to vessels of CNS w/o other apparent
Serum Sickness & Serum Sickness-Like Reactions
systemic vasculitis
Most commonly affected: arteriole
Fever, urticaria, polyarthralgias & lymphadenopathy
7-10 days after primary exposure, and
Inflammatory process: mononuclear cell infiltrates w/ or w/o
2-4 days after secondary exposure to a
granuloma formation
heterologous protein (Classic Serum Sickness) or a
Severe headaches, altered mental fxn, focal neurologic
nonprotein drug such as penicillin or sulfa (Serum
defects
Sickness-Like Reaction)
Systemic sx generally absent
Most manifestations NOT due to vasculitis
Devastating neuro abnormalities depend on extent of vessel
involvement Occasionally, typical cutaneous venulitis (may progress
rarely to systemic vasculitis)
Diagnosis: characteristic vessel abnormalities on angiography +
Vasculitis Associated with Other Underlying Primary
confirmation by biopsy of brain parenchyma & leptomeninges
Diseases
Differential dx: infection, atherosclerosis, emboli, CT disease,
sarcoidosis, malignancy, vasospasm, drug-associated causes Infections may directly trigger an inflam. vasculitic
Poor prognosis process
Glucocorticoid therapy w/ or w/o cyclophosphamide Rickettsias - vasculitis due to invasion &
sustained clinical remissions in small # of px proliferation in endothelial cells of small blood
vessels
COGAN’S SYNDROME
Interstitial keratitis + vestibuloauditory sx
Systemic fungal diseases (e.g. histoplasmosis) –
inflam. response around blood vessels may mimic
May be assoc. w/ systemic vasculitis, particularly aortitis w/ primary vasculitic process
aortic valve involvement
Other infxns (e.g. subacute bacterial
Glucocorticoids: mainstay of treatment endocarditis, EBV, HIV) – leukocytoclastic
Initiate treatment ASAP after onset of hearing loss to improve vasculitis predominantly involving skin w/
outcome occasional involvement of other organ systems