An Bras Dermatol. 2020;95(3):355---371

Anais Brasileiros de Dermatologia

www.anaisdedermatologia.org.br

REVIEW

Update on vasculitis: an overview and dermatological

clues for clinical and histopathological diagnosis --- ଝ,ଝଝ

Part I

a,∗ a

Thâmara Cristiane Alves Batista Morita , Gabriela Franco S. Trés ,

b a b,c

Roberta Fachini Jardim Criado , Mirian Nacagami Sotto , Paulo Ricardo Criado

a

Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

b

Discipline of Dermatology, Faculdade de Medicina do ABC, Santo André, SP, Brazil

c

Postgraduate Program, Faculdade de Medicina do ABC, Santo André, SP, Brazil

Received 30 March 2019; accepted 19 January 2020

Available online 26 March 2020

Abstract The term vasculitis refers to the inflammation of vessel walls. It may range in severity

KEYWORDS

from a self-limited disorder in one single organ to a life-threatening disease due to multiple

Anti-neutrophil

organ failure. It has many causes, although they result in only a few histological patterns of

cytoplasmic

vascular inflammation. Vessels of any type and in any organ can be affected, a fact that results

antibody-associated

in a broad variety of signs and symptoms. Different vasculitides with indistinguishable clinical

vasculitis;

presentations have quite different prognosis and treatments. This condition presents many

Classification;

challenges to physicians in terms of classification, diagnosis, appropriate laboratory workup, and

Diagnosis;

treatment. Moreover, it compels a careful follow-up. This article reviews the Chapel-Hill 2012

Purpura;

classification, etiology, recent insights in pathophysiology, some important dermatological clues

Systemic vasculitis;

for the diagnosis and summarizes treatment of some of these complex vasculitis syndromes.

Vasculitis;

© 2020 Published by Elsevier Espana,˜ S.L.U. on behalf of Sociedade Brasileira de Dermatologia.

Vasculitis,

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ leukocytoclastic, licenses/by-nc-nd/4.0/).

cutaneous

Abbreviations: AAV, ANCA-Associated Vasculitis; ANCA, Anti-Neutrophil Cytoplasmic Antibodies; BD, Behc¸et’s Disease; c-ANCA,

Cytoplasmic-ANCA; CHCC, Chapel Hill Consensus Conference; CLA, Leukocytoclastic Angiitis; CSVV, Cutaneous Small Vessel Vasculitis; CV,

Cryoglobulinemic Vasculitis; DIF, Direct Immunofluorescent; DIV, Drug-Induced Vasculitis; EGPA, Eosinophilic Granulomatosis with Polyangi-

itis; GCA, Giant Cell Arteritis; GPA, Granulomatosis with Polyangiitis; HBV, Hepatitis B Virus; HCV, Hepatitis C Virus; HLA, Human Leukocyte

Antigen; IgAV, IgA Vasculitis; IgM, Immunoglobulin M; IgG, Immunoglobulin G; KD, Kawasaki Disease; MPA, Microscopic Polyangiitis; MPO,

Myeloperoxidase; NETs, Neutrophil Extracellular Traps; PAN, Polyarteritis Nodosa; pANCA, Perinuclear-ANCA; PR3, Proteinase 3; pSS, Primary

Sjogren’s Syndrome; RF, Rheumatoid Factor; RV, Rheumatoid Vasculitis; SLE, Systemic Lupus Erythematosus; SOCV, Single-Organ Cutaneous

Vasculitis; TAK, Takayasu Arteritis.

ଝ

How to cite this: Morita TCAB, Trés GFS, Criado RFJ, Sotto MN, Criado PR. Update on vasculitis: an overview and dermatological clues

for clinical and histopathological diagnosis --- part I. An Bras Dermatol. 2020;95:352---68.

ଝଝ

Study conducted at the Department of Dermatology, Faculdade de Medicina, Universidade de São Paulo and Department of Dermatology,

Faculdade de Medicina do ABC, Santo André, SP, Brazil. ∗

Corresponding author.

E-mail: [email protected] (T.C. Morita).

https://doi.org/10.1016/j.abd.2020.01.003

0365-0596/© 2020 Published by Elsevier Espana,˜ S.L.U. on behalf of Sociedade Brasileira de Dermatologia. This is an open access article

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

356 Morita TC et al.

Introduction purpura, and pyoderma gangrenosum. In some autoinflam-

matory diseases, it is still unclear whether vasculitis is an

integrated clinical manifestation or represents an additional

Vasculitides encompass a large group of heterogeneous dis-

5

independent disease. We have also included these condi-

eases characterized by inflammatory reaction localized in

tions in a proper sub-classification in table 1.

the vascular wall and perivascular tissues. To the concern of

Generally, the size of vessel involvement correlates with

etiology, it is defined as a complex syndrome because several

clinical morphology on the dermatological exam. Small,

types of vasculitides can be elicited by different stimulus,

predominately superficial vessel involvement results in

although most of them are classified as idiopathic. Both,

urticaria, infiltrated erythema, palpable or non-palpable

venous or arterial vessels can be affected, in a pattern of

purpura, vesiculobullous and/or pustules lesions. Ulcers,

single organ or multisystemic disease. Then, dealing with

nodules, pitted scars, white atrophy, or livedo racemosa are

vasculitides often means to study several distinct pathophys-

associated with arterial-muscular vessel involvement, which

iological mechanisms and a wide clinical spectrum. Often

will be located at dermal-hypodermal interface or within the

several authors rely on the blood vessel caliber to classify

subcutis. In vasculitides that involve small and medium-size

them as small, medium or large-vessel vasculitis. However,

vessels all kind of cutaneous lesions previously described

when it is held alone, this classification fails to recognize

can co-exist in the same patient. Finally, a large number of

diversity within vessels of the same caliber, their special-

ulcers, especially when they are extensive and associated

ized roles in several anatomic areas in response to stimuli,

1,2 with necrosis, which may be consequence of deep-vessel

injury, and repair that determine disease patterns.

arterial involvement, often predict recurrent vasculitis and

Cutaneous vasculitides can range in severity from benign,

6

systemic disease (Fig. 1).

self-limited, short-course skin eruption to life-threatening

The recognition of pathologic changes in a cutaneous

disease with multiple-organ failure. Otherwise, systemic

biopsy enables the identification distinct vasculitis condi-

vasculitis is divided into two main categories: primary vas-

tions and signals the possibility of progression from localized

culitis syndrome and secondary vasculitis syndrome. The

6

cutaneous to systemic vasculitis. Skin biopsy is the gold

first one is caused by unknown etiology inflammation of

standard method for the diagnosis of cutaneous vasculitis,

blood vessels, while the second one is induced by underly-

also allowing differential diagnoses from vasculitis mim-

ing conditions, including connective tissue diseases, cancer,

ics, such as vaso-occlusive conditions and other diseases

infections, immunization, and drug allergy. In the majority

(Table 2).

of cases the cutaneous vasculitides syndromes will show a

neutrophilic small vessel vasculitis, often called Cutaneous

3

Leukocytoclastic Angiitis (CLA).

The aim of this review is to clarify the recent concepts

Clues for vasculitis diagnosis

about the etiology of distinct vasculitides, the classifica-

tion preconized for the Chapel Hill Consensus Conference

The clinicians need to keep in mind that cutaneous vasculi-

(CHCC) and to emphasize the clues on dermatological

tis, particularly Cutaneous Small Vessel Vasculitis (CSVV),

physical and/or histopathological exam that may help

is often the most common presentation of several vasculi-

to suggest a specific group of vasculitis in the clinical

1

practice. tis syndromes. It may occur in 3% of Granulomatosis with

Polyangiitis (GPA), 13% of Microscopic Polyangiitis (MPA),

and 28% of Eosinophilic Granulomatosis with Polyangiitis

7

Classification of vasculitis (EGPA) patients. Some steps are essential in the clinical

practice for accurate assistance to the patients with vas-

Clinicians have found it convenient to use vessel size as culitis: (i) meticulous anamnesis and physical exam; (ii)

the most important feature to distinguish different forms inspection and palpation of the cutaneous and subcutaneous

2

of vasculitides. The CHCC published in 2012 proposed lesions; (iii) a proper cutaneous biopsy is necessary accord-

the unification of new types of vasculitis syndromes and ing to the findings of dermatological exam; (iv) accurate

4

their associated illness (Table 1). However, CHCC is only a propaedeutic and complementary exams must be performed

nomenclature system/nosology and not a classification or a to exclude systemic or internal organ involvement; (v) a

diagnostic system that helps to direct clinical management. work-up including indicated laboratory exams for infectious

Thus, it subdivides vasculitides based on combinations of and parasitic infestations, autoimmune collagen diseases,

features that separate different conditions into definable blood marrow neoplasia and/or organ-solid cancer is useful

4

categories. for the evaluation of its etiology.

Some cutaneous manifestations involving small, medium An important definition about the nosology of vasculitis

1

and/or large vessels can be found not only in the autoim- in the skin was revised by Sunderkötter et al. The authors

mune diseases, but also in the autoinflammatory diseases. emphasized that they can be found in distinct clinical set-

This term was coined to describe an emerging family of tings: (i) a cutaneous component of systemic vasculitides

conditions characterized by episodes of unprovoked inflam- (e.g. cutaneous manifestations of IgA vasculitis), (ii) a skin-

mation due to dysregulation of the innate immune system limited or skin-dominant expression or variant of a systemic

without the primary role of autoreactive T lymphocytes vasculitis (e.g. skin-limited IgA vasculitis), or (iii) a Single-

and/or autoantibodies. Skin involvement in autoinflamma- Organ Cutaneous Vasculitis (SOCV) that differs with regard to

tory diseases generally resembles urticarial vasculitis or may clinical, laboratory, and pathologic features from recognized

have features of neutrophilic dermatoses. Additional skin systemic vasculitis (e.g. nodular vasculitis). SOCV does not

lesions include purpuric exanthema, nonthrombocytopenic develop full systemic vasculitis, while skin-dominant forms

Update on vasculitis 357

Table 1 Classification and definitions of vasculitides adapted from data adopted by the 2012 Chapel Hill Consensus Conference.

Group Nomenclature Definitions Main characteristics

Large vessels Takayasu arteritis Arteritis, often granulomatous, predominantly Although any size can be

vasculitides affecting the aorta and/or its major branches. affected, they involve large

Onset usually in patients younger than 50 arteries more often than

years. other vasculitides. Large

Giant Cell Arteritis Arteritis, often granulomatous, usually arteries are the aorta and

(GCA) affecting the aorta and/or its major branches, its major branches.

with a predilection for the branches of the

carotid and vertebral arteries. It frequently

involves the temporal artery. Onset usually in

patients older than 50 years and often

associated with polymyalgia rheumatica.

Medium vessels Polyarteritis Nodosa Necrotizing arteritis of medium or small Vasculitides predominantly

vasculitides (PAN) vessels without glomerulonephritis or vasculitis affecting medium arteries

in arterioles, capillaries, or venules, and not defined as the main visceral

associated with Antineutrophil Cytoplasmic arteries and their initial

Antibodies (ANCA). branches. Arteries of any

Kawasaki disease Arteritis associated with the mucocutaneous size may be affected.

lymph node syndrome and predominantly Inflammatory aneurisms and

affecting medium and small arteries. Coronary stenosis are common.

arteries are often involved. Usually occurs in

infants and young children.

ANCA-Associated Microscopic Necrotizing vasculitis with few or no immune Necrotizing vasculitis with

Vasculitides (AAV) Polyangiitis (MPA) deposits, predominantly affecting small vessels few or no immune deposits

(i.e., capillaries, venules, or arterioles). (pauci-immune),

Necrotizing arteritis involving small and predominantly affecting

medium arteries may be present. Necrotizing small vessels (i.e.

glomerulonephritis is very common. Pulmonary capillaries, venules,

capillaritis often occurs. arterioles, and small

Granulomatosis with Necrotizing granulomatous inflammation arteries), associated with

a

polyangiitis (GPA) usually involving the upper and lower Myeloperoxidase (MPO)

formerly known as respiratory tract, and necrotizing vasculitis ANCA or Proteinase 3 (PR3)

Wegener’s affecting predominantly small to medium ANCA. Not all patients have

granulomatosis vessels (e.g., capillaries, venules, arterioles, ANCA positivity.

arteries and veins). Necrotizing

glomerulonephritis is common.

Eosinophilic Eosinophil-rich and necrotizing granulomatous

Granulomatosis with inflammation often involving the respiratory

a

Polyangiitis (GEPA) tract, and necrotizing vasculitis predominantly

formerly known as affecting small to medium vessels and

Churg-Strauss associated with asthma and eosinophilia. ANCA

syndrome is more frequent when glomerulonephritis is

present.

Immune complex Anti-Glomerular Vasculitis affecting glomerular capillaries, Vasculitis with moderate to

vasculitides Basement Membrane pulmonary capillaries, or both, with GBM marked vessel wall deposits

a

(Ant-GBM) disease deposition of anti-GBM autoantibodies. Lung of immunoglobulin and/or

formerly known as involvement causes pulmonary hemorrhage, complement components

Goodpasture and renal involvement causes predominantly affecting

syndrome glomerulonephritis with necrosis and small vessels.

crescents. Glomerulonephritis is

Cryoglobulinemic Vasculitis with cryoglobulin immune deposits frequent.

vasculitis affecting small vessels (predominantly

capillaries, venules, or arterioles) and

associated with serum cryoglobulins. Skin,

glomeruli, and peripheral nerves are often involved.

358 Morita TC et al.

Table 1 (Continued)

Group Nomenclature Definitions Main characteristics

a

IgA vasculitis Vasculitis, with IgA1-dominant immune

(formerly known as deposits, affecting small vessels

Henoch-Schonlein (predominantly capillaries, venules, or

purpura) arterioles). Often involves skin and

gastrointestinal tract, and frequently causes

arthritis. Glomerulonephritis indistinguishable

from IgA nephropathy may occur.

Hypocomplementemic Vasculitis accompanied by urticaria and

urticarial vasculitis hypocomplementemia affecting small vessels

(Anti-C1q vasculitis) (i.e., capillaries, venules, or arterioles), and

associated with anti-C1q antibodies.

Glomerulonephritis, arthritis, obstructive

pulmonary disease, and ocular inflammation is

common.

Variable Vessels Behc¸et’s Disease (BD) Vasculitis occurring in patients with BD that Vasculitis that can affect

Vasculitides (VVV) can affect arteries or veins. It is characterized vessels of any size (small,

by recurrent oral and/or genital aphthous medium, and large) and

ulcers accompanied by cutaneous, ocular, type (arteries, veins, and

articular, gastrointestinal, and/or central capillaries) with no

nervous system inflammatory lesions. Small predilection.

vessel vasculitis, thromboangiitis, thrombosis,

arteritis, and arterial aneurysms may occur.

Cogan’s syndrome Vasculitis occurring in patients with Cogan’s

syndrome. Cogan’s syndrome characterized by

ocular inflammatory lesions, including

interstitial keratitis, uveitis, and episcleritis,

and inner ear disease, including sensorineural

hearing loss and vestibular dysfunction.

Vasculitic manifestations may include arteritis

(affecting small, medium, or large arteries),

aortitis, aortic aneurysms, and aortic and

mitral valvulitis

Single Organ Cutaneous Cutaneous small vessel vasculitis Vasculitis in arteries or

Vasculitides (SOV) leukocytoclastic veins of any size in a single

angiitis organ that has no features

that indicate that it is a

limited expression of a

systemic vasculitis. The

involved organ and vessel

type should be included in

the name (e.g., cutaneous

small vessel vasculitis,

testicular arteritis, central

nervous system vasculitis).

Vasculitis distribution may

be unifocal or multifocal

Cutaneous E.g. formerly cutaneous PAN. (diffuse) within an organ.

arteritis Macular arteritis, also called lymphocytic Some patients originally

thrombophilic arteritis. diagnosed as having a

Primary central The diagnosis of primary CNS vasculitis single-organ vasculitis will

nervous system (CNS) requires determining that CNS vasculitis is not develop additional disease

vasculitis a component of a systemic vasculitis (e.g., manifestations that warrant

GCA, BD, MPA, GPA, EGPA), caused by infection redefining the case as one

(e.g., syphilis), or associated with a systemic of the systemic vasculitides

disease (e.g., lupus, sarcoidosis). (e.g., cutaneous arteritis

Isolated aortitis Isolated idiopathic (thoracic later becoming systemic

Others and/or abdominal) aortitis. PAN, etc.)

Update on vasculitis 359

Table 1 (Continued)

Group Nomenclature Definitions Main characteristics

Vasculitides Lupus vasculitis Secondary vasculitis due to systemic lupus Vasculitis that is associated

associated with erythematous. with or that may be

systemic disease Rheumatoid vasculitis Secondary vasculitis due to rheumatoid secondary to a systemic

arthritis. disease. The name should

Sarcoid vasculitis Secondary vasculitis due to systemic have a prefix term

sarcoidosis. specifying the systemic

Relapsing Secondary vasculitis due to multi-organ disease (e.g., rheumatoid

polychondritis relapsing polychondritis. vasculitis, lupus vasculitis,

vasculitis etc.).

Others Example, vasculitis cases reports as a

manifestation of monogenic or polygenic

autoinflammatory syndromes: multifactorial

and polygenic autoinflammatory Behc¸et’s

syndrome (small vessel --- skin, retina; medium

vessel/artery --- DVT, dural sinus, intracranial,

pulmonary artery; large vessel); FMF (small

vessel IgA vasculitis; medium vessel --- PAN);

CAPS (small vessels --- skin, testes, kidney; rare

case reports); HIDS (small vessels --- skin);

TRAPS (small vessels --- skin); PAPA syndrome

(medium vessel --- cerebral artery \ vasculopathy vasculitis); DIRA

\

(CNS-vasculitis vasculopathy), Blau syndrome

(small vessel --- retina; skin large vessel

vasculitis); DADA2 (systemic inflammation,

mild immune deficiency, and vasculopathy

manifested as recurrent stroke or PAN).

Vasculitides Hepatitis C virus E.g., hepatitis C virus-associated Vasculitis that is associated

associated with associated cryoglobulinemic small vessel vasculitis. with a probable specific

probable etiology cryoglobulinemic etiology. The name

vasculitis (diagnosis) should have a

Hepatitis B E.g., hepatitis B virus-associated PAN. prefix term specifying the

virus-associated association (e.g.,

vasculitis hydralazine-associated

Syphilis-associated Secondary vasculitis due to syphilis. microscopic polyangiitis,

vasculitis HBV-associated vasculitis,

Drug-associated E.g., serum sickness-associated immune HCV-associated

immune complex complex vasculitis due drugs. cryoglobulinemic vasculitis,

vasculitis etc.).

Drug-associated E.g., hydralazine-associated microscopic

ANCA-positive polyangiitis, propylthiouracil-ANCA-associated

vasculitis vasculitis.

Cancer-associated Hematologic and solid organ neoplasms, as

vasculitis well as clonal B cell lymphoproliferative

disorders and myelodysplastic syndrome can

be associated with and may cause vasculitis.

Others Small-vessel vasculitis due bowel inflammatory

disease.

Adapted from: Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F et al., 2012 revised international chapel hill consensus

conference nomenclature of vasculitides. Arthritis Rheum. 2013;65(1):1---11 and Peleg H, Ben-Cherit E. Vasculitis in the autoinflammatory

diseases. Curr Opin Rheumatol 2017;29:4---11.

a

New nomenclature: DADA2, Deficiency of Adenosine Deaminase type 2; DIRA, Deficiency of Interleukin-1 Receptor Antagonist; DVT,

Deep Venous Thromboembolism; FMF, Familial Mediterranean Fever; HIDS, Hyper IgD with periodic fever Syndrome; PAPA, Pyogenic

Arthritis, Pyoderma gangrenosum, and Acne; TRAPS, TNF Receptor-Associated Periodic Syndrome.

360 Morita TC et al.

Table 2 Classification of vasculitides according to the vessel size and histopathological findings in biopsy specimens.

Small vessels Neutrophilic Immune-complex mediated Cutaneous leukocytoclastic

vasculitides (DIF positive) angiitis (or hypersensitivity

vasculitis, leukocytoclastic

cutaneous vasculitis or small

vessel cutaneous vasculitis)

IgA vasculitis

Acute infantile hemorrhagic edema

Urticarial vasculitis

Chronic localized fibrosing

vasculitis: erythema elevatum

diutinum, granuloma faciale,

inflammatory pseudo tumors

Incidental vasculitis (DIF negative) Sweet’s syndrome and pustular

Eosinophilic Eosinophilic vasculitis vasculitis of the dorsa of the

Recurrent cutaneous eosinophilic vasculitis hands

Granulomatous Postherpetic eruptions

Lymphomatoid granulomatosis

Lymphocytic Rickettsia and viral infections

Lichenoid dermatosis, some cases, perniosis,

pityriasis lichenoides, graft versus host disease

T cell lymphomas: angiocentric T cell

lymphoma, lymphomatoid papulosis

Rare drug reactions and arthropod bites

Mixed, Neutrophilic Immune-complex mediated Cryoglobulinemic vasculitis due

predominately (DIF positive) hepatitis C virus or

small- and paraproteinemia

medium-vessels Hypocomplementemic

vasculitides urticarial vasculitis syndrome

Connective tissue disease

vasculitis (e.g., lupus,

rheumatoid arthritis, Sjogren’s

syndrome)

ANCA-associated/pauci-immune (DIF Granulomatosis with negative) polyangiitis

Eosinophilic granulomatosis

with polyangiitis

Microscopic polyangiitis

Drug-induced

Lymphocytic Degos disease ANCA positive

Rickettsia and viral infections vasculitis

Collagen tissue disease vasculitis (e.g.,

Sjogren’s syndrome, lupus vasculitis)

Behc¸et’s disease

Miscellaneous/other Septic vasculitis

Behc¸et’s disease

Medium (to large) Neutrophilic Polyarteritis nodosa and cutaneous arteritis

muscular vessels Nodular vasculitis (erythema induratum)

vasculitides Eosinophilic Juvenile temporal arteritis

Granulomatous Giant cell arteritis

Takayasu’s arteritis

Postherpetic eruptions

Update on vasculitis 361

Table 2 (Continued)

Lymphocytic Sneddon’s syndrome

Degos disease

Buerger’s disease (thromboangiitis obliterans)

Superficial thrombophlebitis (Mondor’s disease,

sclerosing lymphangitis)

Kawasaki disease

Macular arteritis/lymphocytic thrombophilic

arteritis

Adapted from Carlson JA, Chen K-R. Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes. Am J Dermatopatol

2006;28(6):486---506.

ANCA, antineutrophil cytoplasmatic antibody; DIF positive, direct immunofluorescence examination of the skin lesions showing vessel

wall immune-complexes and/or complement deposition.

may do it. Then, systemic vasculitides are defined as those ing preceding infectious symptoms, usage of medications,

8---10

one presenting in at least one organ in addition to the skin. vaccines and comorbidities. We summarized in table 3

In most cases of CSVV, although nonspecific signs or the red flag symptoms and/or signs, complementary lab-

symptoms of systemic inflammatory reactions, such as oratory exams and etiologic factors to workup systemic

11,12

leukocytosis, raised C-reactive protein, or arthralgia may vasculitis.

1

occur, significant systemic manifestations are unlikely. Some clues may help to recognize both the size of the

After a thorough history, review of systems and physical vessel involved and the suspect diagnosis. Arterial hyper-

examination, a systematic and targeted laboratory workup tension may suggest medium-vessel vasculitis of the renal

should proceed to confirm SOCV. Although no standard pro- vasculature, as seen in systemic PAN. Cutaneous lesions

tocol for this workup exists, screening tests should aim as palpable purpura (the most frequent type of lesion

at elucidating the underlying cause and extent of organ in CSVV), nonpalpable purpura, pinpoint papules, vesicle,

involvement and should be guided by clinical signs and pustules, splinter hemorrhages, and urticaria are often

symptoms. Special attention should be paid to any evi- suggestive of small vessel vasculitis. Vesicles and bullous

dence of systemic vasculitis, such as fever, weight loss, and lesions often arise on purpuric macules. A subsequent hem-

other constitutional symptoms; arthritis; myalgias; abdom- orrhagic pattern is observed, and these lesions may produce

inal pain, melena, or hematochezia; cough, hemoptysis, ulcerations in the skin. Nonpalpable purpura on the lower

or dyspnea; hematuria or frothy urine; sinusitis or rhini- extremities can be found in patients with Sjogren syndrome

tis; and paresthesia, weakness, or foot drop. Clinicians and other conditions that include hypergammaglobuline-

should also ask patients about potential triggers, includ- mic purpura, cryoglobulinemic vasculitis and Waldenström’s

Figure 1 Schematic representation of the skin (epidermis, dermis and subcutaneous tissue), types of blood vessels found in upper

and lower dermis vascular plexus, vessels diameter, site of main vasculitis syndromes and sufficient depth of biopsies to represent

the skin layer in which the disease is localized.

362 Morita TC et al.

hypergammaglobulinemic purpura. Urticarial lesions can cutaneous nodules surrounded by a livedoid pattern are

occur in Systemic Lupus Erythematosus (SLE), Sjogren more characteristic of Polyarteritis Nodosa (PAN), cuta-

syndrome, hypocomplementemic urticarial vasculitis syn- neous arteritis, sarcoidosis vasculitis, or SLE, rather than

13

drome, and EGPA (Fig. 2). Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated

13---19

In medium-sized vessels vasculitides, patients often Vasculitides (AAV) (Figs. 3 and 4).

present with subcutaneous nodules, livedo, large or deep Cutaneous lesions of Winkelmann granulomas are cha-

ulcers, papulonecrotic lesions, and digital infarcts as indica- racterized by the occurrence of tender, erythematous to

tive involvement of occlusive or semi-occlusive of medium violaceous papulonodules, usually symmetrically distributed

vessels vasculature (vascular plexus of dermo-hypodermal on the elbows or distal upper extremities and fingers. Rarely,

junction or exclusively of the subcutaneous tissue). Sub- subcutaneous indurated cord-like bands (‘rope sign’) have

Table 3 Symptoms and signs evaluated to establish the diagnosis of systemic vasculitis and complementary exams needed to

identify etiologic factors associated.

Systemic Hematologic Symptoms and physical exam: lymph node palpation, liver and spleen

involvement conditions palpation.

Laboratorial tests: total blood count cells, serum protein electrophoresis test,

lactate dehydrogenase.

Cardiovascular Symptoms and physical exam: auscultation of the heart, arterial blood

system pressure in both arms, assessment of the arterial pulse characteristics in

carotid, radial, brachial, femoral, popliteal, posterior tibial, and dorsalis

pedis pulses should be routinely examined bilaterally to ascertain any

differences in the pulse amplitude, contour, and upstroke.

Laboratorial tests and other exams: arterial doppler ultrasound evaluation if

abnormal pulses are present or if systemic Polyarteritis Nodosa (PAN) is

suspected --- i n this particular situation aorta and renal arteries should be

evaluated). Doppler echocardiography study when it appears that be a septic

vasculitis case (intermittent or recurrent fever, weight loss, complement

protein system lower levels). In medium-vessel (arteritis) or large-vessel

vasculitis angiotomography or magnetic resonance angiography studies can be

useful. Sometimes the 18F-fluorodeoxyglucose Positron Emission Tomography

(PET) can be added to investigation of medium and large vessel vasculitis.

Deep, large vessels can be examined by Computed Tomography (CT) or

Magnetic Resonance Image (MRI), while ultrasound is the method of choice for

the evaluation of superficial vessels (such as temporal, carotid, and axillary

arteries). PET is very sensitive in detecting large vessel inflammation, but it

11

does not delineate the vessel wall.

Kidneys and Symptoms and physical exam: periorbital, sacral, lower-extremities edema,

genitourinary muscle tenderness, ascites, hypertension. Dilated neck vein, weight loss,

system orthostatic hypotension and tachycardia (acute prerenal kidney injury).

Testicular pain, suggestive of PAN.

Laboratorial tests and other exams: serum blood urea nitrogen and creatinine,

creatinine clearance, urinalysis (urine density, proteinuria, hematuria,

cylindruria) and/or 24 h urine protein test if proteinuria is present. Urine

culture test.

Liver function and Symptoms and physical exam: jaundice, oral ulcerations, gingival hyperplasia,

gastrointestinal dyspepsia, vomiting, diarrhea, abdominal pain, hematochezia or melena,

system gastroduodenal ulcers, peritonitis, bowel perforation. These symptoms and

signs suggest gastrointestinal vasculitis that can occurs in the setting of PAN,

Microscopic Polyangiitis (MPA), Granulomatosis with Polyangiitis (GPA),

Eosinophilic Granulomatosis with Polyangiitis (EGPA), lupus enteritis and

rheumatoid arthritis- associated vasculitis. Recurrent right quadrant pain

gallbladder vasculitis as single Organ Vasculitis of the Skin (SOV) or systemic

vasculitis.

Laboratorial tests and other exams: alanine aminotransferase, aspartate

aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase,

bilirubin levels, serum albumin level, prothrombin time. Fecal occult blood

test is relevant to investigation for IgA-vasculitis and bowel neoplasia

associated vasculitis. Colonoscopy and/or upper gastrointestinal endoscopy in

suspect of active gastrointestinal vasculitis or screening for neoplasia.

Update on vasculitis 363

Table 3 (Continued)

Central and Symptoms and physical exam: depression, anxiety. Migraine localized in the

peripheral nervous temporal area, accompanied by fever, malaise, myalgia, muscle weakness and

system [both anorexia, with swollen and sensitive temporal artery during palpation (often

immune-mediated in Takayasu arteritis). Unilateral or bilateral loss of vision due to ischemic

changes and optic neuropathy (Takayasu arteritis). Aphasia, hemiplegia, visual disturbance

ischemia of the (blurred vision and hemianopia), seizures, transverse myelitis and

vascular wall- the subarachnoid hemorrhage typically in patients with PAN. Mononeuritis

hallmark of multiplex or distal symmetrical sensorimotor polyneuropathy Takayasu

vasculitis, are the arteritis (15%), ANCA-positive Vasculitis (AAV) (60% in EGPA, 10---22% in MPA),

main causes of systemic PAN (65%), cutaneous arteritis (former cutaneous PAN, 20%) and

Central Nervous Sjogren syndrome (30% of patients suffering of distal symmetric sensory or

12

System (CNS) and sensorimotor polyneuropathy and mononeuritis multiplex). In Systemic

Peripheral Nervous Lupus Erythematous (SLE) can be observed two types of lesions and signs in

System (PNS) CNS: (i) non-thrombotic disease (psychoses, seizures, headaches, cognitive

17

symptoms]. dysfunction and chorea) or (ii) thrombotic disease (stroke or recurrent

transient ischemic attacks) and PNS involvement (10%) as trigeminal

12

neuropathy, distal symmetric sensory or sensorimotor polyneuropathy.

Laboratorial tests and other exams: the diagnosis of polyneuropathy is based

on clinical and electrophysiologic studies, but precise histology,

immunohistochemistry and morphometric studies of the peripheral nerve

biopsy may be decisive to make diagnosis.

Upper and lower Symptoms and physical exam: hemoptysis, shortness of breath, hoarseness,

respiratory system cough, wheezing, eye or ear symptoms, sinusitis (suggestive of AAV). Tw o kinds

of lung involvement can be seen, (i) one with acute or subacute presentation,

and with capillaritis as the pathogenic mechanism, giving rise to the syndrome

of diffuse alveolar hemorrhage. It can be part of any of the AAV and manifest

itself with dyspnea, cough, and hemoptysis; (ii) the other, more chronic and

often asymptomatic, mainly seen in GPA, and often with accompanying

otorhinolaryngological involvement, or signs of activity in other organs, is the

development of lung nodules, which clinically represent granulomas.

Hemoptysis (the most feared symptom and sign of lung hemorrhage) occurs in

over half of patients with GPA and a third of patients with MPA.

Laboratorial tests and other exams: the sensitivity of conventional chest X

Rays in patients with suspicion of lung hemorrhage is high, but its specificity is

11

very low. High-resolution CT is a better imaging tool, disclosing typical

patterns such as focal or diffuse infiltrates with ground-glass opacities or 11

alveolar occupation.

Other organs and Symptoms and physical exam: fever, nasal crusting, hearing loss (especially in

organic systems AAV), uveitis (hypocomplementemic urticarial vasculitis syndrome), arthritis

(connective tissue diseases), myalgia with or without consequent severe

limitation in movements (connective tissue diseases, AAV, PAN). Symptoms of

connective tissue diseases should be noted, such as dry eyes or mouth,

photosensitivity and/or facial cutaneous eruption, oral lesions or genital

lesions (aphthous stomatitis, ulcers), or muscle weakness. Past medical

history, including hospitalizations, underlying diseases/disorders (including

febrile diseases), pre-immunization signs and symptoms including

identification of indicators for, or the absence of, a history of allergy to

vaccines, vaccine components or any medications; food allergy; allergic

10

rhinitis; atopic eczema; asthma, autoimmune diseases.

Laboratorial tests and other exams: marked elevation of erythrocyte

sedimentation rate and c-reactive protein, while muscle enzymes were

generally normal (PAN). Electromyography and/or MRI in suspect of myositis.

Muscle biopsies, mostly revealing a histological pattern compatible with PAN,

presenting with necrotizing arteritis, leukocytoclastic angiitis, fibrinoid

necrosis of small and medium arteries and leukocyte infiltration of the vessel

walls or perivasculitis in systemic PAN. Complement serum protein

consumption is suggestive of systemic vasculitis as connective autoimmune

tissue diseases (SLE, rheumatoid arthritis, Sjögren syndrome),

cryoglobulinemic vasculitis, malignancy-associated vasculitis and septic vasculitis.

364 Morita TC et al.

Table 3 (Continued)

Etiologic Drugs, Several medications, as penicillin and derivates, sulfonamides, quinolones, hydantoins,

associated non-prescribed insulin, tamoxifen, oral contraceptives, phenothiazines, allopurinol, thiazides,

factors medicines and retinoids, radiocontrast agents and anti-influenza vaccine. Chemical substances (e.g.,

immunizations insecticides and petroleum products) and foods (e.g., milk proteins and gluten) can also

cause a vasculitis. Many illicit drugs can cause vasculitis, with the best evidence being

that for the sympathomimetic drugs. Vitamins and nutritional supplements have also

been reported to cause vasculitis. Drug-Induced Vasculitis (DIV) is a diagnosis of

exclusion, as there are no laboratory studies diagnostic for DIV. Although eosinophilia is

13

common in systemic DIV (79%), it is present in only 22% of DIV limited to the skin.

Drug-induced AAV may be associated with: propylthiouracil, hydralazine, minocycline,

anti-TNF alfa agents, acitretin, allopurinol, methimazole, and other.

Infections and Infections can cause lesions which both mimic vasculitis as well as those which represent

parasitic either a septic or true reactive vasculitis. Infection can present in many ways, including

infestations septic vasculitis, upper respiratory tract flares of GPA, PAN, cryoglobulinemic vasculitis,

urticarial vasculitis, IgA-vasculitis, and cutaneous small-vessel vasculitis (CSVV, a

13

SOV). Common agents include bacteria, viruses, parasites, and fungi. Special mention

should be given to the known association of hepatitis B virus with PAN and hepatitis C

13

virus with mixed cryoglobulinemia. Other complementary exams should include an

investigation for asymptomatic or oligosymptomatic infections and/or parasite

infestations as anti-streptolysin O, tuberculosis (Mantoux test and/or QuantiFERON-TB

Gold In-Tube assay), Parvovirus B19 (serology IgM and IgG), schistosomiasis (eggs in stool

exam), toxocariasis (serology IgG, peripheral eosinophilia), strongyloidiasis (larvae in

stool exam and serology) and syphilis (serology and/or immunohistochemistry in

cutaneous biopsy). Others agents are reported in case reports or case series as, (i)

Bacterial agents: Streptococcus (Streptococcus viridans; group A, C, and G

streptococci), enterococci, Staphylococcus aureus, Mycobacterium leprae (Lucio’s

phenomenon in leprosy and vasculitis in erythema nodosum), Salmonella species,

Borrelia burgdorferi, Pseudomonas aeruginosa, Legionella pneumophila; (ii) Parasites:

Schistosoma haematobium, Onchocerca volvulus, Cysticercus, Loa loa; (iii) Viruses: HIV

infection, herpes simplex 1 and 2, Cytomegalovirus, Epstein---Barr, Varicella-Zoster,

Rubella, adenovirus, echovirus, coxsackievirus, parainfluenza, hepatitis A virus

14

infections, and (iv) Fungi: Aspergillus spp., Fusarium spp., Coccidioides immitis.

Inflammatory SLE, Sjögren’s syndrome, rheumatoid arthritis, scleroderma, dermatomyositis,

systemic complement deficiency, alpha1 antitrypsin deficiency, inflammatory bowel disease,

conditions chronic active hepatitis, intestinal bypass surgery, primary biliary cirrhosis, relapsing

(autoimmune polychondritis, and other.

diseases)

Neoplasia and Hematologic disorders constitute the most common group of malignancies associated

paraneoplastic with cutaneous vasculitis (lymphoma Hodgkin and non-Hodgkin, acute myelogenous

syndrome leukemia, chronic lymphoid or lymphocytic leukemia, lymphoblastic leukemia,

immunoblastic sarcoma, megakaryocytic leukemia malignant B-cell lymphoma, T-cell

lymphoma, myelodysplastic syndrome, myelofibrosis) and less commonly the vasculitis

related to solid organ tumors (colon carcinoma, renal carcinoma, colon

adenocarcinoma, prostate carcinoma, lung carcinoma, lung squamous carcinoma,

gastric tubular carcinoma, gastric adenocarcinoma, pancreatic carcinoma, breast

carcinoma, ovarian cancer, pharyngeal carcinoma, vocal cord carcinoma, pelvic

15

carcinoma, hepatocarcinoma, urinary bladder carcinoma). Cutaneous paraneoplastic

vasculitis is an entity not uncommonly encountered by clinicians. In these cases, the

presence of cytopenia and immature cells may be red flags for the diagnosis of cancer.

In patients with paraneoplastic cutaneous vasculitis, the prognosis depends on the 15

underlying neoplasia.

Idiopathic Despite the efforts of the clinicians on work-up for an etiology to cutaneous or systemic

vasculitis, most of patients remain as undetermined etiology. Some authors refer an

16 17 18

idiopathic origin for vasculitis in 45---50% to 69 ---79% of the patients suffering of

CSVV. In both CSVV and IgA vasculitis, the most common etiologic association is

idiopathic.

AAV, ANCA-Positive Vasculitis; CNS, Central Nervous System; CSVV, Cutaneous Small-Vessel Vasculitis; CT, Computed Tomography; DIV,

Drug-Induced Vasculitis; EGPA, Eosinophilic Granulomatosis with Polyangiitis; GPA, Granulomatosis with Polyangiitis; MPA, Microscopic

Polyangiitis; MRI, Magnetic Resonance Image; PAN, Systemic Polyarteritis Nodosa; PET, Positron Emission Tomography; PNS, Peripheral

Nervous System; SLE, Systemic Lupus Erythematous; SOV, Single Organ Vasculitis of the skin.

Update on vasculitis 365

Figure 2 Different lesions usually seen in patients with small vessel vasculitis. (a) Purpura, petechiae, vesicles and hemorrhagic

blisters in the lower limbs in a patient with cryoglobulinemic vasculitis, (b) Urticated sometimes confluent lesions and purpura in

the lower limbs very suggestive of urticaria vasculitis.

Figure 3 Distinct lesions normally found on the skin of patients with medium vessel vasculitis: (a) Subcutaneous nodules and

ulcers in a patients with cutaneous arteritis, (b) Extensive ulcers with areas of necrosis and residual atrophic scars in the lower

limbs of a patients with microscopic polyangiitis.

been observed. Histologically, this disease is a variant of as GPA, rheumatoid arthritis, inflammatory bowel disease,

20

CLA with prominent influx of neutrophils with palisading Takayasu’s arteritis and (flaring) SLE.

macrophages surrounding a central necrosis composed of Digital infarcts are commonly seen in vasculitis associ-

basophilic fibrin, degenerative collagen and, of course, ated with rheumatoid arthritis but are also seen in PAN and

21

neutrophils and neutrophilic debris. However often a true AAV (Fig. 5a). Retiform purpura in plaques (Fig. 5b) is an

vasculitis is not observed in histopathology sections. This uncommon finding of palpable purpura in a livedoid, retic-

skin reaction pattern was originally described in EGPA dis- ulate or arciform pattern. This arrange is related to the

ease but subsequently observed in a variety of infectious physiological vascular anatomy and results from ischemia-

diseases such as subacute bacterial endocarditis, hepati- related hemorrhage around a dermal/subcutaneous vessel

tis, lymphoproliferative and autoimmune disorders such prior to complete occlusion. Although retiform purpura may

366 Morita TC et al.

Figure 4 Distinct lesions normally found on the skin of patients with medium vessel vasculitis: (a) Livedo racemosa in the lower

limbs, including the dorsum of the feet in a patient with cutaneous arteritis, (b) Digital necrosis in a patients with ANCA-associated

vasculitis - granulomatosis with polyangiitis.

Figure 5 Retiform purpura in a patient with Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-associated

vasculitis: (a) Palpable purpura in a livedoid, reticulate pattern with a necrotic center located in the tighs. The recognition of a

retiform purpura pattern indicates that a medium vessel component of vasculitis exists, (b) Large ulcerations with irregular borders,

granulating wound bed, areas of necrosis and eschar, and serous discharge.

occur in a variety of clinical settings, retiform purpura specific signs or symptoms. High fever, weight loss, bicy-

in plaques indicates vascular inflammation and more dis- topenia or severe anemia, Raynaud’s phenomenon (in the

tinct pathophysiology, as well non-inflammatory conditions, absence of connective tissue disease), or cryoglobulins

13

without a true vasculitis, didactically grouped as cutaneous should prompt a more thorough search for malignancy.

pseudovasculitis (antiphospholipid syndrome, calciphylaxis, Since only a few vasculitides syndromes have pathog-

warfarin-induced cutaneous necrosis, heparin-induced skin nomonic clinical, radiographic and or laboratory findings

necrosis, cryoglobulinemia, cholesterol or crystal emboli, confident and accurate diagnosis requires a representative

21

and oxalosis). skin biopsy to histological confirmation. On the other hand,

A general panel of complementary exams suggested by a biopsy diagnosis of vasculitis cannot stand alone, as it

our study group includes several tests, previously cited in must be correlated with clinical history, physical and lab-

table 3 and other, especially for those patients without oratory findings and/or angiographic features. For example,

an obvious cause of vasculitis: complete blood cell count a diagnosis of SOCV requires that no evidence of systemic

10

with differential, blood urea nitrogen/creatinine, liver manifestations is found. If systemic vasculitis is suspected,

function panel, urinalysis, stool guaiac, serum protein elec- imaging studies can provide a useful means to determine

trophoresis with immunofixation to search for evidence of a disease extent and activity, and serology, such as C-reactive

paraproteinemia, antistreptolysin-O, HBV/HCV/HIV serolo- protein, erythrocyte sedimentation rate and ANCA levels,

gies, cryoglobulins, complement levels (CH50, C3, C4), and type, can be used to monitor disease activity and predict

9,13

antinuclear antibody, ANCAs and Rheumatoid Factor (RF). mortality risk, respectively.

If the patient is febrile and has a heart murmur, then blood Hence, the classification of cutaneous vasculitis into spe-

cultures and echocardiography should be performed. For cific syndromes is better approached morphologically by

cases with a medium-sized vessel involvement or signs and determining vessel size and main inflammatory response.

symptoms of connective tissue disease, an Antinuclear anti- These histological patterns (Table 2) combined with Direct

13

body (ANA) should be obtained. Immunofluorescent (DIF) examination, ANCA status and

C-reactive protein levels usually reflect AAV activity. findings from work-up for systemic disease, allow for spe-

In both AAV and PAN anti-streptolysin O titers should be cific diagnosis, and ultimately, a more effective therapy.

evaluated because of the common role of streptococci in A neutrophil-predominant small vessel vasculitis primarily

these settings. Chest radiology studies, gastrointestinal affecting upper dermal blood vessels and showing papil-

image exams, gynecological examination for females and lary IgA deposits is diagnostic of IgA-vasculitis, whereas

urological evaluation form male patients are an adequate a neutrophil-predominant small vessel vasculitis affecting

screening for malignancy in the absence of any other dermal and subcutaneous blood vessels with predominance

Update on vasculitis 367

of IgM vascular deposits would implicate Cryoglobulinemic immune complex-mediated vasculitis, 100% of skin samples

22

Vasculitis (CV) or Rheumatoid Vasculitis (RV). will reveal immunoglobulins within the first 48 h, as 70% will

Clinicians more trained in recognizing elementary cuta- do it at 48---72 h. After this interval, despite complement

neous lesions must be able to perform a representative deposits may still be detected in more than 50% of vasculitis

22

biopsy of the necessary skin layers. In general, a deep and skin lesions, immunoglobulins will not.

large punch biopsy ( 5 --- 6 mm in diameter) or an excision Our group performed a retrospective study on the DIF

22

biopsy is the preferred mean to sample vessels of all sizes. results in a tertiary center in Brazil from January 2007 to

Some key points to a proper cutaneous biopsy are listed December 2014. We evaluated 235 cutaneous samples in 282

below: patients with CLA. Age ranged from 5 to 87 years-old, with

a median age of 45 years. 191/282 (67.73%) of the patients

a) A sample biopsy extending to subcutis taken from the were female. DIF analysis showed positivity in 70.21% of

most tender, reddish or purpuric, lesioned skin is the key the samples, and C3 was the most frequent immunoreac-

to obtaining a significant diagnostic result; tant. IgA deposition at the blood vessel wall was related

b) The optimal time for skin biopsy is <48 h after the appear- to age and absence of autoimmune/inflammatory diseases,

ance of a vasculitis lesion. If the biopsy is poorly timed, while Immunoglobulin M (IgM) deposition was related to

the pathological features of vasculitis may be absent, a female gender, autoimmune/inflammatory disorders, C3 and

fact that must be considered when interpreting a nega- C4 consumption, and antinuclear antibody or anti-SSA/anti-

tive biopsy from a patient whose clinical findings suggest SSB positivity. Immunoglobulin G (IgG) deposition at the

vasculitis; blood vessel wall was associated with age and positive ANCA.

c) Purpuric lesions biopsied in the first 24 h display fib- Finally, C3 deposition at the blood vessel wall, the most fre-

rin deposits within the vessel wall accompanied by quent finding of this study, was associated with hematuria

neutrophilic infiltration of the wall and surrounding hem- and renal involvement. Systemic involvement was present

17

orrhage and nuclear debris (leukocytoclasia). After 24 h, in 12.5% of patients with CLA.

neutrophils begin to be replaced by lymphocytes and In summary, in cases of cutaneous vasculitides it is essen-

macrophages. Thus, biopsy of lesions >48 h old, regard- tial to select the proper site of cutaneous biopsy. The

less of the underlying form of vasculitis, may show histopathological features of CLA may include neutrophils

lymphocyte-rich infiltrates, troubling the clinical syn- invading the vessel wall, fibrinoid necrosis or fibrin within

dromic vasculitides diagnosis; the vessel wall, nuclear dust (leukocytoclasia), extravasated

d) Biopsy specimens should be obtained from non-ulcerated erythrocytes, perivascular inflammatory cell infiltration,

skin lesions due to the frequent finding of incidental vas- mainly neutrophils, and endothelial swelling. Biopsies for

culitis underlying an ulcer bed. If only superficial ulcers DIF should be taken in the first 8---24 h of appearance of the

are present, biopsy of the edge is acceptable. In the case lesion. Otherwise, the inflammation destroys the immune

of deep, ‘punched out’ ulcers, biopsy of the subcutis complexes and they become falsely negative. Detection of

including the central ulcerated area increases diagnos- immune complex deposition may have diagnostic and prog-

tic yield and recognition of an arterial vasculitis, such as nostic significance. Besides immunoreactants in the vessel

systemic PAN or cutaneous arteritis; wall, DIF can reveal deposition of IgG and C3 at the dermo-

e) In case of livedo racemosa, a deep biopsy specimen epidermal junction, pointing out a positive lupus band test,

should be taken from the center of the circular livedo or may be related to hypocomplementemic urticarial vas-

22

segment because it is where is located the stenosed ves- culitis with an underlying LES.

sel responsible for the cyanotic periphery. In this setting,

level sections are often required to find the focus of

vasculitis, which is typically focal and segmental. Epidemiology data on vasculitis

23

Mimouni et at. reviewed 29 consecutive patients The annual incidence of CLA is estimated in 45/million in

presenting white atrophy, 6 of whom had underlying the United States (population-based in Olmsted County, Min-

18

medium-sized vasculitis consistent with PAN. Three of them nesota --- cutaneous biopsy-proven cases). It affects both

9

had been previously diagnosed as having livedoid vasculopa- genders equally and patients of all ages. In children, by

thy on superficial biopsies. So, particularly in the setting contrast, IgA-vasculitis is much more common than non-

9

of white atrophy repeated and deep biopsies are often IgA small vessel vasculitis of the skin. The presence of an

necessary to reveal the accurate underlying pathology of underlying systemic vasculitis, connective tissue disease,

necrotizing medium-sized vasculitis in the reticular dermis or malignancy is much more common in adults than in

24 9,18

and the subcutis. Meanwhile, Wohlrab et al. evaluated children.

25

the sensitivity of skin biopsies in Sneddon’s syndrome. The In a review on systemic vasculitides, Elefante et al.

authors collected 5 deep-punch biopsies (4 mm at least) presented some data about the epidemiology of AAV: (i)

from different areas where livedo was detected (3 from ANCA specificity was associated with different genetic

white and 2 from red areas) in 15 patients. The method had background, clinical features, treatment response, and

a sensitivity of 27% with one biopsy, 53% with two biopsies prognosis in terms of relapse rate and survival rate; (ii)

and 80% with three biopsies taken from white areas in all distribution of ANCA specificity differs significantly between

cases. the ethnic groups; (iii) MPO-ANCA resulted significantly

DIF studies should be performed whenever it is possi- more frequent in Asian populations [Japanese OR = 59.2

ble. For example, the diagnosis of IgA-vasculitis can only (95% CI 8.0---440.7), p < 0.001, Chinese OR = 6.8 (95% CI

22

be made when IgA vascular deposits are found. In cases of 2.6---17.8), p < 0.001], Caucasian American [OR = 2.6 (95%

368 Morita TC et al.

CI 1.7---4.0), p < 0.001] and Middle Eastern/Turkish [OR = 2.3 to complement-dependent cytotoxicity or indirect cytotoxic

28

(95% CI 1.3---4.2), p < 0.005], when compared to the Northern effect secondary to antibody-dependent cytotoxicity.

Europeans, who presented more PR3-ANCA specificity; (iv)

ANCA negativity was also significantly more frequent in

Genetic susceptibility for vasculitides

Caucasian Americans than Northern Europeans [OR = 2.0

(95% CI 1.3---3.2), p = 0.002], and (v) there are differences

Genome-wide association studies have revealed a pivotal

in frequency of organ involvement between the ethnic

role of the Human Leukocyte Antigen (HLA) region in the

groups, when compared to Northern Europeans, the Asian

genetic susceptibility to vasculitides. However, each form

population presented significantly less ocular and ear,

has distinct HLA association markers that define them,

nose, and throat involvement while renal involvement

most likely due to disease-specific differences in antigenic

was significantly less frequent in Caucasian Americans and

drivers. Despite the considerable advance in the identifi-

significantly more frequent in Middle Eastern/Turkish, how-

cation of consistent genetic risk factors during the last 10

ever interestingly, some differences were not completely

years, the number of identified risk loci for most types of

determined by the differences in ANCA pattern.

vasculitides remains significantly lower than other immune- 29

mediated diseases.

Pathogenesis There is a strong association with HLA class II alleles with

IgA-vasculitis pathogenesis, specifically HLA-DRB1 in Euro-

peans, mainly due to HLA-DR1*0103.43, suggesting that it

We can simplify the mechanisms involved in the pathogen-

may be related to other class II vasculitides such as giant

esis of vasculitides into two pathways: (i) immune-complex

cell arteritis or AAV. It has also been proposed that, although

associated vasculitides and (ii) AAV. However, several fac-

less strong, there is a potential effect of HLA class I in the

tors are involved as: genetic basis, innate and acquired

pathogenesis of IgA vasculitis. When it comes to AAV, the

immunity, pathogens, immune tolerance disruption, and

genetic distinctions within this group may be related to the

‘‘autoantigens’’.

antigenic specificity of ANCA rather than to the clinical syn-

The causes of CSVV include infections (20%), inflam-

drome. Different AAV subtypes are underpinned by distinct

matory conditions (15---20%), drug reactions (10---15%), and

26 risk factors, with GPA being associated with HLA-DP, SER-

malignancies (5%). Disease-inducing or promoting factors

PINA1, PRTN3 and semaphorin 6A, whereas MPA is mainly

are not known for more than half of the cases, and so 29---31

10 associated with HLA-DQ polymorphisms.

they are currently classified as idiopathic. Although non-

Takayasu arteritis is predominantly related to HLA class I

immunologic factors such as direct infection of endothelial

alleles, in particular to HLA-B52, as it is Behc¸et’s Disease

cells can cause vasculitis, most lesions are mediated by 30

(BD). The strongest single-risk factor for BD was con-

immunopathogenic mechanisms. These mechanisms can be

firmed to be HLA-B51, but other HLA-B alleles with lower

classified into Gell and Coombs’ four types of hypersensi-

independent effects were also observed, for example, HLA-

tivity reactions. The majority of cutaneous lesions are likely 29

B15 and HLA-B27. Outside the major histocompatibility

due to type III hypersensitivity reactions. Immune complexes

complex region, susceptibility to BD has been associated

deposition in postcapillary venules activates complement,

to interleukin 10 and the region of interleukin 23 recep-

which, in turn, induces mast cell degranulation and neu- 29

␤ 10 tor/interleukin 12 receptor 2.

trophil chemotaxis.

The association of HLA-DR alleles with PAN has been

Virtually all drugs have been considered as potential pre-

reported, but with variable results according with the stud-

cipitating agents for vasculitis and CSVV is by far the most

ied population. Unfortunately, there is little information

common form of drug-associated vasculitis. According to the

27 on genetic susceptibility to hypersensitivity vasculitis (CSVV

study of Ortiz-Sanjuán et al. the most frequently asso-

or SCOV). Genetic studies on this vasculitis are scarce

ciated were antibiotics, mainly B-lactams and quinolones.

and no association of this condition with the HLA region

Other agents involved were nonsteroidal anti-inflammatory

was confirmed, suggesting a heterogeneous etiology in the

drugs, paracetamol, allopurinol and anticonvulsants. In

pathogenesis of this vasculitis that often is restricted and

this series of 239 cases, patients with vasculitis due to 30

limited to skin.

major infections, such as endocarditis or pneumonia, were

excluded.

RV is probably the most widely recognized form of sec- Infections as a trigger of vasculitides

ondary vasculitis and is typically seen in long standing,

erosive, seropositive rheumatoid arthritis. Deposition of Various immune mechanisms are involved in infection-

immune complexes and subsequent activation of the com- associated vasculitides pathogenesis. Most of them are

plement cascade is believed to play a key role in the caused by direct invasion and proliferation of pathogens

pathogenesis of RV. An increased expression of inflammatory in the vascular walls causing inflammation. On the other

␣

cytokines such as TNF- , IL-1 and IL-6 is noted, although hand, they can sometimes be attributed to indirect immuno-

their exact role in the pathophysiology of RV remains logical effects such as type II, III, or IV hypersensitivity

unclear. Meanwhile, cutaneous vasculitis may be seen in reactions triggered by the infection. Structures such as fim-

28

approximately 19---28% of patients with SLE. Small ves- briae, besides MSCRAMMs (microbial surface components

sels especially post capillary venules are involved in most that recognize adhesive matrix molecules) and others cell-

28

cases (80---90%). Presence of anti-endothelial antibody is wall-anchored proteins are utilized by bacteria to make

detected in up to 80% of these patients and might contribute their way into vulnerable cells. It has been demonstrated

by activation of endothelial cells, direct cytotoxic effect due that viruses have analogous membrane-adhesion molecules.

Update on vasculitis 369

Nonetheless, whether their density of expression has a role patients of pSS group, 64% of whom had type II cryoglobulins,

in determining the frequency with which distinct organs are and in patients with pSS the presence of cryoglobulins was

affected is a knowledge to be seek in scientific vasculitides- associated with highest systemic activity, suggesting that all

2,32

research related. patients with pSS should be tested for serum cryoglobulins at

Vasculitis has been reported in association with numer- least at the time of their diagnosis; (iii) SLE-related CV was

ous microorganisms, ranging from viruses to fungi. In specific present in 10.9% of cases as well as other immune conditions,

situations, the relationship between etiology and angiocen- HBsAg positivity in 8.6%, lymphoproliferative disease in 6.8%

tric inflammation and destruction is clear, as it is in aortitis and some solid tumors in 2.3%; (iv) type II cryoglobulins were

caused by Mycobacterium tuberculosis or by Treponema pal- present in 54.9% and were independently associated with

lidum, for which there is a predilection for the ascending purpura and fatigue, and (v) older age, male gender, type

aorta. However, other infections, such as HIV, are associ- II cryoglobulins and HBsAg were independently associated

ated with a wide variety of vasculitic phenotypes, affecting with great mortality in patients with HCV-unrelated CV.

small, medium or large vessels. In these cases, necrotizing, PAN is divided into 2 subtypes: systemic and cutaneous.

non-necrotizing, giant cell and eosinophilic arteritis have It predominantly presents between 40 and 60 years of age.

been observed at histology. Direct vessel wall invasion by Besides HBV infection, systemic PAN has been linked to

HIV itself or by opportunistic organisms, and immune com- other infectious agents including HCV, HIV, cytomegalovirus,

plexes containing HIV antigens and antibodies are some of parvovirus B19, and HTLV. The cutaneous PAN has been

33

the mechanisms of injure proposed. attributed to streptococcal infections in the pediatric

26

In fact, several infectious diseases are implicated in population.

the production of immune-complex-mediated forms of

2

vasculitis. IgA vasculitis has been reported to occur in

association with various bacteria, including Mycoplasma ANCA-associated vasculitides

pneumoniae and Clostridium difficile. As Ureaplasma ure-

alyticum, Aerococcus viridians, Burkholderia cepacia and The ANCAs are a group of autoantibodies, mainly of the IgG

33

Listeria monocytogenes have been incriminated in CLA. type, developed and released from B cells against antigens

Although the incidence of PAN has significantly decreased in the cytoplasm of neutrophil granulocytes. One type of

in the prevailing scenario of the vaccination programs and ANCA is associated with diffuse staining of the cytoplasm

blood transfusion screening, more than 30% of the cases are and is known as cytoplasmic ANCA (c-ANCA), whilst the other

secondary to HBV infection. Most evidence supports a type is related with staining around the nucleus and is known

III hypersensitivity injury whereby vascular damage is pro- as perinuclear ANCA (p-ANCA). The major antigen targeted

duced by immune complexes with viral antigens. There have by c-ANCA is PR3 and that targeted by p-ANCA is MPO.

been anecdotal reports of chronic HBV infection associated Both are expressed on the cell surface of neutrophils acti-

with other forms of vasculitides such as GPA, even though vated by pro-inflammatory cytokines such as IL-1␤ and TNF

it still remains unclear whether these reports are causal or generated during infections. ANCAs link to these antigens.

32

coincidental. Meanwhile, the Crystallizable Fragment (Fc) portion of these

The pathogenesis of HCV-associated vasculitis seems to ANCAs binds to Fc␥ receptors on neutrophils, inducing their

involve a direct interaction between the virus and lympho- excessive activation. This fact leads to abnormal cytokine

cytes leading to polyclonal activation and proliferation of production, release of Reactive Oxygen Species (ROS) and

33

B cells producing IgM with RF activity. IgM RF is capable lytic enzymes, and eventually Neutrophil Extracellular Traps

34,35

of activating the complement system through the binding (NET) formation.

of the globular domain of the C1qprotein. C1q receptors AAV constitutes a group of rare diseases characterized

(gC1q-R) are widely expressed on the surface of blood cells by necrotizing inflammation of small to medium-sized blood

and endothelial cells, and they link to large immunocom- vessels and the presence of ANCA. They are represented

plexes containing HCV core protein, facilitating subsequent by GPA, MPA with its renal limited form pauci-immune

vascular inflammation. The immunocomplexes with cryopre- necrotizing crescentic glomerulonephritis and EGPA. Results

cipitate containing viral antigens, IgM RF bound to polyclonal from studies have demonstrated that ANCA, detected by

anti-HCV IgG, and complement are localized to small ves- the immunofluorescence technique (c-ANCA or p-ANCA),

sels of internal organs, although preferentially to the colder are a sensitive marker for the so-called AAV, with sensi-

32

extremities. tivity ranging from 80% to more than 90%. Unfortunately,

HCV-associated CV is a systemic small-to-medium ves- immunofluorescence has a low specificity (80% or less),

sel vasculitis due to vascular deposition of cold-precipitable which is mainly caused by positive p-ANCA in disease con-

serum proteins, called cryoglobulins. Type I cryoglobulins trols, such as in inflammatory bowel diseases. P-ANCA, in

are monoclonal immunoglobulins, type II cryoglobulins con- disease controls, can be also caused by the presence of

sist of monoclonal immunoglobulins with a RF activity, anti-nuclear antibodies. Antigen specificity (PR3 or MPO)

associated with polyclonal IgG, whereas type III cryoglob- does not effectively differentiate among the AAV, however

ulins comprise polyclonal IgG and IgM with RF activity. c-ANCA/PR3-ANCA are mainly found in GPA, while p-

25

Elefante et al. summarized the clinical, laboratorial and ANCA/MPO-ANCA are more prevalent in MPA, pauci-immune

predisposing factors influencing the outcome in patients necrotizing crescentic glomerulonephritis and CSS. ANCA are

with CV unrelated to HCV: (i) essential (no identifiable detected in 70%---90% of active, generalized GPA, but only in

36

underlying disease) CV was the largest group (39.4%) and about 40%---50% of the loco-regional forms. Beyond a diag-

the first associated condition (21.1%) was primary Sjogren’s nostic serological marker, data support a pathogenic role for

syndrome (pSS); (ii) overt purpura was present in 78% of ANCA, which promote activation of primed neutrophils and

370 Morita TC et al.

monocytes, and their adhesion to the endothelium, leading capacity of recognizing integumentary lesions of different

19

to subsequent tissue damage. vasculitides, allied to other systemic symptoms and signs,

The proteins of complement system participate in the an adequate biopsy and proper complementary laboratory

pathogenesis of several small-medium vessels vasculitis and image exams can contribute to the correct diagnosis of

including AAV, CV, IgA vasculitis and urticarial vasculi- this challenging group of diseases.

tis. PR3- and MPO-ANCA-activated neutrophils prompt C5a

release. Subsequent interaction of C5a (a protein derivate

Financial support

from alternative complement pathway activation) with the

C5a receptor 1 (C5aR1) may represent a proinflammatory

30 This study was carried out with support from Coordenac¸ão

amplification loop in AAV. Due this complement activa-

de Aperfeic¸oamento de Pessoal de Nível Superior --- Brasil

tion, elevated serum and plasma concentrations of C5a and

(CAPES) --- Código de Financiamento 001.

C3a have been observed in active AAV, especially MPO-ANCA 31

positive vasculitis.

Besides microbial components such as peptides or Authors’ contributions

lipopolysaccharides and complement, certain drugs mainly

propylthiouracil (PTU), hydralazine and levamisole-

Thâmara Cristiane Alves Batista Morita: Elaboration and

adulterated cocaine stimulate ANCA autoantigen expression

writing of the manuscript; intellectual participation in the

on the membrane surface of neutrophils. Although these

propaedeutic and/or therapeutic conduct of the studied

immune cells are the paramount player in the pathogenesis

cases; critical review of the manuscript.

of AAV, since they are both effector cells responsible for

Gabriela Franco S. Trés: Approval of the final version of

endothelial damage, and targets of autoimmunity, it has

the manuscript; elaboration and writing of the manuscript;

been demonstrated that some others including CD4 T cells

intellectual participation in the propaedeutic and/or ther-

35

and monocytes are also involved.

apeutic conduct of the studied cases; critical review of the

literature; critical review of the manuscript.

Roberta Fachini Jardim Criado: Approval of the final ver-

Neutrophil extracellular traps (NETs) and vasculitis

sion of the manuscript; conception and planning of the

study; elaboration and writing of the manuscript; effective

Neutrophils are able to generate NETs, which are found

participation in research orientation; critical review of the

in a variety of conditions, such as infection, malignancy,

literature; critical review of the manuscript.

atherosclerosis, and as previously mentioned autoimmune

Mirian Nacagami Sotto: Critical review of the manuscript.

diseases, such as AAV. Although several stimuli are respon-

Paulo Ricardo Criado: Approval of the final version of

sible for neutrophil activation and NETs formation, a little

the manuscript; conception and planning of the study;

is known on the exact pathway leading to induction of

37 elaboration and writing of the manuscript; obtaining, anal-

NET formation. The strongest evidence that NETs actually

ysis, and interpretation of the data; effective participation

serve as a source of autoantigens driving autoantibody pro-

in research orientation; intellectual participation in the

duction in vasculitis comes from studies on drug-induced

propaedeutic and/or therapeutic conduct of the studied

vasculitis. MPO-ANCA positivity is relatively common in

cases; critical review of the literature; critical review of

patients treated with propylthiouracil, and some of these

38 the manuscript.

patients develop a vasculitis-like syndrome. MPO and PR3

have been demonstrated within NETs isolated from patients

with AAV, and ANCA can further induce NET formation in Conflicts of interest

these patients. ANCA itself also can induce autophagy of

neutrophils, which promotes NETosis, a unique form of pro- None declared.

38

grammed cell death.

NETs have been shown to be present not only in skin

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