Purpura fulminans is a life threatening disorder characterized by cutaneous hemorrhage and necrosis in the setting of disseminated intravascular coagulation (DIC) . Purpura fulminans may be idiopathic or it can be caused by infections or inherited abnormalities of the coagulation system [1, 2].

Acute infectious purpura fulminans is the most common form and occurs in the setting of severe bacterial infection. Purpura fulminans in neonates and children may be a presenting feature of severe acute sepsis and it is a cardinal feature of meningococcal septicemia in 1–20 % of cases [3, 4]. Purpura fulminans due to inherited abnormalities of coagulation typically presents in the first 72 hours of life [2]. Ecchymotic, petechial and purpuric lesions progress to areas of necrosis and loss of tissue. Disease management involves supportive therapy and treatment of any existing infection.

The histologic changes seen in what is recognized clinically as purpura fulminans are identical, regardless of the underlying etiology. They are those of an obstructive vasculopathy (Fig. 8.1). Vessels within the dermis are occluded with fibrin thrombi without much evidence of an inflammatory infiltrate or vascular wall damage [5] (Fig. 8.2). In older lesions, secondary changes such as tissue necrosis, ulceration and reactive inflammation may be seen, but these are not part of the primary pathology.

Purpura fulminans can be caused by infectious microorganisms, such as Neisseria meningitidis. N. meningitidis are encapsulated bacteria expressing type IV pili (Tfp) , which are essential for meningococcal pathogenesis as they mediate bacterial adhesion onto endothelial cells [6]. Tfp-induced signaling may be responsible for invasive meningococcal infection by enabling crossing of the blood–brain barrier, and the subsequent peripheral thrombosis and leakage syndrome seen in purpura fulminans.

Although rare, purpura fulminans in neonates can be a manifestation of severe heritable defects of the protein C or protein S anticoagulant pathway [7, 8]. Homozygous protein C or protein S deficiency together with homozygous or heterozygous PROC (Protein C, Inactivator Of Coagulation Factors Va and VIIIa) gene mutants often results in fatal cases of neonatal purpura fulminans [9–11]. In some patients, a combination of sepsis and partial defect in the PROC anticoagulant pathway is sufficient to incite purpura fulminans, suggesting synergy between these initiators [3, 12, 13]. The disorder can also occur as an autoimmune phenomenon after an otherwise benign infection, such as Varicella [3].

Anti-phospholipid syndrome is a multisystem autoimmune disorder characterized by venous and arterial thrombosis in the presence of persistent antiphospholipid antibodies. Anti-phospholipid syndrome is rare in children with disease onset before 15 years of age occurring in about 3 % of reported cases [14]. A diagnosis of anti-phospholipid syndrome in the setting of systemic lupus erythematosus is more likely and accounts for 9–14 % of pediatric cases [15]. Cutaneous manifestations of anti-phospholipid syndrome are variable, but can include livedo reticularis, Raynaud’s phenomenon, skin ulcers, and chronic urticaria (Fig. 8.3) [16]. Treatment of the syndrome includes long-term anticoagulation therapy.

Similar to purpura fulminans, the histologic findings of anti-phospholipid syndrome are those of an obstructive vasculopathy . Occlusion of small vessels with fibrin thrombi leads to infarction and secondary tissue necrosis, ulceration and inflammation (Fig. 8.4). Extravasation of erythrocytes is present in some cases. There is minimal inflammation associated with the primary pathology [17–19].

Antiphospholipid-induced thrombosis is thought to result from a hypercoagulable state caused by direct activation of monocytes, platelets, endothelial cells and neutrophils by anti-phospholipid syndrome antibodies [20]. Increased levels of tissue factor, a key molecule in the coagulation cascade, and activated complement factors, which have also been associated with antiphospholipid antibodies, may lead to the activation of the coagulation cascade [21]. In the case of pregnant women, placental dysfunction is a hallmark of anti-phospholipid syndrome with complications including preeclampsia and intrauterine growth restriction. Direct interaction between antiphospholipid syndrome antibodies and trophoblast cells may trigger cellular injury by leading to unchecked coagulation reactions [22, 23].

Henoch–Schonlein purpura is a variant of leukocytoclastic vasculitis. It is an IgA-mediated systemic small vessel vasculitis. It is the most common vasculitis seen in children and affects 8–20 per 100,000 children annually. It typically affects children ages 3–8 years. Henoch–Schonlein purpura is slightly more common in males with a male to female ratio of 1.5:1 [24]. It is often preceded by an acute infectious illness, and more common in the non-summer months.

Clinically, patients present with petechial/palpable purpuric lesions concentrated over the buttocks and legs along with one or more of the following: colicky abdominal pain, arthritis or arthralgia, and renal involvement (proteinuria and hematuria) (Fig. 8.5). Arthritis commonly affects the ankles and knees. Approximately 30 % of children have renal involvement [25].

Treatment is generally supportive, although systemic steroids may be helpful in cases where arthritis is severe or renal involvement is significant. Most patients recover within 6–8 weeks, although a small percentage may develop chronic renal disease and up to one third of patients may experience a recurrence [24].

Acute hemorrhagic edema of infancy is a benign, self-limited leukocytoclastic vasculitis of childhood. It is most common in children between the ages of 4 months and 2 years [26, 27]. Clinically, it is characterized by low-grade fever, edema, and purpura. Purpuric lesions tend to favor the face, ears, and extremities, with relative sparing of the trunk (Fig. 8.6). Treatment is generally supportive and most patients recover spontaneously within 1–3 weeks [26].

Histologic findings of leukocytoclastic vasculitis include an inflammatory infiltrate consisting primarily of neutrophils surrounding and invading dermal blood vessels (Fig. 8.7). In the majority of cases, post-capillary venules are the most affected. In other cases, larger vessels may be involved and extension into the deep dermis and subcutis can be seen. In addition to transmural extension of neutrophils, endothelial swelling and destruction, fibrin thrombi, and extravasated erythrocytes are present [28] (Figs. 8.8 and 8.9). Karyorrhectic debris is commonly seen. In some cases, especially those caused by drugs, eosinophils may be seen in the infiltrate [29]. Infarction with secondary necrosis, ulceration, and diffuse inflammation are seen in florid cases and in late stage lesions . Direct immunofluorescence studies demonstrate IgG, C3, and occasional IgM deposition around and within vessel walls.

Henoch–Schonlein purpura is histologically indistinguishable from other variants of leukocytoclastic vasculitis. In these cases, the vasculitis is usually confined to small vessels in the superficial portion of the dermis. The diagnosis is made based upon a constellation of clinical findings and the presence of IgA deposits as detected by direct immunofluorescence examination.

Septic vasculitis also gives rise to histologic changes of leukocytoclastic vasculitis. In these cases, there is generally more vascular thrombosis and less intense inflammatory infiltrate than is seen in leukocytoclastic vasculitis caused by other etiologies [30].

Acute hemorrhage edema of infancy is another clinical entity that demonstrates histologic changes of leukocytoclastic vasculitis [31–34]. Direct immunofluorescence studies demonstrate IgG, IgM, IgA, IgE, and C3 deposition within and around dermal blood vessels [33].

Urticarial vasculitis is an entity that is best diagnosed based upon the clinical presentation with histologic changes to support the clinical impression. The histologic findings are those of a mild leukocytoclastic vasculitis. In most cases, there is dermal edema, extravasation of erythrocytes, and an infiltrate of mixed neutrophils and eosinophils surrounding vessels of the superficial vascular plexus. However, it is quite difficult to identify fibrinoid necrosis of vessel walls and unequivocal vasculitis in most cases [35].

The histologic differential diagnosis of leukocytoclastic vasculitis includes other neutrophilic dermatoses , most commonly Sweet’s syndrome . While there are cases with overlapping features, Sweet’s syndrome characteristically does not demonstrate vascular thrombosis and transmural neutrophils within dermal vessels. Pigmented purpuric eruptions may share the finding of extravasated erythrocytes within the dermis, but these eruptions are lymphocyte mediated, and neutrophils are not part of the inflammatory infiltrate.

Small vessel vasculitis of the skin is mediated by immune complex deposition in the affected vessels. Antibodies bind to circulating antigens from drugs (e.g., β-lactam antibiotics), infections (e.g., β-hemolytic Streptococcus group A and hepatitis C virus), autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis), or cancer, forming immune complexes that lodge within small vessels in the skin, kidneys, joints, and gut [36]. These complexes can activate the complement cascade and induce an inflammatory response leading to vessel destruction and extravasation of red blood cells (purpura).

Cryoglobulins are circulating immunoglobulins that can complex with other immunoglobulins and precipitate with exposure to cold. They can be associated with a number of infectious, autoimmune, and malignant processes. When these immune complexes are deposited in blood vessel walls, vasculitis can occur. In adults, hepatitis C infection causes 80 % of cryoglobulinemia cases [37].

Cryoglobulinema is extremely rare in children. Patients with cryoglobulinemia often present with purpura, arthralgia, and fatigue. However, those with cryoglobulinemic vasculitis can present with a wide variety of skin findings, including purpura, papules, nodules, skin necrosis, bullae, ulcerations, urticaria, and livedo reticularis [38]. Treatment is supportive therapy and also aimed at treating the underlying disease process. In adults, cryoglobulinemic vasculitis tends to have a relapsing and remitting pattern.

Histologic features of cryoglobulinema differ depending upon the nature of the circulating cryoglobulins. Monoclonal cryoglobulinemias result in occluded small blood vessels with minimal to no inflammatory response (Figs. 8.10 and 8.11). These are best classified as a vasculopathy and not a vasculitis.

Skin biopsies of patients with mixed cryoglobulinemia, however, show changes of leukocytoclastic vasculitis in many cases [39] (Fig. 8.12). Small vessels located within the superficial vascular plexus of the dermis (and occasionally deeper small vessels) demonstrate transmural invasion by neutrophils (Fig. 8.13). Extravasated erythrocytes and karyorrhectic debris are present [40]. Vessels are occluded with eosinophilic material that in some cases may be crystalloid [39, 41]. Secondary ulceration may result from vascular occlusion.

The clinical manifestations of cryoglobulinemia are secondary to cryoglobulin precipitation and blood vessel occlusion [42]. Cryoglobulinemia is related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Chronic hepatitis C virus infection is the main pathogenic factor responsible for mixed cryoglobulinemia with >90 % of patients with essential mixed cryoglobulinemia having the infection [43–45]. A landmark study showed the association of HCV infection with cryoglobulinemia may be linked to the binding of the virus to B-lymphocytes via CD81 [46]. B-lymphocytes generate antibodies against HCV , which crosslink with immunoglobulin M (IgM) with rheumatoid factor activity and form cryoglobulin immune complexes. Cryoglobulinemic vasculitis involves immune complex-mediated tissue injury with deposition of immune complexes, recruitment of neutrophils, and activation of the complement cascade [42]. Monoclonal rheumatoid factor (mRF) antibody is present in patients with mixed cryoglobulinemia and HCV infection [47]. There is specific accumulation of hepatitis C virus in cryoglobulins in association with mRF [43]. In recent years, studies have shown that HCV-infected patients with mixed cryoglobulinemia have fewer peripheral-blood immunoregulatory T cells (Treg) than HCV-infected individuals without cryoglobulinemia [48].

Polyarteritis nodosa is a disease characterized by vasculitis of small and medium-sized blood vessels. There is a cutaneous form and a systemic form that can affect multiple organs. The onset of polyarteritis nodosa is typically between 25 and 50 years of age [49]. It is very rare in children with approximately several hundred cases reported in the literature thus far [50]. Cutaneous polyarteritis nodosa has no diagnostic criteria, but it is defined as a disease affecting the skin but without major organ system involvement. Skin lesions in cutaneous polyarteritis nodosa are variable, but may include livedo reticularis, tender nodules, purpura, and signs of superficial (e.g., splinter hemorrhages) or deep skin infarctions (e.g., necrosis and gangrene). Most patients with the disease are managed with systemic steroids and other immunosuppressive drugs. Most children with cutaneous polyarteritis nodosa have a chronic and relapsing benign course [50].

Polyarteritis nodosa is a neutrophil-mediated vasculitis that involves small to medium-sized vessels [28, 51, 52]. Skin biopsy reveals transmural invasion of vessels with neutrophils, endothelial cell destruction, karyorrhectic debris, extravasation of erythrocytes, and fibrin thrombi within vessels [49] (Figs. 8.14 and 8.15). Small vessels in the superficial dermis are affected in many cases, but the classic diagnostic finding is the involvement of muscular arteries in the deep reticular dermis and the subcutaneous fat. Variants such as benign cutaneous polyarteritis nodosa and microscopic polyarteritis have been described. The benign cutaneous variant demonstrates the classic histologic features but often has clinical manifestations with more cutaneous than systemic symptoms [53]. Smaller vessels are the main focus of vasculitis when the skin is involved with the microscopic variant [54].

The main differential diagnosis of polyarteritis nodosa includes superficial thrombophlebitis , although this is quite rare in children. In some cases, an elastic tissue stain can be used to demonstrate the presence of an internal elastic lamina, which is helpful in distinguishing arteries affected in polyarteritis nodosa from veins in thrombophlebitis. In some cases, vasculitis is identified only in smaller dermal vessels . Differentiation from leukocytoclastic vasculitis is not possible in these situations.

Genetics studies of Georgian Jewish patients with polyarteritis nodosa identified recessive mutations of Gly47Arg substitution in CECR1 gene that encodes adenosine deaminase 2 (ADA2) as a genetic cause of systemic and cutaneous disease [55].

Aside from possible genetic factors, immune complex-mediated reaction with deposition of IgM and C3 may also play a role in the etiology of polyarteritis nodosa [56–58]. Direct immunofluorescence stains often show IgM and C3 deposits within the affected arterial walls. IgM anti-phosphatidylserine–prothrombin complex has been found in patients with the disease, thus raising the hypothesis that prothrombin bound to injured endothelial cells induces an immune response, leading to the development of anti-phosphatidylserine–prothrombin complex antibodies [57]. Underlying infection or medications may also cause cutaneous polyarteritis nodosa. The most common infectious agent identified is Group A β-hemolytic Streptococcus in upper respiratory infections [59–61]. Streptococcal upper respiratory infections preceding the onset of disease was noted in all four children with polyarteritis nodosa in one reported study [62]. There has also been an association of polyarteritis nodosa with hepatitis B (HBV) infection [53]. Viral antigens may trigger the complement cascade, resulting in a neutrophil- and lymphocyte-rich inflammatory infiltrates within the vessel wall [63]. The mechanism by which immune complexes lead to medium-sized arterial inflammation while sparing smaller vessels (such as capillaries) is not known.

Kawasaki disease is an acute febrile vasculitis that typically affects children under the age of 5 years [64]. The most serious potential complication of Kawasaki disease is coronary artery aneurysms. Kawasaki disease accounts for approximately 25 % of vasculitis cases in the United States, and it is the second most common systemic vasculitis in children behind Henoch–Schonlein purpura. It is more common in males with a male to female ratio of 2:1, and occurs more frequently in people of Asian descent [65].

Cutaneous features that can be seen in Kawasaki disease include widespread polymorphous rash, bilateral conjunctival injection, red, cracked lips, strawberry tongue, erythema, angioedema and peeling of the distal extremities as well as unilateral cervical lymphadenopathy. Acute Kawasaki disease is treated with intravenous immunoglobulin therapy (IVIG) and supportive therapy. Chronic Kawasaki disease is treated with long-term antiplatelet doses of aspirin. For patients who receive IVIG within 10 days of onset of fever, transient coronary artery dilation is typically seen in 3–5 % of the cases, and giant aneurysms develop in about 1 % of the cases [65].

Histologic changes of Kawasaki disease are those of a leukocytoclastic vasculitis [66]. In most cases, small vessels alone are involved in the skin; however, in rare cases, involvement of medium-sized muscular artery can give rise to an appearance indistinguishable from polyarteritis nodosa [67]. In a subset of patients, spongiform pustules have been described [68]. Recently, a psoriasiform eruption with histologic changes that resemble classic psoriasis has been reported in some children with Kawasaki disease [69].

Small and medium-sized arteries are the primary vessels affected in Kawasaki disease. Although a variety of vessels are involved, the coronary arteries are the most severely affected and may suffer chronic damage [70]. The vasculitis is characterized by invasion of the vascular wall by neutrophils, eosinophils and lymphocytes (mainly CD8+ T cells) [71, 72]. The later phase of inflammation also involves plasma cells (particularly IgA-producing cells) and macrophages [73]. These findings suggest an inflammatory process involving the innate immune response, followed by an acquired immune response, leading to rapid destruction of vascular endothelial cells and the vascular smooth muscle wall with subsequent loss of structural integrity and aneurysm formation [70].

A unifying model of the pathogenesis of Kawasaki disease has been proposed [74]. Kawasaki disease may be a result of infection by a single viral infectious agent or a group of very closely related agents. The infection is not symptomatic in most individuals, but in a small subset of individuals with genetic predisposition, it can lead to Kawasaki disease [74]. Several candidate susceptibility genes for Kawasaki disease have been identified through genome-wide association studies (GWAS) . These are BLK (which encodes B lymphoid tyrosine kinase involved in B-cell receptor signal transduction and other immune activities); CD40 (which encodes TNF receptor superfamily member 5); FCGR2A (which encodes low-affinity immunoglobulin-γ Fc region receptor IIa); and ITPKC (which encodes inositol 1,4,5-trisphosphate 3-kinase C, a negative regulator of T-cell activation) [75–77]. These genes have been associated with increased susceptibility to Kawasaki disease, especially in European populations and in Japanese and American children.

In addition to susceptibility genes, there is an oligoclonal, antigen-driven IgA immune response characteristic of Kawasaki disease. Synthetic versions of oligoclonal IgA antibodies from Kawasaki disease patients bind to cytoplasmic inclusion bodies in ciliated bronchial epithelium and in macrophages [74]. IgA antibodies in Kawasaki disease appear to target a microbial antigen rather than an autoantigen.

Investigation into biomarkers for Kawasaki disease has revealed increased erythrocyte sedimentation rate (ESR) and increased levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in the acute phase of Kawasaki disease as compared with febrile controls [78–80]. ESR and NT-proBNP may be promising biomarkers that can be incorporated into a standard test for Kawasaki disease [80].

Behcet’s disease is a systemic vasculitis characterized by a triad of recurrent buccal and genital ulcers along with uveitis. Some patients experience involvement of additional organs, particularly in the gastrointestinal and neurologic systems. Behcet’s disease is very unusual in children with an estimated prevalence in children less than 15 years old at 1 in 600,000 [81]. In addition to the classic mucosal oral and genital lesions, approximately 88 % of patients develop other cutaneous manifestations of Behcet’s disease, including erythema nodosum, necrotic folliculitis, erythema, pustules, ulcers, and purpura [82].

Treatment for milder disease is generally supportive. Severe disease is often treated with systemic steroids and other immunosuppressive medications . Some patients experience an indolent course, but the course is typically chronic with unpredictable exacerbations and remissions. There is evidence that onset of disease before the age of 25 years carries a poorer prognosis [83].

The basic pathologic finding in Behcet’s disease is leukocytoclastic vasculitis. A marked neutrophilic infiltrate invades and destroys small vessels in the superficial dermis, resulting in hemorrhage and secondary ulceration. Vascular thrombosis may also be present (Figs. 8.16 and 8.17). Bullous lesions have been described [84]. Suppurative folliculitis has also been described in some patients with Behcet’s disease [85, 86]. A lymphocytic vasculitis has been reported in a minority of patients with the disease [87]. The histologic findings in Behcet’s disease are not specific and identical changes can be seen in leukocytoclastic vasculitis from other etiologies. Correlation with the clinical presentation is essential to make this diagnosis.

Behcet’s disease is a systemic inflammatory disorder with a complex genetic background coupled with immune system activation. HLA-B51 plays an important role in this disease. A recent meta-analysis has shown increased pooled odds ratio of HLA-B51/B5 carriers developing Behçet disease as compared to non-carriers (odds ratio of 5.78, 95 % CI 5.00–6.67) [88]. The role of HLA-B51 in the disease pathogenesis is not known, but may involve presentation of a specific peptide to CD8+ T cells and interactions between natural killer cells, CD8+ T cells and gamma delta T cells [89]. Genome wide association studies (GWAS) have shown an association of Behcet’s disease with IL23/IL17 pathway [90]. Patients with Behcet have reduced production of IL-10, which is an inhibitory cytokine that regulates both innate and adaptive immune responses, and with polymorphisms in IL-23R. Type 17 T helper cells (Th17) have been shown to play key immunomodulatory roles in Behcet disease. There is a predominance of Th17 and type 1 T helper cells (Th1) in the peripheral blood and tissue specimens of Behcet’s patients with a Th17/Th1 ratio in Behcet’s patients being higher than that in healthy controls [91–93]. Other studies have demonstrated a critical role for IL-21 in driving inflammatory lesions in Behcet’s disease by promoting Th17 effectors and suppressing regulatory T cells (Treg) [94].

Granuloma faciale is a rare benign chronic dermatosis that typically occurs on the face. Granuloma faciale is considered a disease of middle-aged white males [95]. It is extremely rare in children with only two known reports in the literature [96]. Granuloma faciale appears as solitary or multiple soft, red brown papules, nodules and plaques (Fig. 8.18). The classic case involves a solitary lesion on the nose, but lesions may also occur on other areas of the face and on extrafacial locations as well.

Granuloma faciale is highly resistant to treatment. Rarely, lesions may resolve spontaneously. A variety of topical and intralesional therapies have been attempted with inconsistent results.

Skin biopsy of granuloma faciale shows a dense polymorphous dermal inflammatory infiltrate. A prominent grenz zone is seen underneath the epidermis and around dermal appendages (Fig. 8.19). Neutrophilic vasculitis involving vessels of the superficial vascular plexus is present along with a dense infiltrate of lymphocytes and eosinophils (Fig. 8.20). Scattered plasma cells are present in some cases. In later lesions, increased dermal fibrosis is seen and the intensity of the inflammatory infiltrate is diminished [96].

The differential diagnosis includes leukocytoclastic vasculitis. Erythema elevatum diutinum is a close histologic mimic, but can be differentiated based upon the clinical presentation [97]. Granuloma faciale usually has a more intense inflammatory infiltrate and lacks the occasional granulomas that can be seen in erythema elevatum diutinum. Given the facial location, pustular folliculitis and granulomatous rosacea could enter into the differential diagnosis, but both of these entities usually do not demonstrate changes of vasculitis .

The etiology of granuloma faciale is unknown. Sun exposure might be a possible predisposing factor given the predilection sites of granuloma faciale for the facial area, and the fact that skin lesions are exacerbated by sunlight exposure [98–100]. Studies have suggested that granuloma faciale is mediated by interferon (IFN)-γ produced by CD4+ T helper cells. In support of this hypothesis, tacrolimus, which is a calcineurin inhibitor that decreases interleukin-2 expression and T-cell activation, has clinical utility in disease treatment [101]. In addition, clonal expansion of CD4+ T cells in the skin and local overproduction of IL-5 with eosinophil activation in the lesion may play a role in the pathogenic mechanism [102, 103]. Modulation of T-cell function by dendritic cells and resultant cytokine production may also contribute to the formation of granuloma faciale lesions [104].

Erythema elevatum diutinum (EED) is a chronic, recurrent form of leukocytoclastic vasculitis, which is thought to be immune complex-mediated. EED is quite rare in children and typically affects adults between the third and sixth decades of life [105]. Patients present with tender red brown papules, nodules, and plaques located symmetrically over the extensor surfaces of the extremities [106]. The course of EED tends to be chronic, although some lesions may resolve spontaneously. Response to treatment, such as topical or intralesional steroids, colchicine and dapsone, has been variable [106].

Erythema elevatum diutinum is a low-grade, chronic leukocytoclastic vasculitis. Histologic changes demonstrate vascular destruction by transmural neutrophils with concomitant endothelial cell damage, fibrinoid necrosis, extravasation of erythrocytes, and thrombosis (Figs. 8.21 and 8.22). As lesions become chronic, perivascular fibrosis develops. Concentric rings of fibrosis are described in some cases. Extravascular deposition of lipid secondary to cellular breakdown products can be present and may be surrounded by granulomatous inflammation [97, 107, 108].

The differential diagnosis includes other types of leukocytoclastic vasculitis, although the fibrosis is not commonly seen in these other types, and clinical correlation serves to make the distinction. Granuloma faciale is probably the closest histologic mimic, but it has a different clinical presentation [97]. Sweet’s syndrome has been described as a differential diagnostic problem in one patient [109]. One child with EED suffered from hyperimmunoglobulin D syndrome and this association was speculated to be causative [110].

The cause of erythema elevatum diutinum is unknown. EED is believed to be a small vessel vasculitis mediated by immune complexes, and has been associated with underlying diseases, including autoimmune (rheumatoid arthritis, diabetes mellitus, Crohn’s disease, and celiac disease), infections (HIV, and streptococcus), malignancies (B-cell lymphoma, multiple myeloma, and breast cancer), and drugs (anti-tuberculosis drugs, cisplatin, and erythropoietin) [111]. Immune complexes may sustain the local inflammatory infiltrate and leukocytoclastic vasculitis that are observed in EED [111–114]. Immune complexes are deposited in post-capillary venules that activate the complement cascade and subsequently initiate an leukocytoclastic vasculitis-type reaction [111]. Langerhans’ cells are thought to be involved in the pathogenesis of EED, suggesting that cell-mediated reactions may play a role [115, 116]. It has been postulated that antineutrophil cytoplasmic antibody (ANCA) (especially IgA) may have a role in the development of EED and may act as a marker of disease activity since ANCAs (IgA/G) have been detected in the serum of patients with neutrophilic dermatoses [117].