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Actas Dermosifiliogr. 2012;xxx(xx):xxx---xxx

REVIEW

Cutaneous Vasculitis�

A. Pulido-Pérez, J.A. Avilés-Izquierdo, R. Suárez-Fernández∗

Servicio de Dermatología, Hospital General Universitario Gregorio Maranón, Madrid, Spain

Received 14 February 2011; accepted 19 June 2011

KEYWORDSVasculitis;Purpura;Skin biopsy

Abstract Vasculitis is a term that refers to damage and inflammation of the walls of bloodvessels of any size. The classification of types of cutaneous vasculitis continues to be a chal-lenge, probably because of our lack of understanding of the etiology and pathogenesis of thiscondition. Changes in the vessel wall will be visible on microscopy and will enable the differ-ent clinical forms to be distinguished according to the caliber of affected vessels, the type ofcell that predominates in the inflammatory infiltrate, or the presence of such key findings asextravascular granulomas. Skin manifestations (macules, papules, nodules, livedo reticularis,etc.) correlate with the size of the vessel affected. The prognosis in cases of vasculitis withskin involvement will be determined by the presence or absence of extracutaneous disease.Systemic vasculitis shows a predilection for certain organs, such as the kidney or lung. Theintroduction of immunosuppressant drug treatments has led to evident improvement in survivalrates for patients with vasculitis. This review covers practical aspects of the pathophysiol-ogy, histopathology, treatment, and differential diagnosis of the main clinical presentations ofvasculitis with cutaneous involvement.© 2011 Elsevier España, S.L. and AEDV. All rights reserved.

PALABRAS CLAVEVasculitis;Púrpura;Biopsia cutánea

Vasculitis cutáneas

Resumen El término vasculitis define el dano e inflamación de las paredes vasculares,con independencia del calibre del vaso afectado. Clasificar las vasculitis con afectacióncutánea constituye un reto aún no superado, como consecuencia, probablemente, de lafalta de conocimiento sobre su etiopatogenia. En la microscopía deben encontrarse datos

vascular, diferenciándose unos cuadros de otros por el calibre

de afectación de la pared del vaso afectado, el tipo celular predominante en el infiltrado inflamatorio o la presen-cia de hallazgos característicos, como los granulomas extravasculares. En la clínica existeuna correlación entre los hallazgos cutáneos (máculas, pápulas, nódulos, livedo reticular. . .)y el calibre del vaso afectado. El pronóstico de las vasculitis con afectación cutánea vienedeterminado por la presencia o no de compromiso extracutáneo, de forma que las vasculitis

� Please cite this article as: Pulido-Pérez A, et al. Vasculitis cutáneas. Actas Dermosifiliogr. 2012;103:179---91.∗ Corresponding author.

E-mail address: ricardosuarezfernandez@gmail.com (R. Suárez-Fernández).

1578-2190/$ – see front matter © 2011 Elsevier España, S.L. and AEDV. All rights reserved.

ADENGL-444; No. of Pages 13

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sistémicas muestran especial predilección por órganos como el rinón o el pulmón. No obstante,tras la introducción de los fármacos inmunosupresores la supervivencia de estos pacientes haexperimentado un cambio ostensible. En este artículo se revisan de forma práctica los aspectosrelacionados con la fisiopatología, histopatología, tratamiento y diagnóstico diferencial de losprincipales cuadros vasculíticos con afectación cutánea.

. y AEDV. Todos los derechos reservados.

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Table 1 Classification of Vasculitides.

1. Small vessel vasculitis1.1. Neutrophilic vasculitides (mediated by immune

complexes)A) Cutaneous leukocytoclastic vasculitis or hypersensitivity

vasculitisB) Henoch---Schönlein purpuraC) Urticarial vasculitisD) Erythema elevatum diutinumE) Acute hemorrhagic edema of infancy

1.2. Eosinophilic vasculitidesA) Hypereosinophilic syndromeB) Vasculitis associated with connective tissue disease

1.3. Lymphocytic vasculitidesA) Pityriasis lichenoides et varioliformis acutaB) Perniosis

2. Small to medium-sized vessels2.1. Neutrophilic vasculitides2.1.1. Mediated by immune complexesA) Cryoglobulinemic vasculitisB) Vasculitis associated with connective tissue diseaseC) Hypocomplementemic form of urticarial vasculitisD) Septic vasculitis

2.1.2. Mediated by antineutrophil cytoplasmic antibodies(ANCA)

A) Microscopic polyangiitisB) Wegener granulomatosisC) Churg---Strauss purpuraD) Drug-induced ANCA-positive vasculitis

2.2. Lymphocytic vasculitidesA) Degos diseaseB) Viral and rickettsial infectionsC) Vasculitis associated with connective tissue disease

3. Medium to large vessels3.1. Neutrophilic vasculitidesA) Polyarteritis nodosa (classic and cutaneous)B) Nodular vasculitis or erythema induratum of Bazin

3.2. Granulomatous vasculitidesA) Giant cell arteritisB) Takayasu arteritis

© 2011 Elsevier España, S.L

ntroduction

asculitis is a term that refers to the inflammation andecrosis of blood vessels irrespective of the type of ves-el involved (veins, arteries, or both), the etiology of therocess, or the organ affected. The condition can be idio-athic or secondary to infection, drugs, neoplastic disease,r systemic inflammatory disease.

Cutaneous involvement is very common in the differentypes of vasculitis. Skin lesions may be the only manifes-ation of the disorder or they may occur in the context ofystemic disease, but there are no clinical, histologic, or lab-ratory criteria that differentiate with certainty betweenasculitides of the skin and systemic vasculitides.

lassification

he development of a standard classification scheme thatould be acceptable to all the professionals involved in theiagnosis and management of the different types of vasculi-is continues to present a challenge.1,2

The first diagnostic classification, which was drawnp by Zeek et al.3 in 1950, was based on the size ofhe vessel involved and has served as a basis for laterchemes.4

In 1990, the American College of Rheumatology pub-ished a classification scheme based on a set of clinicalnd histopathologic criteria and first used the term hyper-ensitivity vasculitis to designate small vessel cutaneousasculitis.5 In 1994, the Chapel Hill Consensus Confer-nce decided to abandon clinical criteria and standardizehe nomenclature on the basis of histopathologic char-cteristics, grouping the different entities according tohe caliber of the affected vessel.6 However, none ofhese systems have managed to overcome the difficul-ies posed by the overlapping clinical features of differentntities or to deal adequately with the question of themmunopathologic mechanisms involved and their corre-ation with prognosis.7 In an effort to overcome thesehortcomings, Carlson et al.8 proposed a framework for clas-ifying cutaneous vasculitides that includes clinical features,istopathologic criteria, laboratory findings, and the rela-ionship of all of these aspects with the different etiologiesTable 1). Unfortunately, in spite of all this work, theres still no universally accepted classification scheme forasculitides.

tiology and Pathogenesis

he development of the different types of vasculitis isffected by many factors. One of these is the deposition of

3.3. Lymphocytic vasculitidesKawasaki disease

Adapted from Carlson et al.8

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Since the term vasculitis corresponds to a purely histo-logic concept, skin biopsy is essential in the management

Table 2 Histopathologic Criteria in the Diagnosis ofVasculitis.

Histologic definition: inflammatory process affecting thevessel wall

Two criteria must be met:1. Inflammatory infiltrate in the vessel wall2. Damage in the form of fibrin deposition and/orendothelial necrosis

Histopathologic criteria for vasculitisMajor

Neutrophils and karyorrhexis (nuclear dust)Necrosis and fibrin deposition

MinorEndothelial cell swellingHemorrhageThrombosisNecrosisEpidermal vesiclesHistiocytes

ARTICLECutaneous Vasculitis

circulating immune complexes within vessel walls, a mech-anism implicated in hypersensitivity vasculitis. Potentialantigens include drugs and chemicals as well as infectiousagents such as viruses or bacteria. Interacting with thecomplement system, the immune complex deposition stim-ulates the production of chemotactic factors, vasoactiveamines (histamine), and proinflammatory cytokines (inter-leukin [IL] 1, tumor necrosis factor �), which in turn inducethe expression of adhesion molecules on endothelial cells(intracellular adhesion molecule-1, vascular cell adhesionmolecule-1, P-selectin, and E-selectin). The hypothesis isthat this phenomenon promotes the recruitment of neu-trophils, which subsequently degranulate by binding withthe Fc portion of the deposited antibodies and release reac-tive oxygen species, collagenase and elastase, which triggerfibrinoid necrosis of the vessel walls.9

Antineutrophil cytoplasmic antibodies (ANCA) also play arole in the development of vasculitis. ANCA are autoantibod-ies directed primarily against the cytoplasmic protein anti-gens proteinase 3 (PR3) and myeloperoxidase. On indirectimmunofluorescence, these antigens adopt a fluoroscopicpattern that is either perinuclear (p-ANCA), cytoplasmic (c-ANCA), or atypical. The atypical pattern (x-ANCA or a-ANCA)includes features common to both. Although most c-ANCArecognize PR3 and most p-ANCA recognize myeloperoxidase,a percentage of p-ANCA are directed against other compo-nents of primary cytoplasmic granules, such as elastase andcathepsin, or components of the secondary granules, suchas lactoferrin.10 These antibodies activate and trigger thedegranulation of polymorphonuclear cells, promoting theiradhesion to the endothelial cells and the generation of reac-tive oxygen species. However, a positive ANCA test resultshould be interpreted with caution because the presenceof ANCA is also associated with infectious diseases (malariaand human immunodeficiency virus [HIV]), gastrointestinaldiseases (inflammatory bowel disease, autoimmune hepati-tis, primary biliary cirrhosis), and connective tissue diseases(lupus erythematosus, rheumatoid arthritis), and they areoccasionally found in healthy individuals.11

Other factors that may be related to the pathophysiologyof systemic vasculitis are antiendothelial cell antibodies,which are also involved in the development of otherautoimmune connective tissue diseases through direct andindirect action on the vascular endothelium.12 Furthermore,a number of authors have described genetic polymorphismsthat are associated, to a greater or lesser degree, withan increased risk of developing autoimmune diseases. Twoexamples are the case of the CD18 gene, associated withmicroscopic polyangiitis and the Churg---Strauss syndrome,13

and human leukocyte antigens A2, A11, and B35 alleles,associated with Henoch---Schönlein purpura.14

Clinical Characteristics

The different types of vasculitis give rise to a variety of pri-mary lesions: the morphology of these lesions depends onvessel size, the anatomical site affected, and the stage of

development of the lesion.

The most common primary lesions are purpuric mac-ules or papules (palpable purpura) (Fig. 1) secondary to theinvolvement of the small caliber blood vessels of the skin.

Figure 1 Palpable purpura.

ther lesions that may occur include hemorrhagic blisters,ustules, urticarial or annular plaques, and nodules of vary-ng depths that can become ulcerated. The nodules maye associated with livedo reticularis and represent damageo the vessels of the deep dermis and hypodermis. All ofhese lesions are found more frequently on the lower limbs,robably owing to hemodynamic factors. Cutaneous involve-ent in sites other than the lower limbs and the presence of

odular lesions, livedo reticularis, and ulcers are indicationsf vasculitis with systemic involvement. Irrespective of thenderlying process or trigger, any vasculitis of the skin maye accompanied by fever, fatigue, or joint pain.15

istopathology

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igure 2 Leukocytoclastic vasculitis: leukocytoclasis,xtravasation of red blood cells (hematoxylin---eosin, ×10).

f suspected vasculitis (Table 2). Biopsy samples shoulde obtained from fresh, nonulcerated lesions that haveppeared within the preceding 48 hours. The type of ves-el involved (small, medium, or large) and the nature ofhe inflammatory infiltrate (neutrophilic, lymphocytic, orranulomatous) are the main factors taken into account inhe histologic study. Neutrophils are found in most cases ofasculitis related to infections, toxic agents, drugs, food,utoimmune connective tissue diseases, type II and III cryo-lobulins, and disease mediated by immunoglobulin (Ig). The disintegration of these neutrophils (leukocytocla-is) gives rise to nuclear dust (Fig. 2). However, in someypes of vasculitis, the predominant cell type can be lym-hocytes or monocytes. Infiltrate content will depend onhe timing of the skin biopsy because polymorphonucleareukocytes may be replaced by lymphocytes and monocytess the lesions develop. In addition, the presence of theharacteristic features of the different types of vasculitis

hould be assessed, for example the presence of extravas-ular granulomas. Edema and inflammatory infiltration ofhe vessel wall lead to progressive thickening of the wall,

igure 3 Fibrinoid necrosis of the vascular wallhematoxylin---eosin, ×40).

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igure 4 Vesiculobullous form of cutaneous small vesseleukocytoclastic vasculitis.

nd very slight fibrinoid necrosis of the vessel walls willometimes be observed (Fig. 3). Endothelial cells are fre-uently swollen and intravascular thrombi or extravasationf red blood cells into the dermis may occasionally bebserved (Table 2). Marked subepidermal edema sometimesives rise to vesiculobullous skin lesions. Direct immunoflu-rescence examination will provide additional informationn the assessment of vasculitis. It should be performedn lesional skin and will reveal deposition of IgM, fibrino-en, and C3 in recent lesions, IgG in completely developedesions, and fibrinogen and C3 in old lesions. The presence ofgA deposits may be more evident in patients at risk for renalailure.16

We describe below some of the different typesf vasculitis with cutaneous manifestations that con-titute separate entities and briefly summarize theain clinical and histopathologic characteristics of each

ne.

ypes of Vasculitis That Constitute Separatentities

mall Vessel Leukocytoclastic Vasculitis

mall vessel leukocytoclastic vasculitis is the most commonype of vasculitis encountered in dermatologic practice. Itas also been called hypersensitivity vasculitis and cuta-eous necrotizing venulitis. The clinical manifestations are

urpuric lesions and, occasionally, erythematous papules,esicles, blisters, pustules, or annular plaques; lesions areenerally located on the lower limbs or in the depen-ent areas of the body (Fig. 4). This clinical picture may

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Table 3 Etiology of Cutaneous Small Vessel Leukocytoclas-tic Vasculitis.a

Associated with precipitating factors--- Infections

+ Bacterial= Streptococcus= Staphylococcus= Meningococcus= Gonococcus= Pseudomonas= Treponema pallidum= Mycobacterium leprae= Mycobacteriumtuberculosis (?)

+ Viral= Hepatitis B= Influenza= Cytomegalovirus

+ Parasitic= Plasmodium

--- Drugs+ Penicillins+ Tetracyclines+ Sulfonamides+ Erythromycin+ Griseofulvin+ Anti-inflammatory agents

(aspirin, phenacetin)+ Thiazides+ Loop diuretics+ Propylthiouracil+ Penicillamine+ Phenothiazines+ Quinidine

--- Chemical substances+ Insecticides+ Herbicides+ Petroleum derivatives

Associated with chronic persistent disorders--- Autoimmune connective tissue diseases

+ Systemic lupuserythematosus

+ Rheumatoid arthritis+ Sjögren syndrome

--- Inflammatory bowel diseases+ Ulcerative colitis+ Crohn disease

--- Mixedcryoglobulinemia

--- Hypergammaglobulinemicpurpura ofWaldenström

Associated with neoplasms--- Hematologic

neoplasms--- Solid tumorsIdiopathic or unclear cause

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sometimes be preceded by or associated with extracu-taneous symptoms such as arthralgia, fatigue, fever, oranorexia. While this entity generally affects only the skin,the same kind of skin lesions can occur in other forms ofvasculitis that do have systemic involvement. Histopatho-logical analysis reveals involvement of dermal postcapillaryvenules, with polymorphonuclear infiltration of the vesselwalls and intravascular and extravascular eosinophils.17

The factors associated with the development of smallvessel cutaneous vasculitis are shown in Table 3.18,88 Thespecific origin of the condition is never determined in upto 50% of patients. Some of these cases are associated withthe presence of ANCA, and particularly antimyeloperoxidaseor p-ANCA, usually in association with the administration ofdrugs such as hydralazine or propylthiouracil.19

Any viral, bacterial, parasitic, or fungal infection cancause cutaneous vasculitis. The pathogenesis of the diseaseprobably involves a combination of the following pathophys-iological mechanisms: the formation of immune complexes(hepatitis B or C virus, or HIV), direct endothelial damage(cytomegalovirus), direct activation of the complement sys-tem (Candida species), or the formation of autoantibodies.20

Paraneoplastic vasculitides, which are mainly associatedwith hematologic neoplasms, may be the result of directinvasion of the vessel wall, the formation of immune com-plexes, or direct stimulation of cellular immunity by tumorantigens.21

Cutaneous vasculitis can occur in the context of anumber of different inflammatory autoimmune diseases,including systemic lupus erythematosus,22,23 rheumatoidarthritis,24 Sjögren syndrome,25 as well as inflammatorybowel disease.26

Finally, there is a group of cutaneous vasculitides sec-ondary to contact with chemicals (insecticides, petroleumderivatives, or topical drugs27) and plant or animalsubstances, or associated with eating certain foods oradditives.28

Henoch---Schönlein Purpura

Henoch---Schönlein purpura, also known as anaphylactoidpurpura and purpura rheumatica, is the most common sub-type of vasculitis in childhood, with peak incidence at 7years of age. While the condition affects both sexes equallyin childhood, there is a slight male preponderance in adults.Although in some cases this condition occurs after a strep-tococcal infection of the upper airways, other factors havealso been implicated in its pathogenesis, including otherbacteria (Staphylococcus aureus, Campylobacter jejuni,Mycoplasma pneumoniae29), certain viruses (hepatitis A andB, adenovirus, coxsackie virus, parvovirus B1930), parasites(Toxocara canis31), drugs, vaccines, and even insect bites.32

IgA appears to play a key role in the pathogenesis of thisentity, as evidenced by the presence of IgA immune com-plexes in dermal vessel walls and the glomerular mesangium.Specifically, it appears that aberrant glycosylation of IgA1determines its affinity for forming circulating immune com-

plexes and depositing them in these areas.33

Clinically, Henoch---Schönlein purpura is characterized bythe presence of signs and symptoms affecting the skin,gastrointestinal system, joints, and kidneys. Skin lesions

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igure 5 The presence of lesions on the buttocks is commonn Henoch---Schönlein purpura.

nitially appear as macules or papules with an urticarialppearance, which subsequently progress to inflammatorynd purpuric papules. Other, less common presentationsnclude vesicles, blisters, and focal areas of necrosis. Lesionsre usually distributed symmetrically across both lowerimbs and buttocks (Fig. 5), although in some cases theyay extend up to the trunk or as far as the arms. Gastroin-

estinal or musculoskeletal involvement is observed in up to5% of patients. In such cases, the manifestations includeausea, vomiting, abdominal pain, gastrointestinal bleed-ng, and arthritis of large joints (for example, the ankles andnees).34,35 Leg edema is not uncommon. Renal involvementccurs in up to 50% of cases and is expressed as hematuriamacroscopic or microscopic), proteinuria, and nephroticr nephritic syndrome. Nephropathy progresses to termi-al renal failure in between 1% and 3% of these patients.rchitis, intussusception, pancreatitis, uveitis, neurologicomplications, and pulmonary hemorrhage have also beeneported.36

Histopathological findings with conventional stainsemonstrate the presence of a leukocytoclastic vasculitisf the small blood vessels in the dermis. If the skin biopsys recent (under 48 h), IgA deposits (usually IgA1) can bebserved in the vessel walls.

There are no laboratory test findings characteristic orathognomonic of the disease, although the concentrationf acute-phase reactants is usually elevated. An increasen circulating polyclonal IgA is observed in 25% to 50% ofases.

Diagnosis is achieved by correlating clinical andistopathological findings, and special consideration shoulde given to the findings of the direct immunofluorescencetudy. However, it should never be forgotten that a diagno-is of Henoch---Schönlein vasculitis is not synonymous withgA mediated vasculitis.

rticarial Vasculitis

rticarial vasculitis is characterized by the presence ofheals that persist for more than 24 h. The condition was

37

nitially called urticariform vasculitis by McDuffie andypocomplementemic vasculitis (although cases were latereported in which circulating complement levels were noteduced).38 The pathogenesis of the hypocomplementemic

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orms has been linked to the presence of anti-C1q antibod-es, a finding that has led some authors to consider that theyhould be included within the spectrum of systemic lupusrythematosus.39,40 The onset of urticarial vasculitis has alsoeen linked to other connective tissue diseases (Sjögrenyndrome41) as well as infections (hepatitis B and infec-ious mononucleosis), drugs,42 IgM and IgA paraproteinemia,erum sickness-like reaction, and certain tumors.43

Clinically, urticarial vasculitis manifests as wheals, whichypically contain purpuric foci at some time during theirevelopment; these lesions are often accompanied byngioedema. The hypocomplementemic form may be asso-iated with systemic symptoms affecting the joints, eyes,ungs, or digestive system. Classically, it has been assumedhat the histopathologic findings would be compatible withmall vessel leukocytoclastic vasculitis of the skin accom-anied by marked edema in the upper dermis. However,ome authors have reported a predominance of neu-rophils in the lesions of the hypocomplementemic forms,hile in the normocomplementemic variants vasculitis is

ymphocytic and accompanied by a variable number ofosinphils.44

rythema Elevatum Diutinum

ythema elevatum diutinum is classified as a neutrophilicermatosis and is characterized by the presence of sym-etrical lesions on the backs of the hands and the

xtensor surfaces of the limbs.45 One of the main factorsnvolved in its pathogenesis is the deposition of circu-ating immune complexes.46 Eythema elevatum diutinumas been associated with infections (group A �-hemolytictreptococcus, HIV, and hepatitis B virus), autoimmune dis-ases (systemic lupus erythematosus, inflammatory bowelisease, rheumatoid arthritis, relapsing polychondritis),lood disorders (myelodysplastic syndrome, myeloprolifera-ive syndromes, multiple myeloma, hairy cell leukemia), andertain solid tumors.47 The clinical presentation includesapules, and violaceous, yellowish, or erythematous plaquesr nodules. Extracutaneous involvement is exceptional,lthough some patients report pain in the joints under-eath skin lesions. Histopathologic findings vary accordingo the timing of the biopsy. Lesions of recent onset dis-lay leukocytoclastic vasculitis of the dermal small vesselsccompanied by perivascular neutrophilic infiltrate of vari-ble intensity. In more developed lesions, the neutrophilsccupy the entire dermis and lymphocytes, histiocytes, andosinophils are also be found. Since erythema diutinum,ike granuloma faciale, is a form of chronic fibrosing leuko-ytoclastic vasculitis, old lesions will display a variableegree of perivascular and dermal fibrosis.48 Extracellularholesterolosis, which refers to the deposition of choles-erol in the extracellular spaces and in the histiocytesf long-standing lesions,49 is now rarely seen because ofhe introduction of dapsone for the treatment of thisondition.

cute hemorrhagic edema of infancy, also known as Finkel-tein disease and Seidlmayer syndrome, is a benign condition

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Cutaneous Vasculitis 7

Figure 7 Predominantly acral purpuric macules: cryoglobu-l

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Figure 6 Bruise-like purpuric macules: acute hemorrhagicedema of infancy.

only observed in infancy. Typically, it develops during thecourse of or after the resolution of urinary or respira-tory tract infection, following the administration of certainvaccines, or during treatment with certain drugs. Likeother immune-mediated forms of vasculitis, it is proba-bly caused by immune complexes that form in responseto an infectious or pharmacologic antigenic stimulus.50 Thecondition is characterized by the sudden appearance ofbruise-like erythmatopurpuric plaques with a nummular orcockade appearance on the face or distal areas of thelimbs (Fig. 6); these lesions may become vesiculobullousor necrotic. Extracutaneous involvement is extremely rare.This type of vasculitis is uncommon in patients over 2years of age. Histopathologic analysis reveals dermal edemain association with small vessel leukocytoclastic vasculi-tis. IgA deposition in the vessel walls is observed in upto one third of cases, leading some authors to considerthat this condition could be a subtype of Henoch---Schönleinpurpura.51 While this is a benign condition that usuallyrequires no treatment, it is essential to rule out pro-cesses such as exudative erythema multiforme, Kawasakidisease, meningococcemia, Sweet syndrome, and even childabuse.

Cryoglobulinemic Vasculitis

Cryoglobulinemic vasculitis affects small and medium-sized

vessels and is caused by the deposition in the vessel wallsof circulating immune complexes formed by cryoglobulins.52

These immunoglobulins precipitate at temperatures below37 ◦C, dissolving again once the temperature rises above

aoo(

inemic vasculitis.

his level. Based on the immunochemical composition of theryoglobulins present we can distinguish 2 types of cryoglob-linemia: monoclonal and mixed. The monoclonal form isssociated with the presence of a monoclonal immunoglob-lin (IgG or IgM) and no rheumatoid factor activity; these IgGnd IgM complexes are classified as type I cryoglobulins. Mostatients with this variant have an underlying hematologicisorder (multiple myeloma, Waldenström macroglobuline-ia, or chronic lymphocytic leukemia), which presents

s purpura, acral cyanosis, ulcers, or livedo reticularis.icroscopy reveals eosinophilic thrombi composed of aeriod-acid-Schiff-positive material that may or may note accompanied by a perivascular inflammatory infiltrateomposed of lymphocytes. In the mixed variant, the cryo-lobulins may comprise either a polyclonal (IgG) and aonoclonal (IgM) component with rheumatoid factor activ-

ty (type II cryoglobulins) or a number of polyclonal IgGnd IgM molecules with rheumatoid factor activity (typeII cryoglobulins).53 The mixed forms are usually associatedith hepatitis C infection, autoimmune diseases such asjögren disease, and lymphoproliferative processes. How-ver, in a not insignificant percentage of patients no causalgent is identified and the condition is called idiopathic orssential mixed cryoglobulinemia. Clinically, cryoglobulemicasculitis is characterized by the presence of predomi-antly acral purpuric lesions (Fig. 7), which are sometimesssociated with ulcers or areas of necrosis. Most patientseport worsening of symptoms with exposure to cold.istopathologic analysis reveals leukocytoclastic vasculitisffecting the small and medium-sized vessels of the der-is and hypodermis. The presence of intravascular hyaline

hrombi is a rare finding, usually observed near ulcer-ted areas. Direct immunofluorescence reveals deposition

f immunoglobulins and C3 in the vessel walls. Otherrgans and tissues commonly affected are the kidneysmembranoproliferative glomerulonephritis), the peripheral

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ervous system, the joints, and, to a lesser degree, theungs.54

Measurement of cryoglobulin levels in serum may giveise to false negatives due to the influence of the ambi-nt temperature on their solubility and the possible declinen such levels during the intercritical period. It should beemembered that the presence of circulating cryoglobulinss not always associated with symptoms. The term cryo-lobulinemic syndrome is only used to describe symptomaticases. A high percentage of patients have elevated plasmaoncentrations of rheumatoid factor and decreased levels ofomplement C4.55

The prognosis in these patients basically depends on thextent of renal involvement, the presence or absence of aoncomitant tumor, or----especially in the mixed forms linkedo hepatitis C virus----progression to a lymphoproliferativerocess.56

eptic Vasculitis

he septic vasculitides are a subgroup of acute vasculitisssociated with septicemia. Patients with acute meningo-occemia develop irregularly shaped purpuric lesions;ndings include a perivascular and interstitial neutrophilic

nflammatory infiltrate, and focal areas of leukocyto-lasis, fibrinoid necrosis, and vessel occlusion.57 Gramtaining reveals the presence of abundant gram-negativeiplococci in endothelial cells and polymorphonucleareukocytes. Immediate treatment with antibiotics is essen-ial, although blood cultures are needed to confirm theiagnosis. The chronic forms of meningococcemia andonococcemia are characterized by a triad of intermit-ent fever, arthralgia, and vesiculopustular or purpurickin lesions. The histopathologic features differ slightlyrom those of the classic forms of hypersensitivity vas-ulitis, and include arteriole involvement, a predominancef neutrophils, and the formation of subepidermal andntraepidermal pustules. Usually, no organisms are visiblen gram staining, although bacteria have been identi-ed in some cases by molecular genetic techniques.58

lood cultures are positive during the febrile phase. Treat-ent with systemic corticosteroids can lead to severe

omplications.59

egener Granulomatosis

egener granulomatosis is a rare disorder characterizedy involvement of the upper and lower airway and theenal glomerulus secondary to the presence of systemicasculitis and focal areas of granulomatous and necroticnflammation. While this disorder affects a wide range ofges, onset usually occurs in patients between 40 and 50ears of age. Its pathogenesis is poorly understood, but theresence of an amplified immune response to a specific anti-enic stimulus could be one of the mechanisms involved.ne of the stimuli suggested as a possible trigger for thisreakdown of immune tolerance is infection with S. aureus.

n addition to the involvement of c-ANCA, there is grow-ng recognition of the role played by T lymphocytes in theathogenesis of this disorder.60 Typically, patients initiallyresent with upper airway symptoms (rhinitis, sinusitis,

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PRESSA. Pulido-Pérez et al.

lceration of the nasal septum) or report nonspecific respi-atory symptoms such as dyspnea or a persistent dry cough.owever, up to 10% of patients may present with hemopty-is or alveolar hemorrhage. Renal involvement is commonnd irreversible glomerular damage is one of the factorshat determines a poorer prognosis. The presence of cuta-eous manifestations is variable and skin lesions are theresenting symptom in under 10% of patients. The most com-on skin lesion is purpura on the lower limbs, although

more specific sign is papulonodular lesions with cen-ral necrosis distributed symmetrically on the trunk andimbs. The second most common finding on examination isucocutaneous ulceration, which usually takes the form of

yperplastic or strawberry-like gingivitis.61 Pertinent labo-atory findings include elevations in white blood cell count,ctivated protein C, and erythrocyte sedimentation rate.n approximately 80% of patients, c-ANCA specific to theR3 antigen are found; the usefulness of PR-3 antigen titerss a predictor of risk of recurrence after treatment is still

matter of debate.62,63 Typically, histopathologic analysiseveals the presence of a triad comprising vasculitis, areasf necrosis, and granulomatous inflammation. The mostommon finding in lesional skin biopsies is a neutrophilicasculitis of the small and medium-sized vessels. A smallumber of patients present with a granulomatous inflam-atory infiltrate composed of macrophages, neutrophils,

nd multinucleated giant cells surrounding areas of necro-is. In some studies, the presence of cutaneous vasculitisorrelated with increased disease activity and progressiono renal involvement.64 The clinical course of the diseases marked by recurrence, observed in up to half of allatients.

icroscopic Polyangiitis

icroscopic polyangiitis, once considered a subtype ofolyarteritis nodosa, is now classified as a separate entity.t is a small and medium-sized vessel vasculitis with sys-emic involvement. The organs most often affected arehe kidneys (79%---90%) with rapidly progressive glomeru-onephritis and the lungs (25%---50%) in the form of pulmonaryemorrhage.65,66 This disorder is usually preceded by arodromal phase characterized by myalgia, arthralgia,ever, and weight loss. Occasionally, patients may presentastrointestinal symptoms or signs of peripheral neuropathy.he cutaneous lesions are indistinguishable from those ofmall vessel cutaneous leukocytoclastic vasculitis. In up to0% patients, p-ANCA are found. Histopathologic analysis ofamples of purpuric skin lesions demonstrates small vesseleukocytoclastic vasculitis, but a direct immunofluores-ence assay does not reveal immune complex deposition.67

number of viruses have been implicated in the etiologynd pathogenesis of this disorder (hepatitis B and C virus),lthough, as in other types of vasculitis, the underlyingausal mechanism is poorly understood.

hurg---Strauss Syndrome

hurg---Strauss syndrome, also known as allergic granulo-atosis, is a type of systemic vasculitis characterized by the

ssociation of persistent severe asthma and eosinophilia in

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9

inflammatory infiltrate predominates, usually extendinginto subcutaneous tissue and giving rise to a microscopicappearance of lobular panniculitis. These neutrophils arelater replaced by a variable number of lymphocytes.Progressive obliteration of vascular lumens is usually an indi-cation of microaneurysms. Laboratory test findings includethe presence of an inflammatory syndrome with an ele-vated erythrocyte sedimentation rate and, occasionally,eosinophilia. ANCA are detected in a small proportion ofpatients (10%---20%), usually distributed in a perinuclearpattern.

A localized form of polyarteritis nodosa exists that pre-dominantly affects the skin. This variant, called cutaneouspolyarteritis nodosa, is a chronic recurrent disorder cha-racterized by the presence of nodular lesions and livedoracemosa particularly on the distal third of the lowerlimbs----symptoms similar to those described for the clas-sic form of the disease. The lesions may spread to otherlimbs and outbreaks are sometimes accompanied by myal-gia, fatigue, edema, and fever.

Diagnosis

Once the diagnosis has been confirmed by skin biopsyfindings, the extent of disease should be assessed. Thefirst step is to obtain a complete medical history andperform a thorough physical examination, paying particularattention to the heart, joints, and respiratory, digestive,and nervous systems. Blood analysis and urine sediment,electrocardiogram, and a chest radiograph should beobtained. Etiology is established by correlating clinicalsigns and laboratory findings specific to or suggestive ofparticular entities. Therefore, in cases of recurrence orwhen systemic involvement is likely, the workup should beexpanded to identify the possible presence in blood of antin-uclear antibodies, ANCA, rheumatoid factor, cryoglobulins,total complement and its fractions, and antistreptococcalantibodies; immunoelectrophoresis of proteins should alsobe performed. In selected cases, additional diagnosticprocedures may be required to determine the involvementof specific organs or tissue (for example, renal or nerve

ARTICLECutaneous Vasculitis

peripheral blood. This disease predominantly affects thoseaged between 30 and 50 years and affects both sexesequally. From onset in adults, respiratory symptoms rangefrom allergic rhinitis, nasal polyposis, and pansinusitis tocorticosteroid-dependent asthma. Response to conventionalasthma treatments is usually poor. Triggering factors includecertain vaccinations, desensitization processes, and abruptwithdrawal of corticosteroid treatment. There is still noconsensus on the possible role in this setting of leukotrienereceptor antagonist therapy or monoclonal anti-IgE anti-bodies such as omalizumab.68,69 Churg---Strauss syndromeevolves in several clinical stages: the first involves respi-ratory symptoms and peripheral eosinophilia; and in thesecond, disease affects the lungs and heart as well asthe digestive, musculoskeletal, and nervous systems. Skininvolvement can occur at onset or, in about 50% of patients,develop at a later stage. The most common cutaneous man-ifestations are purpuric macules or papules on the lowerlimbs. Another common finding in these patients is the pres-ence of intact nodules (which may progress to ulceration)on the scalp and the distal areas of the limbs. Cases havealso been reported in which the predominant cutaneousmanifestations were livedo racemosa, urticarial lesions,or vesiculopustular lesions.70 Pathologic examination canreveal, although not often simultaneously, 3 character-istic features: small and medium vessel leukocytoclasticvasculitis, tissue eosinophilia, and an extravascular granulo-matous inflammatory infiltrate composed of a large numberof eosinophils and their degradation products (red gran-ulomas). Blood analysis shows intense eosinophilia, whichis accompanied by increased IgE during flares. As many ashalf of all patients test positive for p-ANCA, but c-ANCA isfound in only 10% to 20%. In a study by Sable-Fourtassouand colleagues,71 the presence of ANCA correlated with ahigher probability of finding evidence of vasculitis in thehistopathologic study.

Traditionally, the prognosis for patients withChurg---Strauss vasculitis was poor: overall survival wasless than 1 year and the leading cause of death washeart failure. Today, as a result of prompt treatment withcorticosteroid and immunosuppressive therapy, prolongedremission can be achieved in most cases.72

Polyarteritis Nodosa

Polyarteritis nodosa is a vasculitis that affects small andmedium-sized arteries, usually resulting in damage to mul-tiple organs. Incidence is highest between 40 and 60 yearsof age and is related to vaccinations or infection with hep-atitis B,73 hepatitis C, HIV, or parvovirus B19.74 Clinicalsigns vary depending on the organ or tissue affected, butthis entity has a predisposition for the peripheral nervoussystem (polyneuritis), the digestive system (gastrointesti-nal bleeding), and the renal vasculature (hypertension andrenal infarction). Cutaneous symptoms, which may indi-cate disease onset, include purpuric nodules that tend toulcerate, livedo reticularis, and necrotic lesions (Fig. 8).

Histopathologic findings in lesional skin can vary owing tosegmental damage to the vascular wall. Typically, the smallvessels of the dermis and arterioles located in the subcuta-neous tissue are affected. In the early stages, a neutrophilic

Figure 8 Nodules associated with livedo reticularis: cuta-neous polyarteritis nodosa.

ARTICLE IN PRESS+Model

10 A. Pulido-Pérez et al.

Small vessel leukocytoclastic vasculitis in a biopsy of lesional skin

Medical history with particular focus on drugs, infections, environmentalagents, and systemic symptoms such as abdominal pain,

joint pain, headache, dyspnea, etc.

Corticosteroid-dependent asthma,

allergic rhinitis

In all patients: chest radiograph, urinary sediment, and blood workup including kidney function and hemostasis

p-ANCA

c-ANCA

Intense tissue eosinophilia orextravascular red granulomas

Urticarial rash?

Nodular lesions?

Low complementlevels, anti-

double-strandedDNA antibodies

Blood analysis, protein profile,urine analysis,occult blood in feces,

blood pressure

Children up to2 years of age

Children over2 years of age

AdultsYes No

ANCA+Wegener granulomatosis

Microscopicpolyangiitis

Churg-Strauss syndrome

Cutaneousleukocytoclastic vasculitis

Cutaneous polyarteritisnodosa

Normocomplementemicor hypocomplementemic

urticarial vasculitis

Acute hemorrhagic edema of infancy

Henoch-Schönleinpurpura

IgA paraproteinemia

Cryoglobulins

IgA deposition ondirect

immunofluorescenceassay

Cryoglobulinemicvasculitis

In cases of recurrence and when systemic disease is suspected: antinuclear antibodies, antineutrophil cytoplasmic antibodies,cryoglobulins, antistreptococcal antibody titers, rheumatoid factor, protein profile, total complement and complement fractions

rithm

b(

D

Tacipma(aoadpcvpaht

ucnct

T

Ifiu

lldacd

b

Figure 9 Diagnostic algo

iopsy, bone marrow aspiration, or selective arteriography)Fig. 9).75---77

ifferential Diagnosis

he possible implication of nonvasculitic processes mustlso be taken into account when investigating the possibleause of mucocutaneous purpura. Capillary fragility is seenn a large proportion of elderly or corticosteroid-dependentatients and in individuals with vitamin C deficiency78 or pri-ary systemic amyloidosis.79 The pigmented purpuras are

group of benign dematoses, usually of unknown etiologySchamberg disease, lichen aureus, eczematid-like purpura,nd purpura annularis telangiectodes or Majocchi disease)r associated with chronic venous insufficiency (Favre---Chaixngiodermatitis, purpuric dermatitis, and purpuric lichenoidermatitis of Gougerot and Blum).80 The possibility of pur-ura having a primarily thrombotic origin must also beonsidered in the differential diagnosis of the types ofasculitis. For example, thrombosis is involved in antiphos-

holipid syndrome, disseminated intravascular coagulation,nd C and S protein deficiencies. However, in patients whoave undergone endovascular procedures, are polytrauma-ized or have cardioembolic disease, the presence of an

sn1i

for cutaneous vasculitis.

nderlying embolic process should be suspected.81,82 Otheronditions that simulate vasculitis through diverse mecha-isms that cause vascular occlusion include calciphylaxis,holesterol embolism, hyperoxaluria, and hyperhomocys-einemia, among others.

reatment

f there are known predisposing or precipitating factors, therst concern of treatment should be to eliminate possiblenderlying causes.

With respect to the symptomatic treatment of skinesions, we recommend bed rest with elevation of the lowerimbs and treatment with nonsteroidal anti-inflammatoryrugs (as long as these are not the cause of the symptoms) orntihistamines. Good results have also been achieved witholchicine83 at a dose of 0.5 mg/8 h and/or dapsone84 at aose of 50---200 mg/24 h.

In cases of severe cutaneous vasculitis characterizedy large necrotic or ulcerated areas, treatment with

ystemic corticosteroids is necessary; for example, pred-isone in a regimen starting at a dose of 0.5 mg to

mg/kg/d and gradually tapering over 4---6 weeks. If clin-cal relapse occurs when the dose is being reduced,

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corticosteroid-sparing immunosuppressive agents may beprescribed: for example, azathioprine (50---100 mg/d) ormethotrexate (10---25 mg/wk).85

If there is systemic involvement, initial treatment shouldinclude high-dose corticosteroids and/or oral or intravenouscyclophosphamide pulse therapy until remission of symp-toms is achieved. Treatment should be prescribed on acase-by-case basis taking into account the symptoms orentity being treated, the patient’s renal status, and thespecific contraindications that apply in each case.86 Onceremission is achieved, a maintenance regimen can beinstituted with azathioprine, mycophenolate mofetil, ormethotrexate. Intravenous immunoglobulin or plasmaphere-sis can be useful in selected cases. Drugs such as infliximaband rituximab have shown promising results in the treatmentof systemic vasculitis refractory to conventional therapies.87

Conflicts of Interest

The authors declare that they have no conflicts of interest.

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