Chapter 163. Cutaneous Necrotizing Venulitis

Necrotizing angiitis or vasculitis comprises a diverse group of disorders that combine segmental inflammation with necrosis of the blood vessels. The vascular damage may result from immunologic and/or inflammatory mechanisms. Clinical syndromes are based on criteria that include the gross appearance and the histopathologic alterations of the vascular lesions, the caliber of the affected blood vessels, the frequency of involvement of specific organs, and laboratory abnormalities. Necrotizing vasculitis may be a primary disease, may develop as a feature of a systemic disorder, or may be idiopathic. There is no standard classification of the vasculitides; the American College of Rheumatology classification and the Chapel Hill consensus criteria are widely used.1,2 These classifications are limited in clinical practice, owing to the lack of recognition of certain disorders, the overlap of clinical manifestations, and the lack of precision in the description of cutaneous features.

Necrotizing vasculitis in the skin predominantly involves venules and is known as cutaneous necrotizing venulitis/vasculitis (CNV), cutaneous small-vessel vasculitis, and leukocytoclastic vasculitis. The occurrence of CNV in association with systemic involvement of the small blood vessels has been termed hypersensitivity angiitis/vasculitis, systemic polyangiitis, and microscopic polyangiitis (see Chapter 164). CNV may be restricted to the skin, may occur in association with an underlying chronic disease, may be precipitated by infections or drugs, or may develop for unknown reasons (Table 163-1). Systemic forms of necrotizing vasculitis that affect larger blood vessels are considered in Chapter 164.

The age of patients has a limited influence on CNV. An associated chronic disorder usually determines the age of the affected individual. CNV is most commonly described in children as Henoch–Schönlein purpura, with an incidence of 20/100,000 individuals less than age 17 in the United Kingdom.3 CNV was the most common type of vasculitis presenting to a dermatology ambulatory department in India.4 Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are most common in patients older than 50 years of age. Geographic variations in vasculitis may reflect an environmental influence, and seasonal variations in the incidence of vasculitis may suggest an infectious etiology.5

Experimental studies in animal models and observations in humans implicate immune complexes as a major pathobiologic mechanism in the production of CNV. Data obtained in animal models suggest that the localization of immune complexes in venules is related to vasoactive amines and subsequent vasopermeability alterations. Additional factors that are operative in the localization of immune complexes include endothelial-cell surface receptors and the defective clearance of immune complexes by the reticuloendothelial system.

The most frequently postulated mechanisms in the production of CNV are the local deposition of circulating immune complexes that are formed during antigen excess or the formation of immune complexes in situ in the skin. Immune complexes may activate the complement system and lead to the generation of C5a anaphylatoxin that degranulates mast cells and attracts neutrophils, which release lysosomal enzymes that damage tissue. The neutrophil superoxide-generating system may produce reactive oxygen products, which also cause tissue injury. The generation of the chemoattractant leukotriene (LT) B4 from infiltrating neutrophils enhances the influx of neutrophils. An infiltrate composed predominantly of neutrophils in the lesional skin of patients with CNV is consistent with tissue damage, which is induced by immune complexes that activate the complement system. The initial neutrophilic process contains few CD3, CD4, CD1a, and CD36 cells whereas these cells are prominent in the later phase, with the adhesion receptors intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1).6 In Henoch–Schönlein purpura, the fragmentation of neutrophils was attributed to apoptosis on the basis of the detection of inducible nitric oxide synthase and nitrotyrosine in the infiltrates and the detection of interleukin-8 (IL-8) on vascular endothelial cells.7 Long penetration PTX3, which inhibits phagocytosis of apoptotic neutrophils by macrophages, was detected in skin biopsy specimens of idiopathic CNV and of Henoch–Schönlein purpura about blood vessels and at sites of infiltrates with leukocytoclasia.8

In CNV, circulating immune complexes have been demonstrated in serum as mixed-type cryoglobulins and indirectly by assays that detect C1q precipitins, materials that bind to complement receptors on human lymphocytoid (Raji) cells, materials that bind to monoclonal rheumatoid factor, and substances that function in the antibody-dependent cellular cytotoxicity inhibition assay. The presence of immune complexes is inferred from the occurrence of serum hypocomplementemia with activation of the classic activating pathway and by the detection of increased plasma levels of C4a and C3a anaphylatoxins.

In CNV, immune complexes have been detected in lesional tissues by their ultrastructural observation as electron-dense subendothelial deposits; the membrane-attack complex, C5b-9, of the complement system has been detected on the surface of endothelial cells and infiltrating neutrophils. Decay-accelerating factor, a regulatory complement protein that prevents the assembly of the membrane-attack complex, was not present on the surface of endothelial cells of the superficial dermal microvasculature. Tissue immune complexes also have been detected by direct immunofluorescence techniques as deposited immunoglobulins and complement proteins. In time–course studies of the evolution of cutaneous vascular lesions, immune reactants have been identified in lesions that are less than 24 hours old. Antigens have been identified only in a few instances as bacterial, viral, mycobacterial, or rickettsial proteins by direct immunofluorescence techniques or by the polymerase chain reaction.

A role for lymphocytes, mononuclear cells, and Langerhans cells in the production of CNV is suggested by a perivenular infiltrate in skin lesions that is rich in lymphocytes with large and hyperchromatic nuclei and by a prominence of other types of mononuclear cells in the vascular skin lesions of patients with CNV and Sjögren syndrome. The lymphocytes express CD3, CD4, CD1a, CD36, ICAM-1, and LFA-1. Lymphocytes may be activated by immune complexes, by cellular immune mechanisms, and by primary activation in autoimmune disease to produce lymphokines. In cell-mediated immune responses in lymphocytic vasculitis, dendritic cells and lymphocytes contribute to the perpetuation of CNV.9 In CNV, there were increased numbers of factor XIIIa+ derived dendrocytes, which are involved in antigen presentation to T cells.10 Endothelial cells also can present antigens to and activate T lymphocytes. Activated macrophages secrete chemokines and lysosomal enzymes. γ/δ T cells have been detected in CNV with a neutrophil-rich pattern and with an infectious etiology.11 In these specimens, a 72-kDa heat shock protein was expressed by endothelial cells and antigen-presenting cells.

The participation of mast cells in CNV is suggested by hypogranulated mast cells with shed extracellular granules and by the development of vascular lesions after the intracutaneous injection of histamine in patients with active episodes of CNV. Mast cells can be activated directly by immune complexes through FcγRIII or by C5a. Through the production of histamine, prostaglandin D2, and cysteinyl LTs, the mast cell could alter venular permeability; interendothelial cell gaps have been noted in venules in patients with CNV. Eosinophils and neutrophils could be recruited by mast cell-derived chemotactic factors. The neutral proteases and acid hydrolases of mast cells may facilitate tissue damage, and the release of tumor necrosis factor-α (TNF-α) may increase expression of E-selectin on endothelial cells and facilitate neutrophil recruitment.

Evidence for the role of the mast cell also is provided by time–course analyses of the sequential histopathologic changes in individuals with physical urticaria. In a patient with circulating immune complexes and hypocomplementemia, in whom cold and trauma elicited CNV, initial mast cell degranulation was followed by the infiltration of neutrophils, the deposition of fibrin, and venular endothelial-cell necrosis. A postulated sequence of events would be the activation of the mast cell by physical stimuli, the release of vasoactive mediators, the deposition of circulating immune complexes with activation of the complement system, the influx of neutrophils, and the development of CNV.12 Another example of the time–course analysis of CNV in human skin was provided by an individual with exercise-induced vasculitis.13 At 3 hours, the number of mast cells decreased, and the eosinophil was the first cell to appear around the venules with the deposition of eosinophil peroxidase. TNF-α levels were elevated, E-selectin was expressed on endothelial cells, and an influx of neutrophils appeared with the deposition of neutrophil elastase and the development of CNV.

Early in the course of necrotizing venulitis, endothelial cells show increased expression of ICAM-1 and E-selectin without the expression of vascular cell adhesion molecule-1 (VCAM-1) in response to TNF-α (see Chapter 162). Because E-selectin is an adhesion molecule for neutrophils and for skin-homing, memory T lymphocytes, the increase in E-selectin is consistent with the appearance of an infiltrate of neutrophils that express CD11b within the first 24 hours.14

In the acute phase of Henoch–Schönein purpura, endothelin-1, serum insulin-like growth factor-1 (IGF-1), IGF-binding protein-3, plasma matrix metalloproteinase-9 (MMP-9), ICAM-1, VCAM-1, TNF- α, IL-I-β, IL-2 receptor, IL-6, IL-8, transforming growth factor-β, vascular endothelial-cell growth factor (VEGF), and urine leukotriene E4 levels were elevated,15–20 and the interferon-γ-inducible protein 10 level was low.21 However, the pathogenic roles of these mediators remain undefined. IgA antiendothelial cell antibodies bind to endothelial cells and enhance endothelial cell production of IL-8 via the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway.22

In skin biopsy specimens from patients with idiopathic CNV, hypersensitivity vasculitis, urticarial vasculitis, and Henoch–Schönlein purpura, E-selectin was detected on endothelial cells of lesions that were less than 48 hours old and was associated with an infiltrate of neutrophils that expressed CD11b. The endothelial cells expressed human leukocyte antigen DR (HLA-DR) and very late activating antigen-1 but not P-selectin, and the perivascular cells expressed VCAM-1 and HLA-DR. Diminished cutaneous fibrinolytic activity with reduced release of plasminogen activator from venular endothelial cells occurs in patients with CNV; the subsequent reduction in fibrinolytic activity leads to fibrin deposition. Increased levels of plasma thrombomodulin, tissue-type plasminogen activator, and plasminogen activator inhibitor-1 were detected in patients with Henoch–Schönlein purpura.23,24

Cutaneous nerve fibers can release neuropeptides, such as substance P, neurokinin A, and calcitonin gene-related peptide (CGRP), that cause vasodilation (see Chapter 102). Substance P activates mast cells and macrophages and increases fibrinolytic activity that is mediated by plasminogen activator. CGRP induces expression of E-selectin on endothelial cells and is chemotactic for T lymphocytes.

Eosinophils are minor infiltrating cells in CNV except in eosinophilic vasculitis and drug-induced CNV.25 Eosinophils produce LTC4 and platelet-activating factor, which increase vascular permeability. Eosinophil granule proteins are toxic to endothelial cells and cause the release of mediators from mast cells.

Associations have been recognized between small-vessel necrotizing vasculitis and ANCAs, which have specificity for proteins of the cytoplasmic granules of neutrophils and the lysosomes of monocytes. Two forms are recognized: (1) cytoplasmic (c-ANCAs) that are directed against proteinase 3(PR3) and (2) perinuclear (p-ANCAs) that are directed against myeloperoxidase (MPO). TNF-α facilitates neutrophil activation and cell surface expression of PR3 and MPO, which bind to ANCAs and increase the adherence of neutrophils to endothelial cells resulting in endothelial cell injury. Antiendothelial-cell antibodies have been detected in the sera of patients with systemic vasculitis, rheumatoid arthritis with vasculitis, microscopic polyangiitis, and Sneddon syndrome.

An increased prevalence of the HLA haplotype HLA-A11, Bw35 in patients with CNV and associated connective-tissue disorders suggests that genetic factors may be operative. HLA-DRB1 genotype associations were detected in patients with CNV and Henoch–Schönlein purpura in Spain.26

The skin lesions of CNV are polymorphous; however, erythematous papules that do not blanch when the skin is pressed, which are known as palpable purpura, are the signature lesions (Fig. 163-1A). Macules, papules, urticaria/angioedema, pustules, vesicles, hemorrhagic blisters (Fig. 163-1B), necrosis and ulcers (Fig. 163-1C), and livedo reticularis may be present. Occasionally, there is subcutaneous edema below the area of the dermal lesions.

The eruption most often appears on the lower extremities or over dependent areas, such as the back and gluteal regions. The lesions may occur anywhere on the skin but are uncommon on the face, palms, soles, and mucous membranes. The clinical lesions are episodic and may recur over weeks to years. Palpable purpura persists for 1 to 4 weeks and resolves at times with transient hyperpigmentation and/or atrophic scars. Lesional symptoms include pruritus or burning and, less commonly, pain.

An episode of cutaneous vascular lesions may be attended by fever, malaise, arthralgias, or myalgias irrespective of a defined underlying or associated disease. Systemic involvement of the small blood vessels most commonly occurs in the synovia, gastrointestinal tract, voluntary muscles, peripheral nerves, and kidneys.

Associated Chronic Disorders

CNV is associated with connective-tissue diseases, notably rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus (SLE), and hypergammaglobulinemic purpura. It rarely occurs in mixed connective-tissue disease, relapsing polychondritis, and scleroderma. In patients with rheumatoid arthritis and CNV, the development of vascular lesions is related to the severity of the disease, which is generally but not always seropositive, and the presence of anti-Ro antibodies. Subcutaneous nodules and cutaneous ulcers may be present. Patients with rheumatoid arthritis often have involvement of larger vessels with associated peripheral neuropathy, nail-fold infarcts, and digital gangrene.

In patients with SLE, CNV is a frequent manifestation27 and is associated with exacerbations of the underlying disease. Patients with anti-Ro antibody have a greater risk for the development of CNV, with an Odds ratio 1.63.28 Vasculitis, however, is rare in patients with subacute cutaneous lupus erythematosus. Some women with necrotizing vasculitis without connective-tissue disease have anti-Ro antibodies, and their infants may be born with neonatal lupus erythematosus.

In patients with Sjögren syndrome, the vascular lesions are located predominantly on the lower extremities and appear after exercise. Both hyperpigmentation and cutaneous ulcers are common features. Patients with Sjögren syndrome and CNV have a higher prevalence of articular involvement, peripheral neuropathy, Raynaud phenomenon, and renal involvement29 as well as the presence of anti-Ro antibody. Hypergammaglobulinemic purpura occurs in older women and may be associated with Sjögren syndrome, SLE, or a lymphoproliferative disorder. Dermatomyositis in children, but not in adults, may be associated with vasculitis of the gastrointestinal tract.

Paraneoplastic vasculitis describes CNV with associated malignant conditions, which include Hodgkin lymphoma, lymphosarcoma, adult T-cell leukemia, mycosis fungoides, myelofibrosis, acute and chronic myelogenous forms of leukemia, B-cell chronic lymphocytic leukemia, multiple myeloma, IgA myeloma, diffuse large-cell leukemia, hairy-cell leukemia, squamous-cell bronchiogenic carcinoma, adenocarcinoma of the lung, prostatic carcinoma, renal carcinoma, bladder carcinoma, and colon carcinoma.30 However, the association between CNV and neoplasia is rare. It is not necessary to evaluate all patients with CNV for associated malignant conditions.

Cryoglobulins (see Chapter 169), especially mixed types II and III, may be found in patients with idiopathic CNV and in patients with CNV that is associated with connective-tissue diseases, lymphoproliferative disorders, and hepatitis A, B, and C virus infections. Hepatitis C virus is the most common infection, especially when it is associated with cryoglobulinemia.31,32 CNV occurs in patients with cystic fibrosis, inflammatory bowel diseases of the colon, and Behçet disease.33

ANCAs are associated with various forms of necrotizing vasculitis. ANCAs are present in patients with microscopic polyangiitis and cutaneous vasculitis with hepatitis C virus infection (see Chapter 164). The most common cutaneous feature in patients with ANCAs is palpable purpura. Microscopic polyangiitis is associated with small-vessel systemic vasculitis that involves the cutaneous venules and arterioles, the kidneys with necrotizing and crescentic glomerulonephritis, the lungs with pulmonary hemorrhage or interstitial pneumonia, and p-ANCAs. Erythematous macules, purpura, and livedo reticularis are cutaneous manifestations in microscopic polyangiitis.34,35 A male patient has experienced microscopic polyangiitis restricted to the skin and p-ANCAs for 20 years without progression to systemic vascular disease.36 IgA ANCAs are present in acute Henoch–Schönlein purpura in children.

Anticardiolipin antibodies occur in patients with various forms of necrotizing vasculitis. IgA cardiolipin antibodies of the IgA class were detected in 6 of 10 patients with idiopathic CNV.37 IgA anticardiolipin and IgA and IgM antiphosphatidyl serine–prothrombin complex antibody levels are elevated in adults with Henoch–Schönlein purpura and CNV that is restricted to the skin.38 IgG and IgM anticardiolipin antibodies have been detected in some individuals with livedoid vasculitis.39

Precipitating Infections and Drugs

Infections and drugs may precipitate episodes of CNV. The most commonly recognized infectious agents are β-hemolytic Streptococcus, Staphylococcus aureus, Mycobacterium leprae, and hepatitis B and C viruses. Transient episodes of urticaria may occur early in the course of hepatitis B virus infection and represent immune complex-induced vasculitis; episodes of palpable purpura may occur in patients with chronic active hepatitis. Cutaneous vasculitis has been recognized in a limited number of individuals with human immunodeficiency virus infection; the skin lesions consisted of palpable purpura, which at times had a follicular localization, and cutaneous ulcers.

Erythema nodosum leprosum (see Chapter 186), which appears as cutaneous nodules in lepromatous leprosy, is a form of necrotizing vasculitis that involves capillaries, venules, arterioles, small-to-medium-sized arteries, and veins. The vascular lesions occur spontaneously or are precipitated by the administration of chemotherapeutic agents. They may be accompanied by fever, malaise, arthralgias, lymphadenopathy, and polyneuritis.

Necrotizing vasculitis caused by the direct invasion of the blood-vessel wall occurs in septicemia due to Neisseria meningitidis, Neisseria gonorrhoeae, Pseudomonas, Hemophilus influenzae, rickettsia, candida, and infectious endocarditis; in Rocky Mountain spotted fever; and in infections localized at the site of a catheter.

Palpable purpura is one of the less common forms of drug reactions (see Chapter 41). The most commonly incriminated therapeutic agents were propylthiouracil, hydralazine, granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF), allopurinol, cephaclor, minocycline, penicillamine, phenytoin, isotretinoin, and methotrexate in a Medline database search from 1965 to 1999.40 Propylthiouracil41 and hydralazine may cause vasculitis in association with ANCAs. Cutaneous vasculitis also has occurred after the administration of streptokinase, radiocontrast media, staphylococcal protein A column immunoadsorption therapy, drug additives, infliximab, etanercept, adalimumab, and rituximab.42,43

Idiopathic Disorders

Henoch–Schönlein Purpura

The most widely recognized subgroup of idiopathic CNV is Henoch–Schönlein purpura, which was formerly known as anaphylactoid purpura. It occurs predominantly in children, with a peak incidence at 5 to 6 years of age, but it may occur in adults.44,45 Most cases occur in the autumn and winter and often are preceded by a history of a recent upper respiratory tract infections, especially with β-hemolytic Streptococcus, in up to 75% of individuals; however, Henoch–Schönlein syndrome has been associated with other infections.46 Sites of involvement include the skin, synovia, gastrointestinal tract, and kidneys. Symptoms may include colicky abdominal pain, melena, arthralgia, and hematuria. Long-term morbidity from progressive renal disease depends on the degree of initial renal damage. The spread of purpura to the upper parts of the trunk is a predictive factor for renal involvement. Adults have a worse prognosis, owing to an increased risk of renal disease.

Acute Hemorrhagic Edema of Infancy

This uncommon disorder, which often goes unrecognized or has been confused with Henoch–Schönlein purpura, affects infants and children younger than 2 years of age. The lesions appear as painful, edematous petechiae and ecchymoses that affect the head and distal portions of the extremities. Facial edema may be the initial sign. The skin lesions may be associated with a target-like appearance and may develop bullae and necrosis. Infection, drugs, or immunization may be triggering factors. Acute hemorrhagic edema of infancy is distinguished from Henoch–Schönlein purpura by its occurrence in children aged 4 months to 2 years, by its lack of systemic features, and by its resolution within 1 to 3 weeks without sequelae.47

Urticarial Venulitis

Episodes of recurrent and chronic urticaria and angioedema may be a clinical manifestation of CNV.48,49 Known as urticarial vasculitis/venulitis, this edematous form of necrotizing venulitis occurs in patients with serum sickness, connective-tissue disorders, hematologic and other malignant conditions, an IgMK M component, infections, and physical urticarias; after the administration of a variety of therapeutic agents; and as an idiopathic disorder. The term hypocomplementemic urticarial vasculitis syndrome (HUVS) has been used to describe patients with more severe systemic manifestations, hypocomplementemia, and an autoantibody to the collagen-like region of Clq.

The skin lesions appear as erythematous, occasionally indurated, wheals that may contain foci of purpura (Fig. 163-2; see Fig. 164-3 and Chapter 164). Other skin manifestations include angioedema, macular erythema, livedo reticularis, nodules, and bullae. Although the individual urticarial lesions may last for fewer than 24 hours, they often persist for up to 3 to 5 days. The lesions are pruritic or possess a burning or painful quality; they usually resolve without residua although some individuals may develop contusions or hyperpigmentation. The episodes of urticaria are chronic, range in duration from months to years, and vary in frequency. Approximately 70% of affected individuals are women. The prevalence of this disorder remains unknown. General features include fever, malaise, and myalgia; the lymph nodes, liver, and spleen may be enlarged. Extracutaneous features involve the synovial, kidneys, gastrointestinal tract, lungs, eyes, heart, central nervous system, peripheral nerves, and blood vessels (Table 163-2). These extracutaneous features are more extensive in patients with HUVS.

The natural history of urticarial vasculitis is unknown although individuals have been described with historic episodes of cutaneous lesions for up to 25 years. In one series of patients followed for 1 year, 40% experienced complete resolution of skin lesions; in another series of individuals followed for as long as 14 years, resolution occurred in only one patient. Sjögren syndrome and SLE have developed. Deaths have been reported from pulmonary disease, sepsis, and myocardial infarction.

The prevalence of urticarial vasculitis in individuals with chronic idiopathic urticaria is unknown, although series have reported rates ranging from 1% to 50%. Most of these data have been reported from histopathologic studies in tertiary referral centers. The prevalence of urticarial vasculitis in a prospective clinical study in a university hospital in India was 11.4%.50

Necrotizing vasculitis of cutaneous venules has been described in isolated instances of dermographism, cold urticaria, delayed pressure urticaria, solar urticaria, and exercise-induced urticaria. However, the prevalence of necrotizing vasculitis in patients with physical urticaria is unknown, and the importance of this histopathologic finding for prognosis and therapy remains to be elucidated. Individuals with these physical urticarias have provided experimental models for time–course studies of the evolution of necrotizing vasculitis in human skin.

Schnitzler syndrome consists of episodes of urticarial vasculitis that occur in association with a monoclonal IgMK M component. Associated features include fever, lymphadenopathy, hepatosplenomegaly, bone pain, a sensorimotor neuropathy, and renal failure. Evolution into hematologic malignant conditions has been reported in 15% of patients.51

Erythema Elevatum Diutinum

Erythema elevatum diutinum occurs as symmetric, persistent, red–purple or red–brown plaques that are predominantly disposed over the joints of extensor surfaces and over the gluteal area (see Chapter 165).

Nodular Vasculitis

Nodular vasculitis (see Chapter 70) appears as tender, red, subcutaneous nodules over the lower extremities, especially the calves, without systemic manifestations (Fig. 163-3; see Fig. 70-5 and Chapter 70). At times, lesions develop on the thighs, buttocks, trunk, and arms, and ulcerated nodules may be present. Recurrent episodes are common. It is more common in women and has a peak incidence in individuals between 30 and 40 years of age. Erythema induratum is a form of nodular vasculitis, which has been associated with Mycobacterium tuberculosis infection, as demonstrated by polymerase chain reaction amplification for M. tuberculosis DNA in skin biopsy specimens.52 Various sizes of blood vessels, which include venules, are affected.53 Erythema induratum has been associated with hepatitis C virus infection.54

Livedoid Vasculopathy

Livedoid vasculopathy (Fig. 163-4), known also as livedoid vasculitis, livedo vasculitis, segmental hyalinizing vasculitis, and atrophie blanche, occurs as recurrent, painful ulcers of the lower extremities in association with a persistent livedo reticularis (livedo racemosa) that often is deep purple in color (see Fig. 164-11 and Chapter 164). Healing results in sclerotic pale areas that are surrounded by telangiectasias and designated atrophie blanche (Fig. 163-5). Many patients have arteriosclerosis or stasis of the lower extremities. Livedoid vasculitis is more common in women and may occur in patients with connective-tissue disorders, such as SLE, who develop central nervous system features; in malignant conditions; in hypercoagluable states; in thrombophilia; and as an idiopathic disorder. Protein C and S deficiencies,55 factor V Leiden gene mutation, activated protein C resistance, prothrombin gene mutation, hyperhomocysteinemia, and antithrombin deficiency have been reported. Atrophie blanche, however, probably represents the end stage of a variety of forms of vascular damage in the skin (see Chapter 173). Elevated levels of fibrinopeptide A, homocystein, and plasminogen activator inhibitor56 may occur in blood. Pathogenesis has focused on a hypercoagulable state with fibrin thrombi in the lumina of the superficial blood vessels. Some consider this condition to be a thrombogenic vasculopathy rather than a small-vessel vasculitis.57 Antiphospholipid antibodies have been detected in a few individuals.39

Sneddon syndrome58,59 is a condition in which livedo racemosa and livedoid vasculitis are associated with ischemic cerebrovascular lesions, hypotension, and extracerebral arterial and venous thromboses (see Fig. 173-9 in Chapter 173). Antiendothelial cell antibodies were detected in the serum in 35% of individuals; antiphospholipid antibodies, anti-β2-glycoprotein antibodies, and antiprothrombin antibodies60 were detected in some patients.

Genetic Complement Deficiencies

Genetic C2 deficiency has been recognized in association with CNV in three children and in two siblings with HLA-A25, B18, DR2 (w15) haplotype. C4 deficiency was present in one child with CNV. Deficiencies of C4A and C4B isotypes were found in some children and adults with Henoch–Schönlein purpura. A partial C4B deficiency with C4 A1, A3, B1, and a null allele B*QO was reported in a 51-year-old woman with CNV.

Eosinophilic Vasculitis

Eosinophilic vasculitis has been described as an idiopathic syndrome in individuals with recurrent, pruritic, and purpuric papular skin lesions, urticarial plaques, and angioedema. Skin biopsy specimens showed an infiltrate composed of eosinophils expressing CD4061 and VCAM-1 on endothelial cells of involved vessels. Eosinophilic vasculitis also has been described in some individuals with the hypereosinophilic syndrome (see Chapter 36) and in others with connective-tissue disorders.62 There may be depressed complement levels, peripheral eosinophilia, elevated major basic protein levels, and a prolonged eosinophil survival time.

Idiopathic

Individuals with CNV who do not meet the criteria for recognized syndromes are classified as idiopathic.

The laboratory evaluation of patients with CNV depends on information obtained from the history and physical examination (Table 163-3). An elevated erythrocyte sedimentation rate is the most consistent abnormal laboratory finding. The platelet count is usually normal. Other abnormalities reflect either a coexistent chronic disorder or the involvement of additional organ systems. Occasionally, leukocytosis, anemia, thrombocytosis, an abnormal urine sediment, circulating immune complexes, rheumatoid factor, and antinuclear antibodies have been reported in idiopathic disease.

Serum complement levels are usually normal. Hypocomplementemia may develop in patients with concomitant connective-tissue diseases or cryoglobulinemia and reflects the associated disease or the composition of the cryoglobulin. Hypocomplementemia also occurs in some individuals with idiopathic CNV and in 40% of individuals with urticarial venulitis.

In patients with the HUVS, a low-molecular-weight 7s C1q precipitin, which has been identified as an IgG autoantibody against the collagen-like region of C1q, was detected. Autoantibodies to vascular endothelial cells were detected in patients with HUVS, in patients with SLE and urticarial vasculitis, and in patients with urticarial vasculitis alone.63 In Henoch–Schönlein purpura, serum IgA1 levels are elevated, IgA ANCAs may be present, and urinary endothelin-1 levels may be elevated. In patients with CNV, various types of circulating immune complexes and IgA ANCAs64 have been described. IgG autoantibodies to IgE and to FcϵRlα also have been identified in some patients with urticarial venulitis.

In skin biopsy specimens of palpable purpura and urticarial vasculitis stained with hematoxylin and eosin (Fig. 163-6A), the histopathologic criteria requisite for the diagnosis of CNV include necrosis of the blood vessels with the deposition of fibrinoid material and dermal cellular infiltrates that consist of neutrophils with nuclear debris, mononuclear cells, and extravasated erythrocytes. The dermal inflammatory infiltrates vary in intensity and are usually perivenular in location, but at times they are dispersed widely. Some patients with connective-tissue disorders and cutaneous vasculitis have an infiltrate of inflammatory cells composed of eosinophils with deposited major basic protein and decreased numbers of mast cells.62 Eosinophils may be present in increased numbers in drug-induced CNV.25 The fibrinoid material consists of fibrin, necrotic endothelial cells, immunoreactants, and antigens.

Studies with 1-μm-thick sections (Fig. 164-6B) show two distinct cellular patterns in CNV: one rich in neutrophils and the other in lymphocytes.65 The infiltrate of neutrophils regresses with the persistence of an infiltrate of mononuclear cells; repeat biopsy specimens in some patients consistently demonstrated an infiltrate of mononuclear cells. In a time–course study over 6 days of the evolution of experimentally induced CNV in a patient with physical urticarias,12 the number of infiltrating neutrophils decreased without a concomitant increase in lymphocytes although the number of monocyte-macrophages was increased at 48 hours and 72 hours. Other features in both cell patterns of CNV include hypogranulated mast cells, macrophages containing debris, and the perivenular and interstitial deposition of fibrin. Venular alterations in both cell patterns consist of endothelial-cell swelling, activation of nuclei, wrinkling of nuclear membranes, necrosis (Fig. 163-6B), and basement-membrane reduplication and thickening. The arterioles are not affected.

By direct immunofluorescence techniques, fibrin deposition in venules is routinely identified in biopsy specimens, whereas the deposition of immunoglobulins and complement proteins varies widely. IgG is the most commonly deposited immunoglobulin although IgM and IgA also have been detected. IgA is deposited about blood vessels in the skin, intestines, and kidneys in Henoch–Schönlein purpura and has become an immunopathologic marker of this condition. In the skin in Henoch–Schönlein purpura, IgA1 is the dominant subclass deposited.66 C3 is the only complement protein that has been sought with frequency in CNV.

Thrombocytopenia may result in purpura; however, these lesions are flat. Other causes of nonpalpable cutaneous purpura include local trauma to the skin of aged individuals with vascular fragility, chronic sun exposure, and endogenous or iatrogenic hypercorticism. Erythema elevatum diutinum may resemble Kaposi sarcoma (see Chapter 128) or multicentric reticulohistiocytosis (see Chapter 148). Scurvy may appear as hemorrhagic, follicular papules over the lower extremities. Various infectious agents may be associated with hemorrhagic skin lesions that arise from disseminated intravascular coagulation or septic emboli. The cutaneous manifestation of disseminated intravascular coagulation, which is known as purpura fulminans, appears as extensive areas of purpura with a slate-gray color (see Chapter 144). These lesions occur in patients with acute meningococcemia but also with Gram-positive coccal sepsis; skin biopsy specimens show thrombosis but not necrotizing venulitis. Septic emboli occur as finite numbers of hemorrhagic pustules, papules, and vesicles that are distributed over acral areas. Rarely, echo and coxsackievirus infections may cause purpuric papules. Rocky Mountain spotted fever typically begins as purpuric papules over the ankles and wrists that spread to include the trunk. Cholesterol embolization includes purpura, livedo reticularis, ulcers, and nodules. Calciphylaxis may appear as painful plaques with a reticulated or stellate pattern, induration, eschars, and ulcers.

The progressive pigmentary purpuric dermatoses (purpura simplex) (see Chapter 168), which include a number of disorders, appear as macular, petechial, pigmented, or lichenoid lesions.

The differential diagnosis of cutaneous nodules includes erythema nodosum, panniculitis, superficial forms of thrombophlebitis, fat necrosis associated with pancreatic disease, and systemic vasculitides, such as polyarteritis nodosa, granulomatosis with polyangiitis (Wegener's), and Churg–Strauss syndrome.

Therapeutic approaches may be divided into removal of the antigen, treatment of an underlying disease, and treatment of CNV. Therapeutic approaches in the treatment of necrotizing vasculitis consist of prevention of the deposition of immune complexes, suppression of the inflammatory response, modulation of underlying immunopathologic mechanisms, and local therapy. When the eruption is associated with a precipitating event, withdrawal of the medication or treatment of the infection results in resolution of the cutaneous lesions. If a coexistent chronic disease is present, treatment of the underlying disease may be associated with improvement in the cutaneous vascular lesions. In many cases, CNV is a self-limited condition, and double-blind, placebo-controlled, prospective trials of therapeutic agents are usually lacking.

The treatment of CNV (Table 163-4) depends on an analysis of the cutaneous disability as well as on the toxicity and side effects of the therapeutic agents. H1 antihistamines are used in patients with palpable purpura to alleviate lesional symptoms and perhaps to reduce tissue deposition of circulating immune complexes. Nonsteroidal anti-inflammatory agents are combined with the H1 antihistamine. Depending on the therapeutic response, colchicine can be added to or substituted for these agents. However, colchicine was shown to have no significant therapeutic effect in a prospective, randomized, controlled trial. If there is no benefit, dapsone or hydroxychloroquine sulfate can be used. If there still is no therapeutic response, a major decision must be made because the medications systemic glucocorticoids, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, cyclophosphamide, plasmapheresis, intravenous immunoglobulin,67 infliximab,68 and rituximab69,70 are associated with serious side effects. Although all of these agents have been reported to benefit some patients, controlled clinical trials are not available. The administration of interferon-α is associated with clearing of cutaneous vasculitis in patients with hepatitis C virus infection.

The treatment of patients with urticarial vasculitis is similar to those with palpable purpura. Additional case reports exist on the treatment of patients with intramuscular gold therapy, cyclophosphamide-dexamethasone pulse therapy, mycophenolate mofetil,71 thalidomide, anakinra, cinnarizine, and psoralen plus ultraviolet A (PUVA) photochemotherapy.

In patients with erythema elevatum diutinum, dapsone is the drug of choice. The treatment of nodular vasculitis consists of empiric trials of a variety of therapeutic agents that include a saturated solution of potassium iodide, nonsteroidal anti-inflammatory drugs, colchicine, and systemic glucocorticoids. Thalidomide is the treatment of choice for erythema nodosum leprosum.

In the treatment of livedoid vasculitis, support stockings are useful. Empiric trials of aspirin and dipyridamole, colchicine, dapsone, danazol, low-dose heparin, systemic glucocorticoids, nicotinic acid, low-molecular-weight dextran, phenformin and ethylestrenol, nifedipine, and pentoxifylline have been used. Infusions of prostacyclin, prostaglandin E1, intravenous immunoglobulin, rituximab,72 tissue plasminogen activator,73 hyperbaric oxygen therapy,74 and PUVA photochemotherapy have been used successfully in a few patients.