Skin involvement in cutaneous and systemic vasculitis

Autoimmunity Reviews 12 (2013) 467–476

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Skin involvement in cutaneous and systemic vasculitis Angelo V. Marzano a, Pamela Vezzoli a,⁎, Emilio Berti b a b

U.O. Dermatologia, Fondazione IRCCS Cà Granda—Ospedale Maggiore Policlinico, Milan, Italy Università degli Studi di Milano—Bicocca, Milan, Italy

a r t i c l e

i n f o

Available online 16 August 2012 Keywords: Cutaneous vasculitis Systemic vasculitis Connective tissue diseases Livedoid vasculopathy

a b s t r a c t Cutaneous vasculitides are a heterogeneous group of inflammatory disorders affecting skin blood vessels. They may be triggered by several factors, such as infection or drug, or may be related to underlying disease, notably connective tissue or malignancies. However, vasculitis occurs without any demonstrable triggering agents in a relevant number of patients. On the other hand, vasculitic skin lesions may manifest as a component of vasculitis affecting also internal organs; in someone of these patients, skin involvement occurs initially as the sole sign of disease, leading to consider cutaneous vasculitis a diagnosis of exclusion. In this review, we have focused on the most common variants of cutaneous vasculitis, including cutaneous small vessel vasculitis and urticarial vasculitis as well as Henoch–Schönlein purpura, a systemic form in which however skin involvement often predominates. We have also argued on livedoid vasculopathy, a cutaneous entity which, although nonfrankly vasculitic in origin, is frequently associated with connective tissue disease. Finally, we have analyzed the variety of cutaneous manifestations that may develop during the course of the main systemic vasculitides, such as Wegener's granulomatosis, Churg–Strauss syndrome and polyarteritis nodosa. © 2012 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . Cutaneous vasculitides . . . . . . . . . . . . . . 2.1. Cutaneous small vessel vasculitis . . . . . . 2.1.1. Definition . . . . . . . . . . . . 2.1.2. Etiologic factors . . . . . . . . . 2.1.3. Pathogenesis . . . . . . . . . . . 2.1.4. Clinical features . . . . . . . . . 2.1.5. Histopathological aspects . . . . . 2.1.6. Direct immunofluorescence findings 2.1.7. Treatment . . . . . . . . . . . . 2.2. Urticarial vasculitis . . . . . . . . . . . . 2.2.1. Definition . . . . . . . . . . . . 2.2.2. Etiology and pathogenesis . . . . 2.2.3. Clinical features . . . . . . . . . 2.2.4. Histopathologic aspects . . . . . . 2.2.5. Direct immunofluorescence findings 2.2.6. Laboratory changes . . . . . . . . 2.2.7. Treatment . . . . . . . . . . . . 2.3. Livedoid vasculopathy . . . . . . . . . . . 2.3.1. Definition . . . . . . . . . . . . 2.3.2. Etiology and pathogenesis . . . . 2.3.3. Clinical features . . . . . . . . .

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⁎ Corresponding author at: U.O. Dermatologia Fondazione IRCCS Cà Granda—Ospedale Maggiore Policlinico, via Pace 9 20122 Milan, Italy. Tel.: +39 0255035107; fax: +39 02 50320784. E-mail address: [email protected] (P. Vezzoli). 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2012.08.005

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2.3.4. Histopathologic aspects . . . . . . . . 2.3.5. Direct immunofluorescence findings . . 2.3.6. Treatment . . . . . . . . . . . . . . 2.4. Henoch–Schönlein purpura . . . . . . . . . . 2.4.1. Definition . . . . . . . . . . . . . . 2.4.2. Etiology and pathogenesis . . . . . . . 2.4.3. Clinical features . . . . . . . . . . . . 2.4.4. Histopathologic aspects . . . . . . . . 2.4.5. Direct immunofluorescence studies . . 2.4.6. Treatment . . . . . . . . . . . . . . 2.5. Cutaneous vasculitis in connective tissue diseases 2.5.1. Treatment . . . . . . . . . . . . . . 3. Cutaneous manifestations in systemic vasculitides . . . 3.1. Polyarteritis nodosa . . . . . . . . . . . . . . 3.1.1. Definition . . . . . . . . . . . . . . 3.1.2. Cutaneous features . . . . . . . . . . 3.1.3. Histopathologic aspects . . . . . . . . 3.1.4. Treatment . . . . . . . . . . . . . . 3.2. Cutaneous polyarteritis nodosa . . . . . . . . . 3.2.1. Definition . . . . . . . . . . . . . . 3.2.2. Clinical features . . . . . . . . . . . . 3.2.3. Histopathological aspects . . . . . . . 3.2.4. Direct immunofluorescence studies . . 3.2.5. Treatment . . . . . . . . . . . . . . 3.3. Wegener's granulomatosis . . . . . . . . . . . 3.3.1. Definition . . . . . . . . . . . . . . 3.3.2. Cutaneous features . . . . . . . . . . 3.3.3. Histopathological aspects . . . . . . . 3.3.4. Direct immunofluorescence studies . . 3.3.5. Laboratory findings . . . . . . . . . . 3.3.6. Treatment . . . . . . . . . . . . . . 3.4. Churg–Strauss syndrome . . . . . . . . . . . . 3.4.1. Definition . . . . . . . . . . . . . . 3.4.2. Cutaneous features . . . . . . . . . . 3.4.3. Histopathological aspects . . . . . . . 3.4.4. Direct immunofluorescence studies . . 3.4.5. Laboratory findings . . . . . . . . . . 3.4.6. Treatment . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Cutaneous vasculitis is defined as a pathological process characterized by inflammation of the skin blood vessel wall; the disease process causes an alteration of the blood flow, ischemia, and damage to the neighboring tissue [1]. Although any type of vessel can be affected, the skin veins, particularly post-capillary venules, are more often involved than arteries and capillaries. In fact, post-capillary venules are mainly affected in cutaneous small vessel vasculitis (CSVV), also known with the histologic term of leukocytoclastic vasculitis, which is the most common form of vasculitis in dermatology [2]. Cutaneous vasculitides may be triggered by various antigenic agents, such as infection or drug, or may be related to an underlying disease, such as connective tissue, inflammatory bowel, myelodysplastic or other malignancies. However, it is important to note that many vasculitides occur without any demonstrable triggering agents, leading to consider the vasculitic process as “idiopathic”. On the other hand, vasculitic skin lesions may manifest as a component of vasculitis affecting also internal organs, cutaneous involvement being sometimes the initial sign of disease. The classification of vasculitides has been a confusing and debateprovoking topic over the last half century. Despite numerous attempts, the development of a clinically relevant and easy-to use classification system that incorporates clinical features, vessel site, histopathological and laboratory findings, and possible etiologic factors, is a goal that has not yet been fully achieved. Thus, we will adopt a recently proposed working classification for vasculitides [3]

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which is useful for the scope of the present review (Table 1). Here, we will focus on the most frequent clinical variants of cutaneous vasculitis such as CSVV and urticarial vasculitis (UV) as well as the Table 1 Proposed working classification of vasculitis. Small vessel vasculitis Cutaneous small vessel vasculitis Essential mixed cryoglobulinemia Urticarial vasculitis Henoch–Schönlein purpura Associated with connective tissue diseases Erythema elevatum diutinum Larger vessel vasculitis Polyarteritis nodosa • Systemic form • Cutaneous form Microscopic polyangiitis Granulomatous vasculitis • Wegener's granulomatosis • Churg–Strauss syndrome • Granuloma faciale Giant cell arteritis • Temporal arteritis • Takayasu's arteritis Nodular vasculitis Modified from Rook's textbook of dermatology [3].

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variety of cutaneous manifestations that may be observed in the course of the main systemic vasculitides such as polyarteritis nodosa (PAN), Wegener's granulomatosis (WG) and Churg–Strauss syndrome (CSS). Henoch–Schönlein purpura (HSP) will be argued among the cutaneous vasculitides based on that skin involvement is often predominant [1,4,5]. Unique forms of cutaneous vasculitis of specific interest for dermatologists, such as erythema elevatum diutinum, granuloma faciale or nodular vasculitis, will not be discussed. Livedoid vasculopathy (LV), a cutaneous disorder which, albeit nontruly vasculitic in origin, is frequently associated with antiphospholipid antibody syndrome and/or connective tissue diseases [6,7], will be discussed because may be of interest not only for dermatologists but also for immunologists and general readers. 2. Cutaneous vasculitides 2.1. Cutaneous small vessel vasculitis 2.1.1. Definition Affecting mainly cutaneous post-capillary venules, cutaneous small vessel vasculitis (CSVV) is the most common type of vasculitis in dermatology. The cutaneous picture of CSVV is typically polymorphous and may include in particular palpable purpura, ulcers and urticarial lesions mainly involving the legs, while its extracutaneous manifestations are by definition relatively uncommon. It affects both children and adults, and is seen more commonly in women [8–10]. 2.1.2. Etiologic factors The main etiologic factors of CSVV and their relatives prevalences are reported in Table 2. Although attempt to establish its etiology is a pivotal clinical step, a literature review and our experience suggest that at least 50% of cases of CSVV are “idiopathic” [11]. Drugs, infections or an underlying systemic inflammatory disease, most notably systemic lupus erythematosus (SLE), are the most frequently recognized triggering factors. Concerning medications, the interval between the first exposure and the appearance of symptoms for drug-induced vasculitis, can be extremely variable, i.e. hours to years, although in CSVV the incubation time usually ranges from few days to weeks [12–16]. Identifying the offending drug is the most important aspect of treatment as its discontinuation is followed by a rapid improvement of vasculitis in many cases. Among infections, hepatitis C virus is a common etiologic factor for mixed cryoglobulinemia, which may lead to an immune complex vasculitis affecting small and medium size vessels of the skin and kidney, the so-called cryoglobulinemic vasculitis [17]. On the other hand, it is important to be aware that CSVV can occur as part of systemic vasculitides such as Wegener's granulomatosis (WG), Churg–Strauss syndrome or polyarteritis nodosa, and that some patients with Henoch–Schönlein purpura (HSP) may be erroneously thought to have “simple” CSVV if renal involvement is delayed or direct

Table 2 Etiologic factors for cutaneous small vessel vasculitis. Etiologic factors

Prevalences (%)

Drugs (antibiotics, diuretics, NSAIDS, anticonvulsants, antipsychotics, cardiovascular, TNF-α inhibitors, rituximab, interferon beta) Infections Connective tissue disease Malignancy Inflammatory bowel disease Chronic active hepatitis Idiopathic

10–15

15–20 15–20 b5 b5 b5 50

NSAIDS: non steroidal anti‐inflammatory drugs; TNF: tumor necrosis factor.

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immunofluorescence fails to show perivascular IgA deposits as occurs in biopsy of older lesions. Thus, CSVV is really a diagnosis of exclusion. 2.1.3. Pathogenesis The major pathogenetic mechanism in CSVV is an immune complex reaction, namely Gell and Coombs type 3 reaction, which agrees with that, histopathologically, this form of vasculitis is typically leukocytoclastic with a predominantly neutrophilic infiltrate [18– 21]. Formation of immune complexes may be due to several triggers, particularly drugs or bacterial/viral antigens, as mentioned above. The circulating immune complexes mediating vasculitis interact with the complement system, generating C3a and C5a anaphylatoxins, which initiate chemotaxis of neutrophils and release of vasoactive amines, causing endothelial cell retraction. Secreted proinflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF)-α and γ-interferon (INF-γ), as well as chemokines, including IL-8, monocyte chemotactic protein-1 (MCP-1) and RANTES (regulated upon activation, normal T-cell expressed and secreted), cause increased expression of E- and P-selectins and of the adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) by endothelial cells [22,23]. The latter event induces the transendothelial migration, recruitment into the inflammatory site and activation of neutrophils. Degranulation and destruction of these cells with release of collagenases and elastases, and generation of reactive oxygen species, ultimately result in inflammation and fibrinoid necrosis of "bystander" vessel walls. CD4 + T helper lymphocytes act in the CSVV pathophysiology secreting cytokines, notably IL-1, IFN-γ and TNF-α, and recruiting CD8 + cytotoxic T cells, B cells and natural killer (NK) cells, which play a part in the inflammatory network; moreover, a role for γ/δ T lymphocytes has been suggested in the later stages of CSVV [24]. Histologically, T lymphocytes are found in the inflammatory infiltrate of CSVV and may become the mostly represented cell with the passage of time. On the other hand, some authors have proposed the existence of a lymphocytic cutaneous vasculitis as a distinctive subset which has been named lymphocytic thrombophilic arteritis, due to its histologic features that combine lymphocytic vascular inflammation with changes of thrombophilic endovasculitis [25,26]. An additional pathomechanism in CSVV is that of a direct endothelial cell damage, which is triggered especially by vasculotropic viruses; the endothelial changes may also be indirect, caused by an autoimmune response that is generated by exposed autoantigens. The role of autoantibodies, such as antiphospholipid antibodies, antineutrophil cytoplasm antibodies (ANCA) and antiendothelial cell antibodies (AECA), in CSVV is largely debated. Antiphospholipid antibodies may be detected notably in CSVV associated with connective tissue diseases and have numerous actions [27]; in particular, they act pathogenetically by activating the blood coagulation cascade and increasing the levels of tissue plasminogen activator inhibitor. ANCA, which have both diagnostic value and a pivotal role in the pathogenesis of systemic vasculitides [28], are only rarely found in the serum of patients with CSVV. Finally, the potential pathogenetic role of AECA, which has been proposed for systemic vasculitides [29], remains still undefined in CSVV. 2.1.4. Clinical features The major cutaneous manifestation of CSVV is palpable purpura, ranging in site from 1 mm to several centimeters; such purpura can remain the sole feature or may progress to a wide array of manifestations including papules, nodules or plaques as well as pustules or vesiculo-bullae, the latter usually evolving into ulcerative–necrotic lesions which heal with post-inflammatory hyperpigmentation (Fig. 1a and b). Other cutaneous findings include livedo reticularis, which describes a mottled red or bluish discoloration of the skin with a net-like pattern, urticaria and edema. Lesions typically occur in areas prone to stasis, particularly the lower legs; sometimes they

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lesions (Fig. 1d) [9]. IgG is found less often. Direct immunofluorescence may result falsely negative depending on timing of skin biopsy.

Fig. 1. a) Typical polymorphous pattern of cutaneous small vessel vasculitis on the lower legs; b) ulcerative–necrotic lesions in cutaneous small vessel vasculitis; c) histology consistent with leukocytoclastic vasculitis (hematoxylin–eosin stain; original magnification, ×200); d) direct immunofluorescence revealing immunoglobulin M deposits around small blood vessels in the upper dermis.

may extend to involve the ankles, lower portion of the trunk and upper extremities [9,10,18,30–32]. Although often asymptomatic, burning, pain or more rarely pruritus may be experienced. The skin lesions of CSVV typically arise as a simultaneous “crop” and usually resolve within several weeks or a few months. Approximately 10% of patients follow a chronic-relapsing course over a period ranging from few to several years [33,34]. The cutaneous picture may be accompanied by systemic symptoms including fever, arthralgia, myalgia and anorexia. Renal involvement is uncommon in CSVV; in fact, although it was documented in 43% of cases in one study of 90 patients with CSVV [26], renal biopsy led to reclassification of most of them as systemic vasculitides, particularly HSP and WG [35]. As for renal involvement, the presence of symptoms affecting other organ systems should raise the suspicion of systemic vasculitides, making CSVV a diagnosis of exclusion.

2.1.7. Treatment A therapeutic ladder for patients with CSVV is reported in Table 3. Treatment of CSVV may be unnecessary, as the disease is self-limiting in a relevant number of patients. If any triggering agents for CSVV such as a drug or infection are identified, they should be removed or treated; moreover, the patient should be aware to elevate dependent areas with the aim of minimizing stasis. In such patients with mild disease, topical corticosteroids in combination with oral antihistamines can be used to produce a decrease in symptoms like burning or itching [18]; non-steroidal anti-inflammatory drugs should be avoided because they are commonly identified as triggering agents for CSVV. Systemic immunosuppressive regimens are considered to be necessary for more aggressive and/or chronic-relapsing CSVV, although the evidence for efficacy of any therapy is derived from clinical experience rather than controlled trials. In our opinion, systemic corticosteroids, namely methylprednisolone at an initial dosage of 0.8–1 mg/Kg/day and then at progressively tapering dosages until discontinuation after 4–8 weeks, should be regarded as the first-line agents for patients with painful ulcerative–necrotic skin lesions. Several steroid-sparing immunosuppressants may be associated to corticosteroid particularly in highly relapsing cases; such agents include azathioprine, at a dosage of 1–2 mg/Kg/day, methotrexate, at a low dose (10–15 mg/week), and cyclophosphamide at a dose of 1–2 mg/Kg/day [38,39]. The immunomodulating agent dapsone (1–2 mg/Kg/day) may be advantageous for patients with locally less aggressive CSVV [40]. Our group has recently reported the efficacy and safety of ciclosporin in the management of recalcitrant CSVV and proposed this agent as first-choice therapy for patients in whom the use of corticosteroid is contraindicated [41]. In patients with disease refractory to the above therapies, other regimens, including intravenous gammaglobulins, plasmapheresis and biologics, may be considered. Among biologics, the TNF-α blocker infliximab and the anti-CD20 monoclonal antibody rituximab appear to be the most promising [42,43]. However, it is of note that both of these agents have also been reported to cause vasculitis [44,45]. 2.2. Urticarial vasculitis 2.2.1. Definition Of patients with chronic urticaria, approximately 5–10% have UV [46,47]. This is a chronic-relapsing disease, which presents with wheals most often occurring on the proximal limbs and trunk. Lesions differ from those of true urticaria in that individual lesions persist for more than 24 h, are more commonly painful or accompanied by burning sensation than pruritic, and often leave post-inflammatory pigmentation after resolution [48]. Two types of UV have been described: UV

Table 3 Therapeutic ladder for patients with cutaneous small vessel vasculitis.

2.1.5. Histopathological aspects The typical histopathological pattern of CSVV is the so-called leukocytoclastic vasculitis, characterized by upper dermal perivascular infiltrates mainly composed of neutrophils with karyorrhexis of nuclei; swelling of the endothelium, fibrinoid necrosis of vessel walls and extravasation of erythrocytes are the other histological features of CSVV (Fig. 1c) [9,36]. The presence of numerous eosinophils in the inflammatory infiltrate is regarded as a clue to a drug etiology [37]. 2.1.6. Direct immunofluorescence findings In upper dermal vessels, immunoglobulin (Ig) M and/or complement C3 perivascular deposits are demonstrable in over 80% of fresh

Mild/self-limiting disease □ Supportive therapy □ Topical corticosteroids □ Antihistamines Ulcerative/recalcitrant disease □ Methylprednisolone □ Steroid-sparing immunosuppressants: ➢Dapsone ➢Azathioprine ➢Methotrexate ➢Cyclophosphamide ➢Ciclosporin ➢Mycophenolate mofetil

Refractory disease □ Intravenous gammaglobulins □ Plasmapheresis □ Infliximab □ Rituximab

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associated with hypocomplementemia (hypocomplementemic UV syndrome, with or without systemic manifestations), and UV without associated hypocomplementemia (normocomplementemic UV) [47,49,50]. Urticarial vasculitis may be described as a continuum of disease progressing from normocomplementemic UV to hypocomplementemic UV, with or without systemic findings. On the other hand, Wisnieski, based on his retrospective study [47], suggested that there is no transition between these UV subtypes. Normocomplemetemic UV has a slight female predominance, whereas hypocomplementemic UV is seen almost exclusively in female patients. 2.2.2. Etiology and pathogenesis Although most cases of UV are idiopathic, there are a variety of conditions associated with it such as infections, hematologic diseases, malignancy, physical urticarias, exercise, exposure to ultraviolet light and cold, and connective tissue diseases, these last representing the most commonly associated disorders, particularly SLE and Sjögren's syndrome [51,52]. Urticarial vasculitis is thought to represent a type III hypersensitivity reaction, as circulating immune complexes may be demonstrated in up to 75% of patients [53]. Complement and immunoglobulin deposition in vessel walls, with complement cascade activation in patients with UV, further supports this theory [54]. In hypocomplementemic UV, there are IgG serum autoantibodies directed against the collagen-like region of C1q, which form immune complexes and activate the complement pathway, resulting in a reduction of C1q in the serum [55,56]. 2.2.3. Clinical features Cutaneous lesions of both the hypocomplementemic and normocomplementemic forms of UV are erythematous wheals that may contain purpuric foci and may be associated with angioedema. The term angioedema defines localized edema involving the dermis as well as subcutaneous and submucosal tissues. Livedo reticularis as well as the other cutaneous manifestations of CSVV such as papules, nodules, bullae and necrotic–ulcerative lesions may be evident [46–48]. Patients with the hypocomplementemic form may have constitutional symptoms such as fever, malaise and myalgia, arthralgia and arthritis, these last being the most commonly encountered systemic symptoms with roughly 50% of patients reporting arthralgias [57,58]. Renal involvement, manifesting as glomerulonephritis or interstitial nephritis, has been found to occur in 20–30% of patients with hypocomplementemia [57,59]. Chronic obstructive pulmonary disease and asthma can be present in around 20% of hypocomplementemic patients; other respiratory symptoms may be dyspnea and laryngeal edema [58,60]. Gastrointestinal symptoms include abdominal pain, nausea, vomiting and diarrhea and are noted between 15 and 30% of the cases [57]. Ophthalmologic complications, including episcleritis, uveitis, or conjunctivitis, may occur in up to 10% of patients with UV [48]. Finally, UV patients may have lymphadenopathy and/or hepatosplenomegaly. 2.2.4. Histopathologic aspects Lesions of UV typically shows a histologic pattern of leukocytoclastic vasculitis [60]; aspects of true urticaria, namely upper dermal edema with minimal diffuse infiltrate of lymphocytes and eosinophils, may be associated [47]. On the other hand, some UV cases have a lymphocyte-predominant perivascular infiltrate [61]. 2.2.5. Direct immunofluorescence findings Direct immunofluorescence studies on skin biopsy specimens taken from recent lesions reveal IgM, IgG, and/or C3 perivascular deposits in the upper dermis. 2.2.6. Laboratory changes Patients with hypocomplementemic UV demonstrate an elevated erythrocyte sedimentation rate, hypocomplementemia with low C1q,

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C3 and C4 plasma levels and presence of circulating C1q autoantibodies; a low-titer positive antinuclear antibodies are also detectable. 2.2.7. Treatment The majority of patients with UV respond to systemic corticosteroids; in contrast, urticaria-like lesions as well as angioedema are typically resistant to oral antihistamines. If necrotic–ulcerative lesions occur and/or in recalcitrant cases the steroid-sparing immunosuppressive agents argued in detail for CSVV may be considered. 2.3. Livedoid vasculopathy 2.3.1. Definition Livedoid vasculopathy (LV) is a rare, distinctive dermatosis characterized by persistent livedo reticularis and recurrent painful ulcerative skin lesions, usually involving the lower extremities and resolving with hyperpigmentation and atrophic white scars [62,63]. LV may be associated with infections, malignancies and particularly systemic autoimmune diseases [7,64], but sometimes no underlying disorder can be detected [6]. The latter, “idiopathic” form of LV is at present considered to be a non-inflammatory thrombotic disease due to occlusion of dermal small vessels [63,65] that may occur in patients with coagulation abnormalities [66–70]. 2.3.2. Etiology and pathogenesis To date, the pathogenesis of LV is not fully elucidated. There are two forms: a primary or idiopathic form and a secondary form. Hypercoagulable disorders and autoimmune diseases are the conditions most commonly associated with LV, the first being possibly provoking factors for a number of LV cases reported as idiopathic. Among the hypercoagulable conditions, hyperhomocysteinemia, which is characterized by an increased cardiovascular risk and deep vein thrombosis, has been reported with LV [71]. Hyperhomocysteinemia may be genetically determined or acquired, as occurring particularly in patients with chronic renal failure, pernicious anemia or assuming some medications. Activated protein C resistance due to the factor V Leiden mutation is the commonest inherited cause of thrombophilia reported in association with LV [72]. Several reports have associated LV and prothrombin gene mutations [73] or protein C deficiency [68], both conditions representing relevant risk factors for thrombotic events. Livedoid vasculopathy has also been reported in association with increased serum levels of plasminogen activator inhibitor (PAI)-1, a glycoprotein that inhibits the fibrinolytic system [70]. The associations with immune-mediated conditions include antiphospholipid antibody syndrome [64], SLE [74], scleroderma [75], mixed connective-tissue disease [76] and PAN [77]; in these cases, the pathophysiology of LV is debated. Some authors believe that immunemediated mechanisms are responsible for vascular damage, leading to a true small vessel vasculitis process, as confirmed by the effectiveness of immunosuppressive therapy [6]. On the contrary, others suggest that LV is due to the pro-coagulable state induced by the underlying systemic disease rather than being true vasculitis [7]. 2.3.3. Clinical features Purpuric lesions are the primary cutaneous manifestations of LV. With time, purpura progresses to asymmetrical, irregular, painful leg ulcers that heal leaving depressed rounded porcelain-like scars, the latter also known with the term atrophie blanche. The scars are surrounded by telangiectases and hyperpigmentation. Persistent livedo reticularis is commonly present (Fig. 2) [7]. Although the lower extremities are the most commonly involved site in LV, a widespread cutaneous presentation has also been described [6]. The course is typically chronicrelapsing, the disease duration ranging from few months to several years [6]. Both systemic manifestations and cutaneous findings related to an underlying disease can occur during the course of LV.

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2.4. Henoch–Schönlein purpura 2.4.1. Definition Henoch–Schonlein purpura (HSP) is defined as a vasculitis affecting small vessels, involving deposition of IgA immune complexes, that characteristically involves the skin, gastrointestinal system and glomeruli with or without arthralgia or arthritis [2,80]. Cutaneous involvement occurs in virtually all patients affected by this vasculitis and may represent the only sign of the disease in those cases confined to the skin; the latter accounts for about 10% of all cases of cutaneous vasculitis [1,10]. Based on these findings, we discuss HSP within the group of cutaneous vasculitides in the present review. HSP is much more common in childhood, namely 90% of cases occur in children under 10 years [81]. 2.4.2. Etiology and pathogenesis A preceding upper respiratory tract infection occurs in approximately 30% of patients, while a history of recent drug exposure is reported in a minority of patients [82]. Although many pathogens such as group A β-hemolytic streptococcus, Staphylococcus aureus and various viruses have been implicated, a triggering pathogen is not found in the majority of cases. IgA is thought to play a pivotal role in the pathophysiology of HSP, as confirmed by increased serum levels of IgA, increased circulating immune complexes containing IgA and increased deposition of IgA in blood vessel walls and in the renal mesangium in patients affected by this disease. Other antibodies demonstrated in HSP include IgA ANCA, IgA anticardiolipin antibodies and IgA AECA, whose exact role in this disease is still not completely defined. Activation of several cytokines is well documented, particularly TNF-α, whose expression has been detected in HSP lesional skin, IL-6, IL-8, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β, this last enhancing IgA1 responses. Finally, neutrophil activation, elevated nitric oxide levels and reactive oxygen species are all documented [83].

Fig. 2. Necrotic–ulcerative lesions, livedo reticularis and hyperpigmentation on lower extremities in livedoid vasculopathy.

2.3.4. Histopathologic aspects Histology usually shows segmental hyalinization, endothelial proliferation and thrombosis of the upper and mid-dermal small vessels associated with a mild, mainly perivascular, lymphocytic infiltrate. Neutrophilia and leukocytoclasia are more rarely seen, particularly in patients with an underlying immune-mediated disease. At a late stage, epidermal atrophy is evident, with thickened hyalinized vessels and deposition of hemosiderin [6,7].

2.3.5. Direct immunofluorescence findings Direct immunofluorescence usually reveals deposition of IgM, complement C3 and/or fibrin around the upper and mid-dermal small vessels but may be negative in a relevant number of patients [6,7].

2.3.6. Treatment Antiplatelet therapy, such as low-dose aspirin or dipyridamole, is usually chosen as first-line treatment; pentoxifylline or prostacyclin has also been used. If LV lesions recur or extend despite antiplatetelet agents, anticoagulation with warfarin is usually prescribed [7,78]. Sildenafil has been successful in cases of recalcitrant nonhealing skin ulcers [79]. Adding immunosuppressive therapy, including systemic corticosteroid and particularly ciclosporin, is mandatory in cases nonresponsive to the above agents [6].

2.4.3. Clinical features Purpura is a feature in 100% of patients and may be the presenting sign in half of the cases [1]. Purpuric lesions are commonly located on the extremities and buttocks with a symmetrical distribution, and are accompanied, followed, or sometimes preceded by arthralgia (75% of patients) and abdominal pain (65% of cases). The skin lesions present as slightly raised palpable hemorrhagic purpura, which may show a typical retiform pattern and extend to involve also the trunk and rarely the face. In adults, vesiculobullous lesions and necrotic ulcers may develop, while hemorrhagic bullous evolution has been seldom described in childhood [84]. Usually fading within a few days, crops of lesions can recur for a few weeks to several months. Renal involvement occurs in 40–50% of patients with either macroscopic or microscopic hematuria and proteinuria; only 1–3% of these patients progress to end-stage renal failure, but around 20% of patients have renal abnormalities on long-term follow-up [81]. Hematochezia is observed in 30% of patients with HSP [81]. Less common extracutaneous manifestations of HSP comprise orchitis, uveitis and neurological abnormalities [81]. 2.4.4. Histopathologic aspects Biopsy specimens of the purpuric lesions demonstrate leukocytoclastic vasculitis affecting dermal small vessels. 2.4.5. Direct immunofluorescence studies Direct immunofluorescence of lesional and perilesional skin reveals deposition of IgA, C3 and fibrin in dermal small vessel walls. 2.4.6. Treatment For the cutaneous lesions of HSP, the therapeutic ladder presented for CSVV is also applicable for patients with HSP.

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2.5. Cutaneous vasculitis in connective tissue diseases Around 12% of cutaneous vasculitis cases are associated with a connective tissue disease, such as SLE, systemic sclerosis, dermatomyositis, and rheumatoid arthritis [10]. Cutaneous vasculitis can be frequently observed in patients with SLE and less commonly in the other connective tissue diseases. The most common type of cutaneous vasculitis that occur in SLE is CSVV, whose polymorphous cutaneous picture and histopathological pattern of leukocytoclastic vasculitis have been described in detail in the section on CSVV. Conversely to SLE, vasculitic lesions are only rarely seen in cutaneous lupus erythematosus. It is of note that vasculitic lesions clinically and histologically consistent with CSVV, occur in contrast very frequently in the drug-induced variant of the so-called subacute cutaneous lupus erythematosus [85,86]. Cutaneous small vessel vasculitis may develop also in the other disorders within the group of connective tissue diseases, but less frequently than in SLE. The other form of cutaneous vasculitis commonly found in SLE as well as, albeit more rarely, in the other connective tissue diseases is UV, previously discussed in the present review. Livedoid vasculopathy, alone or with coexisting antiphospholipid antibody syndrome, may be associated with SLE as well as with other connective tissue diseases, as argued above. Pioderma gangrenosum is a well documented association with both SLE and rheumatoid arthritis [87]. It is an ulcerative skin disease regarded as non-vasculitic in origin but classified within the spectrum of neutrophilic dermatoses, autoinflammatory disorders caused by the recruitment and activation of neutrophils into the skin [88,89]. 2.5.1. Treatment The therapies for vasculitic skin lesions occurring during the course of a connective tissue disease are those discussed in the sections on CSVV and UV, respectively. 3. Cutaneous manifestations in systemic vasculitides 3.1. Polyarteritis nodosa 3.1.1. Definition Polyarteritis nodosa is a rare, severe necrotizing vasculitis of small- and medium-sized arteries affecting multiple organ systems. The disease has a segmental distribution and localizes chiefly in bifurcations and branchings of arteries [2]. Cutaneous manifestations of systemic PAN should be distinguished from those proper to the benign form confined to the skin [1]. 3.1.2. Cutaneous features Skin involvement can be found in about half of the patients with systemic PAN. The most common skin lesions are palpable purpura associated with erythema mainly on the lower extremities [1]. A subcutaneous nodule or group of nodules ranging from 0.5 to 2 cm may develop, predominantly on the lower limbs and often in proximity to vessels; however, typical nodules are identified in less than 20% of cases, and never in some series of patients [90]. Nodules may become pulsatile due to fibrosis resulting in weakness of the vessel wall or may be secondarily ulcerated with normal or erythematous overlying skin. Livedo reticularis may occur, with or without ulceration; ulceration and gangrene of the digits or penis may also develop. 3.1.3. Histopathologic aspects The histopathological pattern of PAN is that of leukocytoclastic vasculitis; however, the inflammatory infiltrate, which is initially neutrophil-rich, becomes subsequently predominantly lympho/ histiocytic. The vasculitis may cause development of microaneurysms

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as blood vessel walls become weak and may rupture leading to luminal thrombosis and obliteration, thus resulting in distal tissue ischemia and ultimately necrosis [91]. 3.1.4. Treatment Cutaneous manifestations of PAN are usually responsive to immunosuppressive agents introduced to control systemic disease. 3.2. Cutaneous polyarteritis nodosa 3.2.1. Definition Cutaneous polyarteritis nodosa (C-PAN) is a variant of PAN confined to the skin, although controversy exists on whether or not it simply represents an early or more limited form of PAN [92]. Thus, diagnosis of C-PAN comes only from the exclusion of visceral changes and involves a better prognosis, although lesions may persist, relapse, and cause a high degree of discomfort. Extracutaneous involvement is limited to adjacent muscles, nerves, and joints, and may manifest as myalgias, peripheral neuropathy and arthralgias, sometimes accompanied by fever [6]. 3.2.2. Clinical features Nodular lesions, which vary in color from pink to purple-red, are most commonly located on the distal lower extremities near the malleoli and may extend proximally to the thighs, buttocks, arms or hands; patients may report tenderness associated with the nodules. Nodules may ulcerate and crops of more than 50 lesions can be appreciated on an area of livedo reticularis, which is often an accessory sign [6]. Gangrene of digits can ultimately occur, most commonly in children [93]. 3.2.3. Histopathological aspects Early in the course of C-PAN, lesions show the same histopathology as in the systemic form, namely a leukocytoclastic vasculitis affecting the walls of medium-sized arteries and arterioles of septae in the upper portions of the subcutaneous fat. The involved vessels typically demonstrate a target-like appearance resulting from an eosinophilic ring of fibrinoid necrosis. As in the systemic PAN, later in the disease process the infiltrate is predominantly composed of lymphocytes and histiocytes [91]. 3.2.4. Direct immunofluorescence studies Direct immunofluorescence can provide positive results for IgM and C3, either alone or combined, and sometimes detectable only in superficial and uninvolved derma. 3.2.5. Treatment Although no double-blind controlled trials have been performed, systemic corticosteroids, namely methylprednisolone at the initial dosage of 0.8–1 mg/Kg/day, usually control C-PAN [94]. Low-dose weekly methotrexate (7.5–20 mg/week) may be considered for patients with skin lesions unresponsive to corticosteroids [95]. Other treatments recently documented in anecdotal reports include warfarin [96] and infliximab [97]. 3.3. Wegener's granulomatosis 3.3.1. Definition Wegener's granulomatosis is a rare immune-mediated multisystem disease of unknown etiology which is characterized by a pathological triad consisting of granulomatous inflammation of the upper and/or lower respiratory tract, glomerulonephritis and systemic necrotizing vasculitis of small and medium vessels [98,99]. Without treatment, the mainstay of which is the combination of cyclophosphamide and systemic corticosteroids, it may run a fatal course. Although 40% of patients with WG will eventually manifest

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skin findings, cutaneous manifestations and oral ulcers are only found in 13% and 6% of patients at initial presentation, respectively [100]. 3.3.2. Cutaneous features The most common skin lesion of WG is palpable purpura on dependent skin sites; tender subcutaneous nodules, papules, vesicles and petechiae as well as non-specific ulcers or pyoderma gangrenosumlike ulcerative lesions complete the wide clinical spectrum [101]. Nodular or necrotic–ulcerative lesions most commonly occur on the extremities but may also occur on the face and scalp. A rare distinctive subset of WG limited to the facial region and upper airway mucosa, lacking systemic involvement but showing a locally aggressive behavior with cartilage and bony destruction, has recently been described (Fig. 3) [102,103]. Oral involvement may manifest as nonspecific erosive/ ulcerative lesions or rarely present with the so-called strawberry gingivitis, which is a hyperplastic granular gingivitis nearly pathognomonic for WG [104–106]. 3.3.3. Histopathological aspects The histopathological pattern of leukocytoclastic vasculitis is present in up to 50% of skin biopsy specimens, sometimes with associated granulomatous inflammation. Granulomatous inflammation around vessels or palisading necrotizing granulomas as seen in the internal organ infiltrates are uncommonly demonstrated in WG lesional skin. In the remaining cases, histology shows non-specific perivascular lymphocytic infiltrates [103]. 3.3.4. Direct immunofluorescence studies Immunofluorescence may show IgM and C3 in the wall of dermal vessels [1]. 3.3.5. Laboratory findings It is of note that c-ANCA, which are considered the marker for multisystem WG, have been reported to be absent in up to 40% of WG cases, particularly in those lacking renal involvement [107]. In

contrast, other studies found a high frequency of ANCA-positive patients with localized disease [102]. However, we emphasize that c-ANCA may be negative in patients with localized WG, as previously reported [103]. 3.3.6. Treatment Cutaneous manifestations of WG are usually responsive to immunosuppressive agents given to control systemic disease. For the recently described subset of WG limited to the face and upper airway mucosa, the combination of prednisone and cyclophosphamide represents the mainstay of treatment as for systemic disease, due to its locally aggressive behavior [103]. 3.4. Churg–Strauss syndrome 3.4.1. Definition Churg–Strauss syndrome (CSS) is a rare systemic vasculitis involving small vessels (i.e. arterioles, venules, and capillaries) and affecting several organs and systems. It usually starts with asthma, often accompanied by allergic rhinitis and sinusitis, before progressing to peripheral and tissue eosinophilia and eventually resulting in overt necrotizing vasculitis with extravascular granulomas [108]. The survival rate of CSS ranges from 68% to 100% at 5 years [109]. There have been several reports of an association between CSS and thrombosis [110,111], as documented for hypereosinophilic syndromes [112]. A prothrombotic state in CSS has recently been demonstrated [113]; with this background, it has been suggested that eosinophilderived tissue factor, activating the coagulation cascade, may play a role in the mechanism leading to thrombosis in patients with CSS or hypereosinophilic syndromes as well as in patients with bullous pemphigoid, an eosinophil-mediated autoimmune skin disease [114,115]. Two-third of patients with CSS demonstrate cutaneous findings while in the active phase of the disease, and the skin lesions may appear also in its early stages [1]. 3.4.2. Cutaneous features Palpable purpura and nodules, typically located on the limbs and scalp, are the most common skin manifestations, but livedo reticularis, vesicles, aseptic pustules, petechiae, ecchymoses and urticarial lesions can also appear at the same time or in different stages of the disease; papular and nodular lesions may undergo a necrotic– ulcerative evolution [1,116]. A maculopapular erythematous eruption resembling erythema multiforme has also been described [3]. 3.4.3. Histopathological aspects The skin biopsy shows a leukocytoclastic vasculitis mostly involving venules; in some lesions, the vessel wall reveals fibrinoid changes surrounded by a granulomatous inflammatory process. Peculiar to this form of vasculitis is the finding of numerous eosinophils in the infiltrate, in addition to neutrophils, lymphocytes and macrophages, that has an important diagnostic value. A relevant number of eosinophils are detectable also in CSS granulomas, where they are associated with macrophages and multinucleated giant cells [1]. 3.4.4. Direct immunofluorescence studies Direct immunofluorescence may show the presence of IgM and C3 in dermal blood vessels [1]. 3.4.5. Laboratory findings Peripheral blood eosinophilia (defined as a persisting eosinophil count > 1500/μL) is the most striking laboratory finding in CSS.

Fig. 3. Skin ulcer with cartilage and bony destruction involving the nose in localized Wegener's granulomatosis.

3.4.6. Treatment Cutaneous manifestations of CSS are usually responsive to immunosuppressive drugs administered to control systemic disease.

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Take-home messages • Cutaneous vasculitis is a heterogeneous group of inflammatory disorders affecting skin blood vessels, particularly post-capillary venules. • Cutaneous small vessel vasculitis (CSVV), also known as leukocytoclastic vasculitis, is the most common entity within this group. • Many triggering factors may be identified in cutaneous vasculitis, but it is idiopathic in a relevant number of cases. • The cutaneous picture of CSVV is polymorphous, including purpura, urticarial lesions and ulcers, while its extracutaneous manifestations are uncommon. • Urticarial vasculitis is a cutaneous vasculitis in which wheals, persisting more than 24 h, are the major skin finding. • Cutaneous vasculitis lesions arise as simultaneous “crop” and resolve within weeks or months; recalcitrant forms require immunosuppressive treatment. • Cutaneous vasculitis can occur as part of systemic vasculitides, with skin involvement possibly preceding visceral disease. • Based on the latter finding, cutaneous vasculitis must be regarded as a diagnosis of exclusion.

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