J Cutan Pathol 2003: 30: 161^173 Copyright # Blackwell Munksgaard 2 0 03

Blackwell Munksgaard . Printed in Denmark

Journal of
Cutaneous Pathology
ISSN 0303-6987

Cutaneous vasculitis: a review

As the skin is commonly involved in systemic vasculitic disorders as well as A. Neil Crowson1, Martin C. Mihm Jr2
those hypersensitivity states whose expression is largely skin-confined, and Cynthia M. Magro 3
cutaneous vasculitic lesions offer a window to diagnosis and a ready source 1
Dermatology and Pathology,University of
of accessible tissue for biopsy. In this review, we discuss the pathologic Oklahoma and,Regional Medical Laboratory,
manifestations of chronic vasculitic syndromes such as granuloma faciale St. John Medical Center,Tulsa,OK,
2
and erythema elevatum diutinum; IgA-associated vasculitis including Massachusetts General Hospital and Harvard
Medical School,Boston,MA,USA
Henoch-Schonlein purpura; vasculitis seen in the setting of 3
Department of Pathology
cryoglobulinemia and hypergammaglobulinemia of Waldenstrom, Ohio State University,Columbus,OH, USA
hereditary deficiencies of complement, and IgA deficiency; those
leukocytoclastic vasculitides resulting from hypersensitivity reactions to
drug, chemical and foodstuff ingestion; and those vasculitides seen in
patients with systemic diseases such as polyarteritis nodosa, rheumatoid
arthritis, mixed connective tissue disease, systemic lupus erythematosus, A.N.Crowson,MD,Regional Medical Laboratory,St. John
Sjogren's syndrome, relapsing polychondritis, Behcet's disease,Wegener's Medical Center,1923 S.Utica,Tulsa,OK 74114,USA
granulomatosis, and allergic granulomatosis of Churg and Strauss. Tel: 918-744-2553
Fax: 918-744-3327
e-mail: [email protected]
Crowson AN, MihmJr MC, Magro CM. Cutaneous vasculitis: a review
JCutan Pathol 2003; 30: 161^173. # Blackwell Munksgaard 2003. Accepted September 25, 2002

Systemic vasculitides constitute a significant diagnostic ferative disease. Identification of the type and calibre
challenge in the inpatient and ambulatory care set- of vessels involved and the pattern of inflammation is
tings. Accurate diagnosis requires a careful integration integral to isolating the etiology.5 A vasculitis confined
of clinical findings with the results of serologic, patho- to capillaries and post capillary venules of the super-
logic and diagnostic imaging studies. The skin is com- ficial plexus is typical for LCV related to ingestion or
monly involved in vasculitic disorders reflecting exposure to drugs, chemicals, foodstuffs and low-
systemic disease states as well as inthe context of hyper- grade infection.6 Neutrophilic and/or lymphocytic
sensitivity disorders in which disease expression is lar- infiltrates with mural necrosis and thrombosis of capil-
gely confined to the skin. The skin therefore offers a laries and venules throughout the sampled dermis is
window to diagnosis and affords a ready source of prototypically seen in cases of acute and chronic septic
accessible tissue for biopsy. With respect to disease vasculitis, systemic vasculitic syndromes and con-
mechanisms, the skin manifests a spectrum of vasculi- nective tissue disease (CTD).Vasculitis confined to the
tides that reflect injury by circulating immune com- subcutaneous fat may be observed in benign cutaneous
plexes, antiendothelial cell antibodies, and cell polyarteritis nodosa (PAN) and in superficial migra-
mediated immunity (CMI). Arthus type III reactions tory thrombophlebitis, the latter a manifestation of
occur when antigencomplexedto IgG or IgM activates certain systemic diseases such as BD, Buerger's disease,
the direct complement cascade sequence; a leuko- underlying malignancy and lupus anticoagulant. The
cytoclastic vasculitis (LCV) is the hallmark.1^4 The vasculitides are broadly classified inTable1.7
type II immune mechanism is operative when anti-
bodies directed against endothelial antigenic targets
such as in patients with systemic lupus erythematosus Leukocytoclastic vasculitis
(SLE), rheumatoid arthritis (RA), dermatomyositis, The classification of LCV involving small vessels in the
scleroderma and Behcet's disease (BD) generate what skin is broad. It encompasses serum sickness,6 chronic
is typically a pauci-inflammatory thrombogenic vas- vascultic syndromes such as granuloma faciale and
culopathy and/or a lymphocytic vasculitis. A type IV erythema elevatum diutinum,8^13 IgA-associated
(CMI) immune reaction may be the operative vasculitis including Henoch Schonlein purpura
mechanism underlying a granulomatous vasculitis in (HSP) (Fig.1),14^22 abnormal serum proteins including
the setting of Crohn's disease, sarcoidosis, postherpetic cryoglobulinemia and hypergammaglobulinemia
zosteriform eruptions, tuberculosis and lymphoproli- of Waldenstrom,23^28 hereditary deficiencies of

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Crowson et al.
Table 1. Modified Lie classification of vasculitis (after Bonsib, 2001)7
A.Infectious angiitis
Spirochetal
Mycobacterial
Pyogenic bacteria
Rickettsial
Viral
Whipple
B.Noninfectious angiitis
Involving large, medium-sized, and small vessels
Takayasu's arteritis
Granulomatous (giant cell),Cranial (temporal) and
Extracranial giant cell arteritis
Arteritis of rheumatic diseases and spondyloarthropathies
Involving medium-sized and small vessels
Thromboangitis obliterans
Polyarteritis (periarteritis)
Polyarteritis nodosa
Microscopic polyarteritis
Infantile polyarteritis
Kawasaki's arteritis
Pathergic-allergic granulomatosis and angiitis
Wegener's granulomatosis
Churg ^ Strauss syndrome
Necrotizing sacroid granulomatosis
Vasculitis of collagen vascular disease
Rheumatoid arthritis
Seronegative arthropathies
Systemic lupus erythematosis
Dermatomyositis/polymyositis
Relapsing polychondritis
Systemic sclerosis Fig. 1. L e u ko c y to c l a st ic va s c u l it i de s : pa lp able pu r p u r a .
Sjogren's syndrome Leukocytoclastic vasculitides (LCVs) prototypically produce a pattern
Behcet's syndrome of palpable purpura affecting dependent parts, as exemplified in this case
Cogan's syndrome of Henoch-Schonlein purpura. Such a pattern will be manifested in
Rheumatic fever systemic vasculitic processes as well as in those cases of LCV reflecting
Involving small vessels localized cutaneous hypersensitivity states such as in the setting of drug-
Serum sickness induced LCV.
Henoch-Schonlein purpura
Drug-induced
Malignancy-associated related to hepatitis C (19%) or B (5%) infection,34
Retroperitoneal fibrosis while 10% reflected underlying malignancy, and
Lymphocytic vasculitis 9% an underlying CTD.34
Mixed cryoglobulinemia
Hypocomplementemia
Inflammatory bowel disease
Primary biliary cirrhosis Drug-induced leukocytoclastic vasculitis
Goodpasture's syndrome Drug-based etiology is implicated in approximately
Transplant vasculitis
10^24% of cases of LCV. 34,35 The most frequently
implicated agents are propylthiouracil, dilantin, quin-
complement,29^31 IgAdeficiency, 32 drug, chemical and idine, sulfonamides, penicillins, and allopurinol.34,35
foodstuff ingestion,33^35 systemic diseases such as In addition, roughly six per cent of patients with
PAN,36^40 RA,13,41^50 mixed connective tissue chronic cyclic neutropenia receiving granulocyte col-
disease,51 systemic LE,30,52^54 Sjogren's syndrome ony stimulating factor develop vasculitis within one
(SS), relapsing polychondritis,55 BD,56,57 Wegener's week of recovery of their absolute neutrophil count.33
granulomatosis (WG),58^61 allergic granulomatosis of Although some cases of drug-induced LCV manifest a
ChurgandStrauss(AGCS),4,62 inflammatoryboweldis- severe pan-dermal and/or pustular vasculitis, such as
ease (IBD),34 and infection. With respect to the LCVs those associated with calcium channel blockers and
of infection-based etiology, one must consider those to carbamazepine, the typical drug-induced LCV is
include id reactions to non-viable microbial antigens in mild in character and is confined to the superficial
the context of streptococcus, staphylococcus, hepatitis vascular plexus.
B and C, influenza, cytomegalovirus, parvovirus B19
and Mycobacterium sp. infection,20,34,65^78 as well as
septic vasculitides resulting from hematogenous dis- Urticarial vasculitis and serum sickness
semination of viable microbes. In one study from Urticarial vasculitis manifests recurrent episodes of
Spain, where the incidence of hepatitis C seroposi- raised edematous weals with blanchable erythema,
tivity is 0.8%, some 24% of cases of LCV were which typically last from 24 to 72 h and are associated

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 Cutaneous vasculitis
with pigmented residua and episodic arthritis.30,79
This condition results from complement activation
and may reflect a variety of underlying CTDs, most
commonly LE and SS, C1q esterase inhibitor defi-
ciency, underlying malignancy, and circulating
immune complexes containing an antigen that may be
exogenous, such as a drug, or endogenous, such as a
cryoprecipitate.30 The identification of an exogenous
antigen does not exclude the possibility that a given
patient may have a predisposing CTD diathesis. The
syndrome of serum sickness comprises fever, lympha-
denopathy, arthralgia, peripheral neuropathy, cuta-
neous vasculitis, and renal disease, and typically
occurs within10 days of administration of heterologous
serum in vaccines or antithymocyte globulin, intra-
venous and intracoronary streptokinase, drugs such as Fig. 2. Granuloma faciale: acute lesion. Perivascular nodules
predominated by neutrophils are seen in the mid dermis; there is a grenz
penicillin, sulfapyridine, sulfonamides, streptomycin, zone of papillary dermal sparing.
thiouracil and hydantoin and, exceptionally, insults
such as mosquito bites.80 Patients may experience pain
at the injection site 3 days before onset of the fully
expressed syndrome. Urticarial vasculitis and serum arthralgia respond dramatically to dapsone and sul-
sickness both prototypically manifest an interstitial phonamides.9,10,12 Early lesions manifest angiocentric
and perivascular neutrophilic infiltrate accompanied neutrophilic infiltrates with leukocytoclasia and only
by slight leukocytoclasia and mild injurious vascular minimal fibrin deposition in the vessels of the upper
alterations, although when large amounts of serum are and mid dermis. Characteristic is a prominent extra-
used vasculitis may be intense. vascular infiltrate of neutrophils and lymphocytes
with a minor population of eosinophils, plasma cells,
or lipid-laden histiocytes, thus the alternate designa-
tion of extracellular cholesterolosis. Older lesions mani-
Chronic cutaneous LCV syndromes fest as a nodular angiocentric eosinophilic fibrous
homogenization of the dermis associated with capil-
Granuloma faciale lary proliferation. One putative antigen source in
Granuloma faciale is a localized craniofacial LCV that EED may derive from bacteria of Streptococcus sp., as is
presents as recurrent brown-red plaques on the fore- suggested by the striking immunoreactivity seen after
head, cheeks, and ears.8 Similar lesions of the intradermal skin testing with streptokinase and strepto-
upper aerodigestive tract are termed eosinophilic dornase. Lesions of EED are also associated with
angiocentric fibrosis.81 Angiocentric mixed nodular underlying IgA myeloma, myelodysplasia and acute
inflammatory infiltrates with leukocytoclasia and myelogenous leukemia11 IBD, relapsing polychon-
mural fibrin deposition involve the mid dermis and dritis, and RA. Other syndromes that combine a LCV
spare the deep, papillary and adventitial dermis and with prominent extravascular neutrophilia include
subcutis (Fig. 2). Mononuclear cells and plasma cells WG, septic vasculitis, IBD, BD, and RA.41,45,56 The
may predominate, imparting a pseudolymphomatous dermal fibrogenesis is postulated to reflect activation
appearance to the more florid examples. Laminated of factor XIIIa-expressing dermal dendrocytes.82
angiocentric fibrosis with diminution in the intensity
of the inflammation typically ensues with advanced
lesional age. In the nasal cavity, this process results in Systemic neutrophilic vasculitic syndromes with
a nodular onion-skin pattern of hyalinization, which cutaneous LCV
produces a distinctive morphology. The principal systemic vasculitic syndromes are
PAN, Kawasaki's disease, mixed cryoglobulinemia, LE,
RA, BD,WG, and AGCS.4,59,60,62,83 All of these systemic
Erythema elevatum diutinum vasculitic syndromes can demonstrate a necrotizing
The symmetrical localization of disease in erythema cutaneous LCV and in some cases cutaneous involve-
elevatum diutinum (EED) is typically to the extensor ment may be their initial manifestation.
surfaces of joints and occasionally the buttocks, and
manifests as papules which progress to larger annular Systemic polyarteritis nodosa (seeTable 2)
lesions. The older lesion is an elevated red, purple, or The two major forms of systemic systemic polyarteritis
brown plaque. The cutaneous manifestations and the nodosa (PAN) are macroscopic PAN (MaPAN) and

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Crowson et al.
Table 2. Clinical differences between polyarteritis nodosa and microscopic
polyangitis
Clinical feature Polyarteritis nodosa Microscopic polyangitis
Microaneurysms by angiography Yes No
Rapidly progressive nephritis No Yes
Pulmonary hemorrhage No Yes
Renovascular hypertension Yes (10^33%) No
Peripheralneuropathy Yes (50^80%) Yes (10^20%)
Positive hepatitis B serology Uncommon No
Positive ANCA serology Rare Frequent
Relapses Rare Frequent

After Jennette et al. 2001.84

microscopic PAN (MiPAN). Some authorities prefer

to designate the latter as `microscopic polyangitis'and
the former as `polyarteritis nodosa' without further
modifiers, terminology that reflects the size of the
blood vessels involved and that is perhaps, in conse-
quence, more appropriate.84 There is also a distinctive
cutaneous vasculitis, benign cutaneous PAN, in which
a morphology resembling the extracutaneous small
artery disease of MaPAN may be present but in which
systemic organ involvement is typically absent.8,36 Fig. 3. Benign cutaneous polyartertitis nodosa. There is an ulcerated
Kawasaki's disease, an acute vasculitic syndrome of nodule on the lower leg of this 42-year-old woman. She has no internal
infancy, is considered a variant of MaPAN. 85 organ disease.

Macroscopic polyarteritis nodosa

Macroscopic PAN is a necrotizing segmental vasculitis
involving vessels ranging from arterioles to medium-
sized arteries, which typically affect men in the 5th
decade of life. Typically, MaPAN manifests as a seg-
mental necrotizing vasculitis in which fibrinoid necro-
sis of the media and destruction of the internal elastic
lamina is accompanied by mural infiltration initially
by neutrophils and later by mononuclear cells. The
result of this vascular insult is intimal fibroblastic pro-
liferation, secondary thrombosis, aneurysmal dilata-
tion and infarction. The reparative response is
characterizedby replacement of the media by granula-
tion and fibrous tissue.The pathology of this segmental
arteriopathy varies with the phase of the process, as
the early and late lesions involve different foci of the
same artery. In any given area not all vessels are
affected, nor are they in the same temporal lesional Fig. 4. Benign cutaneous polyartertertis nodosa.There is a thrombogenic
leukocytoclastic vasculitis affecting an intermediate-sized subcutaneous
phase. Skin manifestations are infrequent and com- artery (same case as Fig. 3).
prise a severe pandermal LCV involving venules that
frequently extend into the subcutis to involve small
arteries and arterioles. A dominant localization to congestion, reddening of the oropharynx and lips,
medium-sized vessels of the subcutis defines the induration of acral parts, desquamation of the toes
histomorphology of benign cutaneous PAN, which is and fingers with palmar erythema, a polymorphous
generally unaccompanied by internal organ disease rash over bony areas, trunk and extremities, and lym-
(Figs. 3 and 4). phadenopathy.85 Five of the aforementioned features
are required to make the diagnosis.The morbidity and
Kawasaki's disease mortality reflects the development of a PAN-like vas-
Kawasaki's disease most commonly affects infants in a culitic syndrome involving coronary, iliac and cerebral
seasonal fashion and manifests as fever, conjunctival arteries. Failure of resultant aneurysmal lesions to

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 Cutaneous vasculitis
regress correlates with longer duration of the acute
febrile phase and an age at onset of more than 2 years.
There is a subacute form that exhibits myocarditis,
arthritis and thrombocytosis. A minority of patients
manifest an arteritis that involves the skin. 86 The
histopathology of the skin rash is not well defined but
includes a psoriasiform dermatitis and an erythema
multiforme-like interface injury pattern. Homology
between microbial antigens and endogenous heat-
shock proteins has been suggested as the possible
pathogenetic basis, whereby possible infective triggers
include viruses such as Epstein^Barr virus and bac-
teria including pseudomonas, streptococcus, staphylo-
coccus, and rickettsia.

Microscopic polyarteritis nodosa (seeTable 2)

Fig. 5. Microscopic polyarteritis. There is a pandermal leukocytoclastic
Skin involvement is frequent in patients with vascultis comprising a neutrophilic infiltrate with fibrinoid necrosis of the
MiPAN,39,40 which manifests as a necrotizing vasculitis vessel wall.
involving capillaries, venules, and arterioles in patients
who often have a focal segmental necrotizing glomeru-
lonephritis. Lung and nasopharyngeal involvement is
common, characterized clinically in the former more often a sequel of chronic hepatitis C (HCV)
instance by hemoptysis as a result of a neutrophilic infection.27,28 The mixed cryoprecipitate comprises
capillaritis, and in the latter by oral ulceration, sinusitis polyclonal IgG with specificity against HCV antigen
and epistaxis. The skin pathology comprises a severe complexed to an IgM rheumatoid factor; HCV par-
pandermal LCV, which differs from that of WG by the ticles form part of a cold insoluble immune complex
absence of extravascular inflammation (Fig. 5). A cross-linked to monoclonal IgM rheumatoid factor
patient who is seropositive for a perinuclear antineutro- produced when HCV binds to B cells through inter-
phil cytoplasmic antibody (pANCA) with myeloper- action between the HCV envelope glycoprotein E2
oxidase specificity and who has a pulmonary/renal and the CD81 receptor.9,87 As well, HCV apparently
vasculitic syndrome almost invariably represents a causes low-grade extranodal non-Hodgkin's lympho-
case of MiPAN.Those patients who have MiPAN with mas of B-cell phenotype.89 Cryoglobulinemia is classi-
cytoplasmic (c)ANCA positivity and a pulmonary/ fied by the composition of the cryoprecipitate. Type I
renal vasculitic syndrome may be difficult to separate cryoglobulinemia reflects the presence of a monoclonal
from WG clinically. This distinction is based on the immunoglobulin without rheumatoid factor activity,
absence microscopically of extravascular inflam- and is usually seen in the setting of lymphoproliferative
mation including in the context of palisading disease.Type IIcryoglobulinemia represents a mixture
granulomata. Immune complexes are generally not of monoclonal and polyclonal immunoglobulins and
implicated in idiopathic PAN, although a PAN-like may be seen in association with CTD, infection and
immune complex-based vasculitis has been reported essential mixed cryoglobulinemia; the polyclonal
with intravenous drug abuse, CTD, and infection by protein is usually IgG while the monoclonal protein is
cytomegalovirus, hepatitis B and Streptococcus sp. typically IgM-eª, which functions as a rheumatoid
factor. In type III cryoglobulinemia, the antiglobulin
is polyclonal including in the context of an antibody
Cryoglobulinemic vasculitis of IgM subtype with rheumatoid factor activity seen
Cryoglobulins, which are normally present in small in similar clinical settings to those of type II cryo-
amounts in serum, may be present in high concentra- globulinemia.Types I, II and III represent 25%, 25%,
tion in the setting of multiple myeloma,Waldenstrom's and 50% of cryoglobulinemic states, respectively.
macroglobulinemia, mycosis fungoides, chronic lym- Patients are most often women in the 4^5th decades of
phocytic leukemia, CTDs such as RA, SLE and SS, life whose course is one of relapses and spontaneous
HSP, and in the setting of infections with pathogens recovery. The most common clinical manifestation is
such as hepatitis B, Epstein^Barr virus, cytomegalo- lower extremity purpura precipitated by cold,
virus, Treponema pallidum, and Mycobacterium leprae, as prolonged standing, trauma, or a reaction to a drug or
well in patients with poststreptococcal glomerulo- infection. Glomerulonephritis, arthralgia, migratory
nephritis. Roughly one-third of cases represent `essen- myalgia and neuropathy may be present. A minority
tial mixed cryoglobulinemia', once attributed to of patients will develop pulmonary vasculitis that
hepatitis B infection24,25,73 but since established to be manifests as dyspnea and hemoptysis. Monoclonal

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Crowson et al.
cryoglobulinemia causes a pauci-inflammatory
thrombogenic vasculopathy leading to tissue infarc-
tion. A necrotizing systemic PAN-like vasculitis char-
acterizes the type II and type III cryoglobulinemias.
Skin biopsies show a severe pandermal LCVextending
to subcutaneous arteries and veins. In addition to
intraluminal and mural fibrin deposition, eosinophilic
globular precipitates are seen in the lumina of the
inflamed vessels. Mononuclear cells predominate in
chronic lesions and some cases exhibit granulomatous
vasculitis. Precipitates of cryoglobulin are easy to dis-
tinguish from fibrin by their intense staining reaction
with periodic acid-Schiff.

Fig. 6. Pustular vasculitis in Henoch-Schonlein purpura. A dermatitis

Pustular vasculitis herpetiformis -like papillary microabscess is accompanied by
leukocytoclastic vascultis.
A neutrophilic vascular reaction in association with a
spongiform pustulation, at times with acrosyringeal or
follicular accentuation, dermatitis herpetiformis
(DH)-like microabscesses, and/or a neutrophilic inter-
face dermatitis, defines the entity of pustular vasculitis
(Figs. 6 and 7), which encompasses the bowel arthritis
dermatosis syndrome,90,91 septic vasculitis, BD,56
acute pustular bacterid,78 IgA-associated vasculitis
(particularly infection-related HSP15,20), LCV in
patients with a psoriasiform diathesis, Reiter's dis-
ease77, following BCG vaccination, and pustular drug
reactions.20 Either a Sweet's-like vascular reaction as
defined by a neutrophilic vascular infiltrate with
leukocytoclasia and hemorrhage but without vascular
fibrin deposition or an LCV may be observed.20 The
presence of a pustular follicular response may lead to a
misdiagnosis of bacterial folliculitis. The latter pattern
has been designated sterile neutrophilic folliculitis
with perifollicular vasculopathy, and is described in Fig. 7. Pustular vasculitis in Henoch-Schonlein purpura: leukocyto-
association with acute pustular bacterid, BD, Reiter's clastic vascultis (same case as Fig. 6).
disease, tuberculids, hepatobiliary disease, IBD,
and CTD.92^94
blockers, and IgA paraproteinemia.20 Most cases of
IgA-associated vasculitis that fulfill American College
IgA-associated vasculitis or Rheumatology criteria for HSP are associated with
The clinical expression of a cutaneous LCVassociated infection in the context of pathogens derived from gut,
with vascular IgA deposition is commonly equated respiratory, or urinary tract mucosa; all are sites of
with HSP, in which an excessive response to mucosal IgA production.19,20 Implicated microbial antigens
pathogens is implicated. However, the diagnosis also include those of Streptococcus sp., Mycoplasma pneumoniae,
requires the presence of extracutaneous involvement yersinia, Salmonella hirshfeldii, Pseudomonas aeruginosa,
of renal, gastrointestinal, or musculoskeletal systems. hepatitis A or C, parvovirus B19, denatured microbes,
Vascular IgA deposits are also seen in non-lesional and streptokinase administered following myocardial
skin of patients with DH, IgA nephropathy, and infarction.19,20 Those patients who develop HSP as a
chronic excessive alcohol intake.20 The differential sequel of infection may have underlying immune dys-
diagnosis of diseases and/or conditions associated with regulation, such as seen in the setting of atopy or RA,
IgA vasculitis (i.e. non-HSP related IgA vasculitis) a small vessel microangiopathy such as diabetic micro-
include underlying IBD, ankylosing spondylitis, SS in angiopathy and/or vascular cofactors including a
the setting of anti-Ro antibodies, RA, prostatic and lupus anticoagulant or anti-Ro antibodies, all of which
bronchogenic carcinoma, hypersensitivity reactions to predispose an individual to the development of
drugs including carbamazepine and calcium channel vasculitis. 20,95 Although the histology varies with

166
 Cutaneous vasculitis
respect to the presence or absence of antecedant infec- Systemic vasculitic syndromes with hybrid patterns
tion, extravascular neutrophilia as characterized by of vascular injury
epidermal pustulation or DH-like microabscesses is Certain CTD and systemic vasculitic syndromes may
seen in most infectious cases, and almost invariably manifest cutaneous lesions having two or more vascu-
the patient has other symptoms of HSP.20 lar reaction patterns. In patients with LE, RA, SS,
relapsing polychondritis, WG, and AGCS, pauci-
Bowel bypass syndrome/bowel arthritis dermatosis syndrome inflammatory thrombogenic vasculopathy, lympho-
An intermittent cutaneous eruption occasionally fol- cytic thrombogenic vasculopathy and vasculitis, LCV,
lows intestinal bypass surgery for morbid obesity or granulomatous vascultis, and pustular vasculitis may
extensive small bowel resection and comprises pur- be seen in concert or in isolation.
puric macules and papules on trunk and extremities
that evolve into necrotizing vesiculo-pustular lesions, Lupus erythematosus
sometimes accompanied by polyarthritis, malaise, and Clinical manifestations of LE range from a skin rash
fever. Originally termed bowel bypass syndrome, it with arthralgia to progressive multisystem organ fail-
is similar to that seen in patients with diverticulosis, ure and death. The diagnosis of SLE is based on the
peptic ulcer disease, and IBD, thus the more fulfillment of four of 11 criteria established by the
appropriate designation bowel arthritis dermatosis American College of Rheumatologists.97 In particular,
syndrome.90,91,94 An LCV may be present, but a one arrives at a diagnosis through the association of
Sweet's-like vascular reaction is prototypic. Skin serological abnormalities with clinical features includ-
biopsies also show papillary dermal edema, which ing a skin rash, arthralgia, arthritis, fever, Raynaud's
may lead to subepidermal vesiculation, epidermal pus- phenomenon, anemia, leukopenia, serositis, nephritis
tulation with variable necrosis and marked superficial and central nervous system disease.98,99 The vascular
dermal neutrophilic infiltrates. Most patients manifest lesions of SLE involve all calibers and types of vessels
demonstrable circulating immune complexes, includ- in all organ systems. The histologic patterns of blood
ing those containing cryoproteins. The principle anti- vessel injury encompass a pauci-inflammatory throm-
genic trigger may be peptidoglycans that derive from bogenic vasculopathy, lymphocytic vasculitis, and
intestinal bacteria, many of which are structurally and neutrophilic vascular reactions including LCV and a
antigenically similar to those of Streptococcus pyogenes. In systemic MaPAN-like vasculitis. A severe pandermal
addition to direct immunofluorescence testing, which vasculitis accompanied by thrombosis and resultant
has shown linear and granular deposits of immuno- infarction is the most common cutaneous manifesta-
globulins and complement along the dermoepidermal tion. The mechanism of vascular injury often reflects
junction (DEJ) and in vessels, one study demonstrated circulating immune complexes comprising immuno-
Escherichia coli antigens in a granular array along the globulin complexed to endogenous antigens such as
DEJ.96 cryoglobulins and nuclear components, while the
mechanisms of thrombosis include antibodies directed
Septic vasculitis at endothelial antigenic targets,100^103 deposition on
Skin biopsies from patients with acute septic vasculitis endothelium of circulating immune complexes that
demonstrate a severe pandermal LCV with neutro- result in endothelial cell injury with activation of the
phil- and bacteria-containing thrombi, extravascular clotting pathway, and other procoagulant factors such
neutrophilia including DH-like microabscesses and as lupus anticoagulant. In SLE, acute endothelial cell
neutrophilic exocytosis, and papillary dermal edema. injury has also been implicated in the evolution of a
The implicated microbial pathogens include meningo- symptom complex mimicking thrombotic thrombo-
coccus,staphylococcus,GroupAstreptococcus,pneumo- cytopenic purpura. The phenomenon of deep blood
coccus, pseudomonas, Vibria vulnificus, rickettsia vessel injury in LE and in other syndromes associated
except C. burnetti and candida.71 Vascular injury results with pro-coagulant states can effect deep vascular
from embolization of organisms, whereby bacterial occlusion, particularly in the lower extremities. The
endotoxins provoke complement activation and tumor result is a livedoid pattern (Fig. 8).
necrosis factor production rendering the endothelium
procoagulant and generating release of tissue factor
which promotesthrombosis. In chronic septic vasculitis Rheumatoid arthritis
the luminal thrombi are paucicellular and it is difficult Rheumatoid arthritis is a chronic inflammatory dis-
to demonstrate organisms within vessels despite the order that results in destruction of joints, articular
presence of immune complexes comprising bacterial cartilage and adjacent structures, with extra-articular
antigenic components and antibody. The prototypic manifestations including subcutaneous and dermal
organisms associated with chronic septic vasculitis are rheumatoid nodules and papules, episcleritis, inter-
meningococcus and gonococcus.68^72 stitial lymphocytic pneumonitis, hypersplenism

167
Crowson et al.

Fig. 9. Rheumatoid vasculitis. A thrombogenic pan-dermal vasculitis is

present.There is both a neutrophilic component (not shown) and a mixed
lymphohistiocytic vasculitis with a granulomatous morphology
comprising aggregated histiocytes and multinucleated giant cells.

by vasculitic alterations. The systemic disorders that

generate this pattern of palisading granulomatous
inflammation with vasculitis include WG, LE, IBD, a
Fig. 8. Livedoid vasculopathy. A reticulated or net-like eruption is seen paraneoplastic syndrome in the setting of malignant
on the lower extremities in patients with deep-seated vascular occlusion
of diverse cause. The color results from the shunting of de-oxygenated lymphoma, and infection with HIV, HCV, and parvo-
blood to the venular bed near the skin surface (photograph courtesy of virus B1944,65 There is a correlation between the NL
Dr George Monks, Oklahoma City, OK).
tissue reaction in the setting of RA and the presence of
antiphospholipid antibodies, similar to the association
and vasculitis.13, 41^50,95,104 Those patients with extra- observed between antiphospholipid antibodies and the
articular disease usually have a positive rheumatoid rheumatoid nodule. 49,95 In those lesions of pyoderma
factor. The skin manifestations of vascular injury gangrenosum in the setting of RA, a dichotomous
include the rheumatoid nodule and papule, palpable tissue reaction with central neutrophil-rich tissue
purpura, recurrent urticaria, superficial ulcers, livedo pathergy and a peripheral non-necrotizing lympho-
reticularis, digital infarcts around the nail fold, seg- cytic vascular reaction is observed. Older vasculitic
mental infarcts of the hands, feet, and legs, erythema lesions may manifest endarteritis obliterans with inti-
nodosum-like nodules, granuloma annulare-like mal fibrosis. Two other cutaneous manifestations of
lesions that occur particularly overlying the elbow and RA are the rash of Still's disease, characterized
metacarpal phalangeal joints, necrobiosis lipoidica histologically by a sparse neutrophilic infiltrate with
(NL)-like lesions, and pyoderma gang- spotty keratinocyte necrosis, and rheumatoid neutro-
renosum.13,41^50,104 Other manifestations of vasculitis philic dermatosis,50 which comprises symmetrical
include visceral and cerebral infarcts and mononeuritis urticarial plaques over joints and extensor surfaces
multiplex.The vasculitis involves all types and calibers from which skin biopsies show dense neutrophilic
of vessels with frequent thrombosis and a variably infiltrates, leukocytoclasia, and intraepidermal and
dense inflammatory infiltrate that may be lympho- DH-like pustulation in the absence of vasculitis.
cytic,granulomatousorneutrophil-predominant(Fig. 9).
When neutrophils predominate, the vasculitic lesions Aphthosis (Behcet's disease)
may resemble either systemic PAN if larger caliber Behcet's disease is a symptom complex of oral and
vessels are affected or LCV if there is involvement of genital ulceration and iritis that has a global distri-
capillaries and venules; a Sweet's-like vascular reac- bution but is preponderant in the Pacific rim and
tion may be seen.The vasculitis may have as its epicen- eastern Mediterranean. Oral ulcers plus any two of
ter a necrotizing suppurative folliculitis92 or there may genital ulcers, skin and eye lesions is diagnostic.56
be large areas of collagen necrobiosis resembling Oral aphthosis that recurs at least three times over a
GA,44 NL44 or chondrodermatitis nodularis helicus 12-month period is essential to the diagnosis. The
(personal observation). Other authors have used the extracutaneous manifestations are categorized as oral
appellations rheumatoid papule and superficial and/or genital aphthae, vasculo-, ocular, entero- or
ulcerating rheumatoid necrobiosis104 to describe the neuro-BD, renal disease, and arthritis. The disease
phenomenon of palisading necrobiosis accompanied may be complicated by aneurysms and by occlusive

168
 Cutaneous vasculitis
large vein and artery disease. The ocular manifesta- MiPAN. The combination of vasculitis and folliculitis
tions include uveitis, hypopyon iritis, optic neuritis is seen in pyoderma gangrenosum, mixed cryoglobuli-
and choroiditis. The intestinal manifestations of nemia, BD, IBD, RA (personal observation) and
entero-BD include diarrhea, constipation, abdominal pyodermatous eosinophilic folliculitis.92,105 Vascular
pain, vomiting, and melena, while neuro-BD com- thrombosis attributable to antibody mediated
prises brain stem dysfunction, meningoencephalitis, endothelial injury, protein C or S deficiency, factor
organic psychiatric symptoms, and mononeuritis mul- XII deficiency, inhibition of plasminogen activator,
tiplex. Renal disease is expressed as asymptomatic and circulating lupus anticoagulant has been
microhematuria and/or proteinuria, while an oligo- described.
arthritis may involve the wrist, elbow, knee, or ankle
joints.56 The skin lesions include erythema nodosum- Wegener's granulomatosis
like nodules, vesicles, pustules, pyoderma gangreno-
sum, Sweet's syndrome, a pustular pathergic tissue Cutaneous lesions of Wegener's granulomatosis include
reaction to needle trauma, superficial migratory subcutaneous nodules, ulcerating lesions producing a
thrombophlebitis, ulceration, infiltrative erythema, `malignant pyoderma' mainly in the head and neck,
acral purpuric papulonodular lesions, and acneiform hemorrhagic bullae, pustules, papules, ulcers, vesicles,
folliculitis.7,56 petechiae, and palpable purpura. LimitedWG encom-
The histopathology of the skin lesions has three main passes pulmonary disease with or without skin or gut
expressions: vascular, extravascular with or without lesions in the absence of upper respiratory tract and
vasculopathy, and acneiform. The cutaneous vasculo- kidney involvement. Superficial limited WG confined
pathy comprises a lymphocytic or granulomatous vas- to the skin or oral mucosa has been described. The
culitis with or without thrombosis, necrosis, or mural cutaneous manifestations of WG encompass collagen
fibrin deposition, a paucicellular thrombogenic vascu- degeneration, extravascular inflammation, and vascu-
lopathy, and a neutrophilic vascular reaction that litis. In cases of WG limited to the skin, upper respira-
involves capillaries as well as arteries and veins of all tory tract, mediastinum and/or retropertitoneum,
calibers. Neutrophilic vasculopathies include an LCV extravascular inflammation without vasculitis may
and a Sweet's-like reaction. With or without blood be seen. The extravascular inflammation includes
vessel injury, one may see extravascular mononuclear suppurative or suppurative and granulomatous inflam-
cell- or neutrophil-predominant inflammation of the mation with pseudoepitheliomatous hyperplasia and
dermis and/or panniculus. A histiocytic panniculitis intraepithelial microabscess formation; palisading
may be seen, while suppurative or mixed suppurative granulomata of Churg Strauss, GA or NL subtypes;
and granulomatous folliculitis characterizes the acnei- and foreign body giant cells with or without extravas-
form lesions.56 Acral purpuric papulonodular lesions cular neutrophilia.The vasculitic lesions involve capil-
show a lymphocytic interface dermatitis with lympho- laries, venules, arterioles, small arteries and veins
cytic exocytosis, dyskeratosis and a perivascular which show necrosis with an angiocentric infiltrate
lymphocytic infiltrate that recapitulates the mucosal ranging from a granulomatous to a neutrophil-
histology;57 the extracutaneous pathology tends to predominant pattern. Any of neutrophilic capillaritis,
mirror that found in the skin. For example, while the LCVor a PAN-like vasculitis may be seen, usually in
centers of oral aphthae manifest a dense neutrophilic concert with extravascular inflammation and collagen
infiltrate with necrosis of the epithelium and con- degeneration. Patients presenting with cutaneous
nective tissue pathergy of the submucosa, the peripheries LCV often have widespread disease whereas those
show dense lymphocytic infiltration of the submucosa, presenting with granulomatous inflammation without
lymphocytic exocytosis and epithelial degeneration; LCV less often have pulmonary and renal manifesta-
genital aphthae have the same appearance. The large tions. Some patients with cutaneous LCV may have a
vessel arteriopathy is an ischemic sequel of a mono- protacted superficial form of WG of skin and upper
nuclear cell vasculitis of the vasa vasorum, while venous respiratory tract, developing lung or kidney involve-
thrombosis may partly reflect hypercoagulability. The ment years later.59,60
renal manifestations include IgA nephropathy, focal
and diffuse proliferative glomerulonephritis, and amy- Allergic granulomatosis of Churg and Strauss
loidosis. The lymphocytic vasculitis recapitulates that Allergic granulomatosis of Churg-Strauss (AGCS) is a
seen with the CTDs, Degos'disease, and paraneoplas- systemic vasculitis in the setting of an atopic diathesis
tic vasculitis. A granulomatous vasculitis may also be comprising allergic rhinitis and/or asthma along with
observed in WG, AGCS, Crohn's disease, sarcoidosis, marked peripheral blood eosinophilia. In some
acquired hypogammaglobulinemia, a post-Herpetic patients vasculitis develops 30 years after the onset of
eruption, paraneoplastic syndromes, RA, hypersensi- asthma, the latter abating with the onset of vasculitis.
tivity to certain infections including syphilis and tuber- The vasculitis closely resembles WG or MiPAN and
culosis, scleroderma, and the late-stage lesions of mainly involves small arteries and veins with a few

169
Crowson et al.
Table 3. Frequency of anti-neutrophil cytoplasmic antibody (ANCA) with specificity
of proteinase 3 or myeloperoxidase in patients with active untreated microscopic
polyarteritis,Wegener's granulomatosis, and Churg ^ Strauss syndrome
Micro-
scopic Wegener's Churg-Strauss
polyangitis granulomatosis syndrome
PR3  ANCA 40% 75% 10%
MPO-ANCA 50% 20% 60%
Negative 10% 5% 30%

After Jennette et al. 2001.84

PR3-ANCA,proteinase 3; MPO-ANCA,myeloperoxidase.

there are morphologic similarities between these three

conditions, which principally affect smaller blood ves-
Fig. 10. Allergic granulomatosis of Chrug and Strauss.The characteristic sels.4,62 The ANCAs are antibodies targeted against
Churg-Strauss granuloma combines stellate necrobiosis with encrustation constituents of neutrophil primary granules and
of degenerating collagen fibers by eosinophil granules, which also distend
an adjacent blood vessel. monocyte lysosomes, seen in approximately 90% of
patients withWG, AGCS and MiPAN; these ANCAs
react with either myeloperoxidase (pANCA) or pro-
cases showing medium-sized vessel disease reminis- teinase-3 of the a-granules (cANCA).106,107 An IgA
cent of MaPAN. Some authors consider AGCS to cANCA is detectable in 10% of HSP cases, as well as
represent PAN or WG in a patient with atopy, but in select cases of IBD, SS, EED and bacterial endocar-
unlikeWG, gastrointestinal disease and heart involve- ditis.22 An atypical pANCA, termed `xANCA', with
ment are common in AGCS, while renal disease and a specificity for a 50-kDa myeloid envelope protein,108
obstructing aneurysmal medium vessel lesions are is seen in patients with IBD, autoimmune hepatitis
rare. Unlike PAN, hepatitis B is not implicated in the and1 sclerosing cholangitis108,109 (see Table 3).
pathogenesis of AGCS; in contrast, drug allergy or
allergy shots may be precipitating events. In WG and Sjogren's syndrome
PAN, vascular immune complex deposition is not Sjogren's syndrome is an autoimmune syndrome with
observed, in contrast to a high percentage of AGCS a lymphocytic CMI reaction directed against the lacri-
cases showing vascular IgE immune complex deposits. mal and/or salivary glands. The sequel include, inter
In the skin, AGCS manifests as a severe LCV that alia, dry eyes and mouth and a 40-fold increased risk
extends to subcuticular vessels. The vasculitis in the of lymphoid malignancy. Antibodies to SSB/La are
lung resembles that of WG or MiPAN with tissue typically seen in cases of SS, except for those examples
eosinophilia, which, in the lung, may produce a picture mediated by viruses such as HIVor HCV; SS may be
cognate to eosinophilic pneumonia. In other organs a 1CTD or a 2 syndrome complicating SLE or RA.
the vasculitis resembles that of MaPAN. A distinctive Vasculitis seen in patients with SS may either be
finding is the palisading granuloma of Churg and lymphocytic or neutrophilic or manifest a hybrid
Strauss (PGCS), which comprises collagen necrobiosis pattern. Cutaneous vasculitis may be associated with
with a palisading histiocytic infiltrate and disintegrat- mononeuritis multiplex or neuroaxial involvement;
ing eosinophils within the necrobiotic zones, the gran- such patients often have anti-Ro antibodies,110 a posi-
ules of which encrust degenerating collagen fibers tive rheumatoid factor, and mixed cryoglobulinemia
(Fig.10). In contrast, neutrophils infiltrate the necro- included in the context of Waldenstrom's macroglobu-
biotic collagen in the PGCS seen in WG, subacute linemia. Young women with recurrent leg purpura
bacteria endocarditis, and hematopoietic malignancy. and polyclonal hyper-g-globulinemia may represent a
The most common cause of death in AGCS is an possible forme fruste of SS termed `hypergammaglo-
eosinophilic cardiomyopathy, albeit only a minority of bulinemia of Waldenstrom', in whom vascular IgA
patients die from coronary or myocardial vasculitis or deposition may be seen.
a restrictive cardiomyopathy resembling Loffler's
eosinophilic endocarditis. Involvement of the skin is
common and characteristically presents as nodules on Conclusion
the scalp and/or extensor surfaces of the arms. Other Systemic vasculitides represent a diagnostic challenge
features of the disease include eosinophilic gastroenter- in the inpatient and ambulatory care settings, with
itis and mononeuritis multiplex. Many patients with accurate diagnosis requiring a careful integration of
AGCS have ANCAs similar to WG and MiPAN and clinical findings with the results of serologic, pathologic

170
 Cutaneous vasculitis
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be cognizant of the limitations of morphology when epidemiological study of hypersensitivity vasculitis versus
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