Vasculitides encompass a large group of heterogeneous diseases characterized by inflammatory reaction localized in the vascular wall and perivascular tissues. To the concern of etiology, it is defined as a complex syndrome because several types of vasculitides can be elicited by different stimulus, although most of them are classified as idiopathic. Both, venous or arterial vessels can be affected, in a pattern of single organ or multisystemic disease. Then, dealing with vasculitides often means to study several distinct pathophysiological mechanisms and a wide clinical spectrum. Often several authors rely on the blood vessel caliber to classify them as small, medium or large-vessel vasculitis. However, when it is held alone, this classification fails to recognize diversity within vessels of the same caliber, their specialized roles in several anatomic areas in response to stimuli, injury, and repair that determine disease patterns.1,2

Cutaneous vasculitides can range in severity from benign, self-limited, short-course skin eruption to life-threatening disease with multiple-organ failure. Otherwise, systemic vasculitis is divided into two main categories: primary vasculitis syndrome and secondary vasculitis syndrome. The first one is caused by unknown etiology inflammation of blood vessels, while the second one is induced by underlying conditions, including connective tissue diseases, cancer, infections, immunization, and drug allergy. In the majority of cases the cutaneous vasculitides syndromes will show a neutrophilic small vessel vasculitis, often called Cutaneous Leukocytoclastic Angiitis (CLA).3

The aim of this review is to clarify the recent concepts about the etiology of distinct vasculitides, the classification preconized for the Chapel Hill Consensus Conference (CHCC) and to emphasize the clues on dermatological physical and/or histopathological exam that may help to suggest a specific group of vasculitis in the clinical practice.

Clinicians have found it convenient to use vessel size as the most important feature to distinguish different forms of vasculitides.2 The CHCC published in 2012 proposed the unification of new types of vasculitis syndromes and their associated illness (Table 1).4 However, CHCC is only a nomenclature system/nosology and not a classification or a diagnostic system that helps to direct clinical management. Thus, it subdivides vasculitides based on combinations of features that separate different conditions into definable categories.4

Some cutaneous manifestations involving small, medium and/or large vessels can be found not only in the autoimmune diseases, but also in the autoinflammatory diseases. This term was coined to describe an emerging family of conditions characterized by episodes of unprovoked inflammation due to dysregulation of the innate immune system without the primary role of autoreactive T lymphocytes and/or autoantibodies. Skin involvement in autoinflammatory diseases generally resembles urticarial vasculitis or may have features of neutrophilic dermatoses. Additional skin lesions include purpuric exanthema, nonthrombocytopenic purpura, and pyoderma gangrenosum. In some autoinflammatory diseases, it is still unclear whether vasculitis is an integrated clinical manifestation or represents an additional independent disease.5 We have also included these conditions in a proper sub-classification in table 1.

Generally, the size of vessel involvement correlates with clinical morphology on the dermatological exam. Small, predominately superficial vessel involvement results in urticaria, infiltrated erythema, palpable or non-palpable purpura, vesiculobullous and/or pustules lesions. Ulcers, nodules, pitted scars, white atrophy, or livedo racemosa are associated with arterial-muscular vessel involvement, which will be located at dermal-hypodermal interface or within the subcutis. In vasculitides that involve small and medium-size vessels all kind of cutaneous lesions previously described can co-exist in the same patient. Finally, a large number of ulcers, especially when they are extensive and associated with necrosis, which may be consequence of deep-vessel arterial involvement, often predict recurrent vasculitis and systemic disease (Fig. 1).6

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.

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The recognition of pathologic changes in a cutaneous biopsy enables the identification distinct vasculitis conditions and signals the possibility of progression from localized cutaneous to systemic vasculitis.6 Skin biopsy is the gold standard method for the diagnosis of cutaneous vasculitis, also allowing differential diagnoses from vasculitis mimics, such as vaso-occlusive conditions and other diseases (Table 2).

The clinicians need to keep in mind that cutaneous vasculitis, particularly Cutaneous Small Vessel Vasculitis (CSVV), is often the most common presentation of several vasculitis syndromes.1 It may occur in 3% of Granulomatosis with Polyangiitis (GPA), 13% of Microscopic Polyangiitis (MPA), and 28% of Eosinophilic Granulomatosis with Polyangiitis (EGPA) patients.7 Some steps are essential in the clinical practice for accurate assistance to the patients with vasculitis: (i) meticulous anamnesis and physical exam; (ii) inspection and palpation of the cutaneous and subcutaneous lesions; (iii) a proper cutaneous biopsy is necessary according to the findings of dermatological exam; (iv) accurate propaedeutic and complementary exams must be performed to exclude systemic or internal organ involvement; (v) a work-up including indicated laboratory exams for infectious and parasitic infestations, autoimmune collagen diseases, blood marrow neoplasia and/or organ-solid cancer is useful for the evaluation of its etiology.

An important definition about the nosology of vasculitis in the skin was revised by Sunderkötter et al.1 The authors emphasized that they can be found in distinct clinical settings: (i) a cutaneous component of systemic vasculitides (e.g. cutaneous manifestations of IgA vasculitis), (ii) a skin-limited or skin-dominant expression or variant of a systemic vasculitis (e.g. skin-limited IgA vasculitis), or (iii) a Single-Organ Cutaneous Vasculitis (SOCV) that differs with regard to clinical, laboratory, and pathologic features from recognized systemic vasculitis (e.g. nodular vasculitis). SOCV does not develop full systemic vasculitis, while skin-dominant forms may do it. Then, systemic vasculitides are defined as those one presenting in at least one organ in addition to the skin.

In most cases of CSVV, although nonspecific signs or symptoms of systemic inflammatory reactions, such as leukocytosis, raised C-reactive protein, or arthralgia may occur, significant systemic manifestations are unlikely.1 After a thorough history, review of systems and physical examination, a systematic and targeted laboratory workup should proceed to confirm SOCV. Although no standard protocol for this workup exists, screening tests should aim at elucidating the underlying cause and extent of organ involvement and should be guided by clinical signs and symptoms. Special attention should be paid to any evidence of systemic vasculitis, such as fever, weight loss, and other constitutional symptoms; arthritis; myalgias; abdominal pain, melena, or hematochezia; cough, hemoptysis, or dyspnea; hematuria or frothy urine; sinusitis or rhinitis; and paresthesia, weakness, or foot drop. Clinicians should also ask patients about potential triggers, including preceding infectious symptoms, usage of medications, vaccines and comorbidities.8–10 We summarized in table 3 the red flag symptoms and/or signs, complementary laboratory exams and etiologic factors to workup systemic vasculitis.11,12

Some clues may help to recognize both the size of the vessel involved and the suspect diagnosis. Arterial hypertension may suggest medium-vessel vasculitis of the renal vasculature, as seen in systemic PAN. Cutaneous lesions as palpable purpura (the most frequent type of lesion in CSVV), nonpalpable purpura, pinpoint papules, vesicle, pustules, splinter hemorrhages, and urticaria are often suggestive of small vessel vasculitis. Vesicles and bullous lesions often arise on purpuric macules. A subsequent hemorrhagic pattern is observed, and these lesions may produce ulcerations in the skin. Nonpalpable purpura on the lower extremities can be found in patients with Sjogren syndrome and other conditions that include hypergammaglobulinemic purpura, cryoglobulinemic vasculitis and Waldenström's hypergammaglobulinemic purpura. Urticarial lesions can occur in Systemic Lupus Erythematosus (SLE), Sjogren syndrome, hypocomplementemic urticarial vasculitis syndrome, and EGPA (Fig. 2).13

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.

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In medium-sized vessels vasculitides, patients often present with subcutaneous nodules, livedo, large or deep ulcers, papulonecrotic lesions, and digital infarcts as indicative involvement of occlusive or semi-occlusive of medium vessels vasculature (vascular plexus of dermo-hypodermal junction or exclusively of the subcutaneous tissue). Subcutaneous nodules surrounded by a livedoid pattern are more characteristic of Polyarteritis Nodosa (PAN), cutaneous arteritis, sarcoidosis vasculitis, or SLE, rather than Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitides (AAV) (Figs. 3 and 4).13–19

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.

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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.

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Cutaneous lesions of Winkelmann granulomas are characterized by the occurrence of tender, erythematous to violaceous papulonodules, usually symmetrically distributed on the elbows or distal upper extremities and fingers. Rarely, subcutaneous indurated cord-like bands (‘rope sign’) have been observed. Histologically, this disease is a variant of CLA with prominent influx of neutrophils with palisading macrophages surrounding a central necrosis composed of basophilic fibrin, degenerative collagen and, of course, neutrophils and neutrophilic debris. However often a true vasculitis is not observed in histopathology sections. This skin reaction pattern was originally described in EGPA disease but subsequently observed in a variety of infectious diseases such as subacute bacterial endocarditis, hepatitis, lymphoproliferative and autoimmune disorders such as GPA, rheumatoid arthritis, inflammatory bowel disease, Takayasu's arteritis and (flaring) SLE.20

Digital infarcts are commonly seen in vasculitis associated with rheumatoid arthritis but are also seen in PAN and AAV (Fig. 5a).21 Retiform purpura in plaques (Fig. 5b) is an uncommon finding of palpable purpura in a livedoid, reticulate or arciform pattern. This arrange is related to the physiological vascular anatomy and results from ischemia-related hemorrhage around a dermal/subcutaneous vessel prior to complete occlusion. Although retiform purpura may occur in a variety of clinical settings, retiform purpura in plaques indicates vascular inflammation and more distinct pathophysiology, as well non-inflammatory conditions, without a true vasculitis, didactically grouped as cutaneous pseudovasculitis (antiphospholipid syndrome, calciphylaxis, warfarin-induced cutaneous necrosis, heparin-induced skin necrosis, cryoglobulinemia, cholesterol or crystal emboli, and oxalosis).21

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.

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A general panel of complementary exams suggested by our study group includes several tests, previously cited in table 3 and other, especially for those patients without an obvious cause of vasculitis: complete blood cell count with differential, blood urea nitrogen/creatinine, liver function panel, urinalysis, stool guaiac, serum protein electrophoresis with immunofixation to search for evidence of a paraproteinemia, antistreptolysin-O, HBV/HCV/HIV serologies, cryoglobulins, complement levels (CH50, C3, C4), antinuclear antibody, ANCAs and Rheumatoid Factor (RF).9,13 If the patient is febrile and has a heart murmur, then blood cultures and echocardiography should be performed. For cases with a medium-sized vessel involvement or signs and symptoms of connective tissue disease, an Antinuclear antibody (ANA) should be obtained.13

C-reactive protein levels usually reflect AAV activity. In both AAV and PAN anti-streptolysin O titers should be evaluated because of the common role of streptococci in these settings. Chest radiology studies, gastrointestinal image exams, gynecological examination for females and urological evaluation form male patients are an adequate screening for malignancy in the absence of any other specific signs or symptoms. High fever, weight loss, bicytopenia or severe anemia, Raynaud's phenomenon (in the absence of connective tissue disease), or cryoglobulins should prompt a more thorough search for malignancy.13

Since only a few vasculitides syndromes have pathognomonic clinical, radiographic and or laboratory findings confident and accurate diagnosis requires a representative skin biopsy to histological confirmation. On the other hand, a biopsy diagnosis of vasculitis cannot stand alone, as it must be correlated with clinical history, physical and laboratory findings and/or angiographic features. For example, a diagnosis of SOCV requires that no evidence of systemic manifestations is found.10 If systemic vasculitis is suspected, imaging studies can provide a useful means to determine disease extent and activity, and serology, such as C-reactive protein, erythrocyte sedimentation rate and ANCA levels, and type, can be used to monitor disease activity and predict mortality risk, respectively.

Hence, the classification of cutaneous vasculitis into specific syndromes is better approached morphologically by determining vessel size and main inflammatory response. These histological patterns (Table 2) combined with Direct Immunofluorescent (DIF) examination, ANCA status and findings from work-up for systemic disease, allow for specific diagnosis, and ultimately, a more effective therapy. A neutrophil-predominant small vessel vasculitis primarily affecting upper dermal blood vessels and showing papillary IgA deposits is diagnostic of IgA-vasculitis, whereas a neutrophil-predominant small vessel vasculitis affecting dermal and subcutaneous blood vessels with predominance of IgM vascular deposits would implicate Cryoglobulinemic Vasculitis (CV) or Rheumatoid Vasculitis (RV).22

Clinicians more trained in recognizing elementary cutaneous lesions must be able to perform a representative biopsy of the necessary skin layers. In general, a deep and large punch biopsy (5–6mm in diameter) or an excision biopsy is the preferred mean to sample vessels of all sizes.22 Some key points to a proper cutaneous biopsy are listed below:

• a)

  A sample biopsy extending to subcutis taken from the most tender, reddish or purpuric, lesioned skin is the key to obtaining a significant diagnostic result;

• b)

  The optimal time for skin biopsy is <48h after the appearance of a vasculitis lesion. If the biopsy is poorly timed, the pathological features of vasculitis may be absent, a fact that must be considered when interpreting a negative biopsy from a patient whose clinical findings suggest vasculitis;

• c)

  Purpuric lesions biopsied in the first 24h display fibrin deposits within the vessel wall accompanied by neutrophilic infiltration of the wall and surrounding hemorrhage and nuclear debris (leukocytoclasia). After 24h, neutrophils begin to be replaced by lymphocytes and macrophages. Thus, biopsy of lesions >48h old, regardless of the underlying form of vasculitis, may show lymphocyte-rich infiltrates, troubling the clinical syndromic vasculitides diagnosis;

• d)

  Biopsy specimens should be obtained from non-ulcerated skin lesions due to the frequent finding of incidental vasculitis underlying an ulcer bed. If only superficial ulcers are present, biopsy of the edge is acceptable. In the case of deep, ‘punched out’ ulcers, biopsy of the subcutis including the central ulcerated area increases diagnostic yield and recognition of an arterial vasculitis, such as systemic PAN or cutaneous arteritis;

• e)

  In case of livedo racemosa, a deep biopsy specimen should be taken from the center of the circular livedo segment because it is where is located the stenosed vessel 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.

Mimouni et at.23 reviewed 29 consecutive patients presenting white atrophy, 6 of whom had underlying medium-sized vasculitis consistent with PAN. Three of them had been previously diagnosed as having livedoid vasculopathy on superficial biopsies. So, particularly in the setting of white atrophy repeated and deep biopsies are often necessary to reveal the accurate underlying pathology of necrotizing medium-sized vasculitis in the reticular dermis and the subcutis. Meanwhile, Wohlrab et al.24 evaluated the sensitivity of skin biopsies in Sneddon's syndrome. The authors collected 5 deep-punch biopsies (4mm at least) from different areas where livedo was detected (3 from white and 2 from red areas) in 15 patients. The method had a sensitivity of 27% with one biopsy, 53% with two biopsies and 80% with three biopsies taken from white areas in all cases.

DIF studies should be performed whenever it is possible. For example, the diagnosis of IgA-vasculitis can only be made when IgA vascular deposits are found.22 In cases of immune complex-mediated vasculitis, 100% of skin samples will reveal immunoglobulins within the first 48h, as 70% will do it at 48–72h. After this interval, despite complement deposits may still be detected in more than 50% of vasculitis skin lesions, immunoglobulins will not.22

Our group performed a retrospective study on the DIF results in a tertiary center in Brazil from January 2007 to December 2014. We evaluated 235 cutaneous samples in 282 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 were female. DIF analysis showed positivity in 70.21% of the samples, and C3 was the most frequent immunoreactant. IgA deposition at the blood vessel wall was related to age and absence of autoimmune/inflammatory diseases, while Immunoglobulin M (IgM) deposition was related to female gender, autoimmune/inflammatory disorders, C3 and C4 consumption, and antinuclear antibody or anti-SSA/anti-SSB positivity. Immunoglobulin G (IgG) deposition at the blood vessel wall was associated with age and positive ANCA. Finally, C3 deposition at the blood vessel wall, the most frequent finding of this study, was associated with hematuria and renal involvement. Systemic involvement was present in 12.5% of patients with CLA.17

In summary, in cases of cutaneous vasculitides it is essential to select the proper site of cutaneous biopsy. The histopathological features of CLA may include neutrophils invading the vessel wall, fibrinoid necrosis or fibrin within the vessel wall, nuclear dust (leukocytoclasia), extravasated erythrocytes, perivascular inflammatory cell infiltration, mainly neutrophils, and endothelial swelling. Biopsies for DIF should be taken in the first 8–24h of appearance of the lesion. Otherwise, the inflammation destroys the immune complexes and they become falsely negative. Detection of immune complex deposition may have diagnostic and prognostic significance. Besides immunoreactants in the vessel wall, DIF can reveal deposition of IgG and C3 at the dermo-epidermal junction, pointing out a positive lupus band test, or may be related to hypocomplementemic urticarial vasculitis with an underlying LES.22

The annual incidence of CLA is estimated in 45/million in the United States (population-based in Olmsted County, Minnesota – cutaneous biopsy-proven cases).18 It affects both genders equally and patients of all ages.9 In children, by contrast, IgA-vasculitis is much more common than non-IgA small vessel vasculitis of the skin.9 The presence of an underlying systemic vasculitis, connective tissue disease, or malignancy is much more common in adults than in children.9,18

In a review on systemic vasculitides, Elefante et al.25 presented some data about the epidemiology of AAV: (i) ANCA specificity was associated with different genetic background, clinical features, treatment response, and prognosis in terms of relapse rate and survival rate; (ii) distribution of ANCA specificity differs significantly between the ethnic groups; (iii) MPO-ANCA resulted significantly more frequent in Asian populations [Japanese OR=59.2 (95% CI 8.0–440.7), p<0.001, Chinese OR=6.8 (95% CI 2.6–17.8), p<0.001], Caucasian American [OR=2.6 (95% CI 1.7–4.0), p<0.001] and Middle Eastern/Turkish [OR=2.3 (95% CI 1.3–4.2), p<0.005], when compared to the Northern Europeans, who presented more PR3-ANCA specificity; (iv) ANCA negativity was also significantly more frequent in Caucasian Americans than Northern Europeans [OR=2.0 (95% CI 1.3–3.2), p=0.002], and (v) there are differences in frequency of organ involvement between the ethnic groups, when compared to Northern Europeans, the Asian population presented significantly less ocular and ear, nose, and throat involvement while renal involvement was significantly less frequent in Caucasian Americans and significantly more frequent in Middle Eastern/Turkish, however interestingly, some differences were not completely determined by the differences in ANCA pattern.

We can simplify the mechanisms involved in the pathogenesis of vasculitides into two pathways: (i) immune-complex associated vasculitides and (ii) AAV. However, several factors are involved as: genetic basis, innate and acquired immunity, pathogens, immune tolerance disruption, and “autoantigens”.

The causes of CSVV include infections (20%), inflammatory conditions (15–20%), drug reactions (10–15%), and malignancies (5%).26 Disease-inducing or promoting factors are not known for more than half of the cases, and so they are currently classified as idiopathic.10 Although non-immunologic factors such as direct infection of endothelial cells can cause vasculitis, most lesions are mediated by immunopathogenic mechanisms. These mechanisms can be classified into Gell and Coombs’ four types of hypersensitivity reactions. The majority of cutaneous lesions are likely due to type III hypersensitivity reactions. Immune complexes deposition in postcapillary venules activates complement, which, in turn, induces mast cell degranulation and neutrophil chemotaxis.10

Virtually all drugs have been considered as potential precipitating agents for vasculitis and CSVV is by far the most common form of drug-associated vasculitis. According to the study of Ortiz-Sanjuán et al.27 the most frequently associated were antibiotics, mainly B-lactams and quinolones. Other agents involved were nonsteroidal anti-inflammatory drugs, paracetamol, allopurinol and anticonvulsants. In this series of 239 cases, patients with vasculitis due to major infections, such as endocarditis or pneumonia, were excluded.

RV is probably the most widely recognized form of secondary vasculitis and is typically seen in long standing, erosive, seropositive rheumatoid arthritis. Deposition of immune complexes and subsequent activation of the complement cascade is believed to play a key role in the pathogenesis of RV. An increased expression of inflammatory cytokines such as TNF-α, IL-1 and IL-6 is noted, although their exact role in the pathophysiology of RV remains unclear. Meanwhile, cutaneous vasculitis may be seen in approximately 19–28% of patients with SLE.28 Small vessels especially post capillary venules are involved in most cases (80–90%).28 Presence of anti-endothelial antibody is detected in up to 80% of these patients and might contribute by activation of endothelial cells, direct cytotoxic effect due to complement-dependent cytotoxicity or indirect cytotoxic effect secondary to antibody-dependent cytotoxicity.28

A great number of significant contributions have been made on the classification, pathogenesis, clinical sub-setting of cutaneous and systemic vasculitides in this paper. The chief reason for the ongoing research is to strive a personalized medicine based on endotypes rather than phenotypes. The capacity of recognizing integumentary lesions of different vasculitides, allied to other systemic symptoms and signs, an adequate biopsy and proper complementary laboratory and image exams can contribute to the correct diagnosis of this challenging group of diseases.

This study was carried out with support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Código de Financiamento 001.

Thâmara Cristiane Alves Batista Morita: Elaboration and writing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.

Gabriela Franco S. Trés: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.

Roberta Fachini Jardim Criado: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; effective participation in research orientation; critical review of the literature; critical review of the manuscript.

Mirian Nacagami Sotto: Critical review of the manuscript.

Paulo Ricardo Criado: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.

None declared.