The vasculopathic reaction pattern

Histopathology

Senile purpura is characterized by extravasation of red blood cells into the dermis ( Fig. 9.1 ). This is most marked in the upper dermis and in a perivascular location. There is also marked solar elastosis and often some thinning of the dermis with atrophy of collagen bundles.

Histopathology

Fibrin-platelet thrombi are present in venules and arterioles in the deep dermis and subcutis. There is variable hemorrhage and subsequently the development of infarction. Large areas of the skin may be involved.

Histopathology

The changes will depend on the age of the lesion that is biopsied. The primary event is the formation of hyaline thrombi in the lumen of small vessels in the upper and mid dermis. Rarely, deeper vessels are involved. Polyarteritis nodosa is rarely present. Fibrinoid material is also present in the walls of these blood vessels and in perivascular stroma ( Fig. 9.2 ). This material is periodic acid–Schiff (PAS) positive and diastase resistant. There is usually infarction of the superficial dermis, often with a small area of ulceration. Sometimes a thin parakeratotic layer is present overlying infarcted or atrophic epidermis. The epidermis adjacent to the ulceration may be spongiotic. A sparse perivascular lymphocytic infiltrate may be present, but there is no vasculitis. Neutrophils, if present, are usually sparse and confined to the infarcted upper dermis and ulcer base. There are often extravasated red cells in the upper dermis. Small blood vessels are often increased in the adjacent papillary dermis, but this is a common feature in biopsies from the lower parts of the legs and is therefore of no diagnostic value.

In older lesions, there is thickening and hyalinization of vessels in the dermis with some endothelial cell edema and proliferation. Fibrinoid material may also be present in vessel walls. Note that fibrinoid material is almost invariably present in blood vessels in the base of ulcers, of many different causes, on the lower legs. In atrophie blanche, the involved vessels are not only in the base of any ulcer but also may be found at a distance beyond this. In even later lesions, there are dermal sclerosis and scarring with some dilated lymphatics and epidermal atrophy. There may be a small amount of hemosiderin in the upper dermis. Because these areas may become involved again, it is possible to find dermal sclerosis in some early lesions.

Immunofluorescence will demonstrate fibrin in vessel walls in early lesions, whereas in later stages there are also immunoglobulins and complement components in broad bands about vessel walls.

Histopathology

In early lesions, fibrin thrombi are present in capillaries and venules of the papillary dermis and occasionally in vessels in the reticular dermis and subcutis ( Fig. 9.3 ). Hemorrhage is also present, but there is no vasculitis or inflammation.

In older lesions, of 2 to 3 days’ duration, there may be epidermal necrosis, subepidermal bullae, extensive hemorrhage, and patchy necrosis of eccrine glands, the pilosebaceous apparatus, and the papillary dermis. Nearby blood vessels are thrombosed, but there is only mild inflammation in the dermis. In chronic states, some vascular proliferation and ectasia may occur.

Histopathology

Fibrin thrombi fill most of the venules and capillaries in the skin. There is a mild perivascular infiltrate in some areas, but no vasculitis. Extensive hemorrhage is present with the subsequent development of epidermal necrosis. Occasionally, a subepidermal bulla develops.

Histopathology

Platelet-rich thrombi admixed with a small amount of fibrin deposit in vessels at the level of the arteriolocapillary junction. They may also involve small arteries. There may be slight dilatation of vessels proximal to the thrombi. The material is PAS positive. There is no evidence of any associated vasculitis. Extravasation of red blood cells also occurs. In severe cases, necrosis of the epidermis may ensue.

Histopathology

If biopsies are taken from areas of erythromelalgia, there is fibromuscular intimal proliferation involving arterioles and small arteries similar to the changes seen in Sneddon's syndrome.

In a case associated with both erythromelalgia and livedo reticularis, biopsy of the latter showed hyalinized, thrombosed deep dermal vessels with perivascular lymphohistiocytic infiltrates. If ischemic areas are biopsied, there is vascular thrombosis, which may involve vessels of all sizes. Infarction of the dermis and/or epidermis may accompany these thrombosed vessels.

Monoclonal cryoglobulinemia

The monoclonal variant, which accounts for approximately 25% of cases of cryoglobulinemia, is associated with the presence of immunoglobulin G (IgG) or IgM cryoglobulin or, rarely, of a cryoprecipitable light chain. Monoclonal cryoglobulins, also known as type I cryoglobulins, are usually seen in association with multiple myeloma, Waldenström's macroglobulinemia, and chronic lymphatic leukemia. Sometimes, no underlying disease is present (essential cryoglobulinemia). The condition may be asymptomatic or result in purpura, acral cyanosis, or focal ulceration, which is usually limited to the lower extremities. Generalized livedo reticularis is another manifestation. In a study of 15 patients with leg ulcers associated with cryoglobulinemia, 8 patients had type I cryoglobulins and 7 patients had type II. Plasma exchange combined with immunosuppressive drugs usually cures the ulcers. Thalidomide, rituximab, and bortezomib have also been used.

Mixed cryoglobulinemia

In the mixed variant, the cryoglobulins are composed of either a monoclonal immunoglobulin that possesses antibody activity toward, and is attached to, polyclonal IgG (type II) or two or more polyclonal immunoglobulins (type III). Mixed cryoglobulins usually take the form of immune complexes and interreact with complement. They are seen in autoimmune diseases such as rheumatoid arthritis, SLE, and Sjögren's syndrome; in lymphoproliferative diseases; as well as in various chronic infections resulting from the hepatitis and Epstein–Barr viruses. Numerous cases associated with infection with the hepatitis C virus have been reported in recent years. Vasculitis can also occur in patients with hepatitis C virus who do not have mixed cryoglobulinemia; clinical differences are slight, except for a higher incidence of arthralgias among those who do have mixed cryoglobulinemia. A mixed cryoglobulinemia may be the cause of some cases of the “red finger syndrome” seen in patients with HIV or hepatitis infection. Association with parvovirus B19 infection has been reported on several occasions. In other patients, no etiology or pathogenesis is apparent. In approximately 50% of cases, no detectable autoimmune, lymphoproliferative, or active infective disease is present. These cases of essential mixed cryoglobulinemia are characterized by a chronic course with intermittent palpable purpura, polyarthralgia, Raynaud's phenomenon, and occasionally glomerulonephritis. In a recent survey of mixed cryoglobulinemia, 13 of 33 patients had essential mixed cryoglobulinemia; these individuals tended to have more severe disease than those with secondary forms of the disease, and they more often developed renal and peripheral nerve involvement. Other cutaneous manifestations that may be present include ulcers, urticaria, digital necrosis, and, rarely, pustular purpura.

A localized cryoglobulinemic vasculitis can be seen in tick bite reactions, particularly when tick mouthparts are retained in the tissue.

Histopathology

Monoclonal cryoglobulinemia

Purpuric lesions will show extravasation of red blood cells into the dermis. Small vessels in the upper dermis may be filled with homogeneous, eosinophilic material that is also PAS positive. These intravascular deposits are seen more commonly beneath areas of ulceration. Although there is generally no vasculitis, there may be a perivascular infiltrate of predominantly mononuclear cells ( Fig. 9.4 ). Microscopic changes of leukocytoclastic vasculitis have been reported in one case of monoclonal cryoglobulinemia (associated with Waldenström's macroglobulinemia). Vacuole-like cytoplasmic inclusions were found in peripheral blood neutrophils, monocytes, lymphocytes, and platelets (but not in bone marrow cells) in cryoglobulinemia associated with IgG-κ monoclonal gammopathy; this was of undetermined significance.

Differential diagnosis

Despite the possible clinical resemblance between lesions of perniosis and cryoglobulinemia, these diseases are not associated in adult patients. The microscopic findings are quite different, with perniosis showing perivascular lymphocytic infiltrates with evidence for lymphocytic vasculitis.

Histopathology

Multiple sections are sometimes required to find the diagnostic acicular clefts indicating the site of cholesterol crystals in arterioles and small arteries in the lower dermis or subcutis. A fibrin thrombus often surrounds the cholesterol material. Foreign body giant cells and a few inflammatory cells may also be present. Rarely, there are numerous eosinophils. Cutaneous infarction and associated inflammatory changes sometimes develop. Cholesterol emboli may be an incidental finding.

Deposits of atrial myxoma in peripheral arterioles and small arteries may at first glance be mistaken for cholesterol emboli. However, a loose myxoid stroma and lack of cholesterol clefting should allow a confident diagnosis of “metastatic” atrial myxoma.

Deposits of catheter tip can also form cutaneous emboli if fragments break off during a procedure. In one such case, purpuric lesions developed on the palm and fingers following percutaneous cardiac catheterization through the brachial artery.

Arterial embolization may follow the injection of hyaluronic acid used for tissue augmentation, and follow the use of acrylic cement during vertebroplasty.

Histopathology

In early cutaneous lesions, there is prominent dermal edema and hemorrhage with thrombi in both arteries and veins. Some endothelial cells may have pyknotic nuclei, whereas others are swollen and disrupted. There is usually a mild lymphocytic infiltrate around involved vessels, and sometimes there are plasma cells as well. There is no vasculitis. In livedo reticularis lesions, thrombosis is not generally identified, except in catastrophic disease; instead, one may see vascular proliferation or endarteritis obliterans. Painful, small ulcers show fibrin deposition in and around dermal vessels and hyalinization of vessel walls.

In later lesions, there is organization of thrombi and subsequent recanalization. Reactive vascular proliferation develops. Some endothelial cells may be prominent and contain eosinophilic globules similar to those seen in Kaposi's sarcoma. Hemosiderin pigment is also present in late lesions. Some vessels may show intimal hyperplasia. This may reflect organization of earlier mural thrombi. A panniculitis has been described, manifesting as tender nodules on the legs. Microscopic features included a mixed septal and lobular panniculitis, with septal fibrosis, fat necrosis, mucin deposition, and an infiltrate composed of histiocytes, neutrophils, and eosinophils.

Histopathology

The sensitivity of skin biopsies in Sneddon's syndrome has been evaluated. The white areas, rather than the red areas, should be biopsied. The sensitivity of one 4-mm biopsy is only 27%, but if three biopsies are taken, it increases to 80%. In the skin, small to medium-sized arteries near the dermal–subcutaneous junction are affected in a stage-specific sequence. The initial phase involves attachment of lymphohistiocytic cells to the endothelium with detachment of the endothelium (“endothelitis”). This is followed by partial or complete occlusion of the lumen by a plug of fibrin admixed with the inflammatory cells. This plug is replaced by proliferating subendothelial cells, which have the markers of smooth muscle cells. A corona of dilated small capillaries usually develops in the adventitia. Fibrosis of the intima or the plug may occur. Shrinkage and atrophy of these vessels then occurs.

Differential diagnosis

Although the differential diagnosis among possible causes of leukocytoclastic vasculitis or small vessel thrombosis is broad, the combination of these two changes raises three major considerations: levamisole-adulterated cocaine, septic vasculitis, and cryoglobulinemia.

Pathogenesis of urticaria

Urticaria results from vasodilatation and increased vascular permeability associated with the extravasation of protein and fluids into the dermis. Angioedema results when a similar process occurs in the deep dermis and subcutis. Histamine has generally been regarded as the mediator of these changes, although other mediators such as prostaglandin D ₂ and IL-1 are possibly involved in some circumstances. IL-1 and other cytokines can induce the expression of endothelial adhesion molecules, which is upgraded in urticarial reactions. Both immunological (type I and type III) and nonimmunological mechanisms can cause mast cells and basophils to degranulate, liberating histamine and other substances. Although immediate (type I), IgE-mediated mast cell release is the classic underlying mechanism of urticarial reactions, there is evidence that delayed-type hypersensitivity reactions are often involved as well. For example, the cytokine IL-4 can upregulate IgE secretion, whereas the opposite occurs with IFN. There is also an increase in IL-10-secreting T cells in chronic idiopathic urticaria. IL-18 is not increased compared with controls. The neuropeptide substance P, derived from unmyelinated sensory nerve endings, can also evoke the release of histamine, but not prostaglandin D ₂ , from cutaneous mast cells. ACE is one of the major peptidases for the degradation of substance P, but polymorphisms in the ACE gene do not appear to increase the risk of developing chronic urticaria, although they can be a contributing factor to susceptibility of angioedema accompanying chronic urticaria. Eosinophil degranulation occurs in most urticarias. The number of free eosinophil granules correlates with the duration of the wheal; granules are numerous in wheals of long duration. The granules may provoke the persistent activation of the mast cells in the wheal.

Other research has been directed at aspects of urticaria not necessarily involving mast cells in the first instance. It has been found that oxidative stress is common to the physical urticarias. Basophils have become the center of attention once again in chronic urticaria. In addition to the basopenia, intrinsic defects of the anti-IgE cross-linking signaling pathway of basophils have been described. Basophils in these patients have an activated profile, possibly because of an in vivo priming by IL-3.

Various studies have shown that approximately one-third or more of patients with chronic urticaria have circulating autoantibodies to FcεRIα (the high-affinity IgE receptor), resulting in the release of histamine from mast cells. This subset of patients (autoimmune chronic urticaria) has more severe disease. An association with HLA class II has been reported. The beneficial effect of cyclosporine and IVIG on chronic urticaria provides further support for the role of histamine-releasing autoantibodies in its pathogenesis. Extensive laboratory investigations do not contribute substantially to the diagnosis of chronic urticaria or the detection of underlying disorders.

In summary, several different mechanisms have been elucidated that are capable of stimulating the release of histamine from mast cells and/or basophils.

An excellent evidence-based protocol on the management of urticaria has been published by the British Association of Dermatologists. Practitioners should be aware of dosing, side effects, and potential interactions of the drugs mentioned. A nonsedating H1 antihistamine is the treatment of choice, although not all patients respond. A sedating antihistamine is sometimes used at bedtime. One study demonstrated the effectiveness of the monoclonal antibody, omalizumab, for physical urticarias. This agent selectively binds to free IgE. Rapid desensitization to autologous sweat has been used in the treatment of cholinergic urticaria. Other agents used in varying circumstances include corticosteroids, cyclosporine, intravenous immunoglobulin, mycophenolate mofetil, doxepin, scopolamine (in cholinergic urticaria), methotrexate, sulphasalazine, antibiotics, and anticoagulants (for the prevention of NSAID-induced urticaria.

Histopathology of urticarias

The cell type and the intensity of the inflammatory response in urticaria are quite variable. There is increasing evidence that the age of the lesion biopsied and the nature of the evoking stimulus may both influence the type and the intensity of the inflammatory response.

Dermal edema, which is recognized by separation of the collagen bundles, is an important feature of urticaria. Mild degrees may be difficult to detect. Urticarial edema differs from the mucinoses by the absence of granular, stringy, basophilic material in the widened interstitium. There is also dilatation of small blood vessels and lymphatics, and swelling of their endothelium is often present ( Fig. 9.5 ). The histopathological changes in urticaria are most marked in the upper dermis, but involvement of the deep dermis may be present, particularly in those with coexisting angioedema.

The cellular infiltrate in urticaria is usually mild and perivascular in location. It consists of lymphocytes and, in most cases, a few eosinophils. Occasional interstitial eosinophils and mast cells are also present. Eosinophil granule major basic protein has been identified in the dermis in several types of urticaria. Neutrophils are often noted in early lesions, but in most cases they are relatively sparse; there is evidence that they are more prominent in the physical urticarias, particularly delayed pressure urticaria. A recent study of this form of urticaria, elicited by a pressure-challenge test, emphasized the prominence of eosinophils. Eosinophil extracellular traps have been identified in bullous delayed pressure urticaria using confocal scanning laser microscopy. These structures contain mitochondrial DNA and eosinophil cationic protein and can be found using dual-labeling fluorescent methods. They are believed to constitute a primitive antibacterial defense mechanism. An important diagnostic feature of many early urticarias is the presence of neutrophils and sometimes eosinophils in the lumen of small vessels in the upper dermis. The presence of neutrophils in other circumstances is discussed later. Although mast cells are often increased in early lesions and even in nonstimulated skin of patients with chronic urticaria, they appear to be decreased in late lesions, apparently as a result of the failure of histochemical methods to detect degranulated mast cells.

Neutrophils have been described in urticaria in several different circumstances. As previously noted, a few intravascular and perivascular neutrophils are a common feature in early urticaria. At times, there may be sufficient transmigration of neutrophils through vessel walls to give a superficial resemblance to vasculitis, but there is no fibrinoid change, hemorrhage, or leukocytoclasis. A more diffuse dermal neutrophilia has also been described in nearly 10% of urticarias. The term neutrophilic urticaria is used in these circumstances. In these cases, neutrophils are scattered among the collagen bundles, usually in the upper dermis but sometimes throughout its thickness. The infiltrate is usually mild in intensity. Rare nuclear “dusting” may also be present. Interstitial eosinophils and perivascular eosinophils and lymphocytes are usually noted as well. Neutrophils are also present in the leukocytoclastic vasculitis that sometimes accompanies chronic urticaria. The term urticarial vasculitis has been applied to cases of this type in which the clinical picture is that of an urticaria and the histopathology is a vasculitis. In urticarial vasculitis (also see p. 260 ) the urticarial lesions are usually of longer duration than in the usual chronic urticaria and may be accompanied by systemic symptoms. The incidence of vasculitis in chronic urticaria varies with the strictness of the criteria used for defining vasculitis. There appears to be a continuum of changes, with a few intravascular and perivascular neutrophils at one end of the spectrum and an established leukocytoclastic vasculitis at the other. In a large series of patients with urticaria subjected to biopsy, 57% were found to have “neutrophilic urticaria.” This high percentage was attributed to the tendency to biopsy lesions of new onset. There was no difference in prevalence of rheumatic disease among those with neutrophilic compared with conventional urticaria.

Zembowicz and colleagues examined 16 skin biopsies from patients with aspirin-induced chronic idiopathic urticaria. A classic urticarial pattern occurred in the majority of cases (12 of 16). Two biopsies showed an interstitial fibrohistiocytic (granuloma annulare–like) pattern, one showed a sparse perivascular lymphocytic infiltrate, and the other showed a paucicellular dermal mucinosis.

Other histopathological features have been described in several of the specific types of urticaria. In dermographism, perivascular mononuclear cells are increased, even before the initiation of a wheal. In contact urticaria, subcorneal vesiculation and spongiosis have been reported, but this may simply reflect a concomitant allergic or irritant contact dermatitis. In papular urticaria, the inflammatory cell infiltrate is usually heavier than in other chronic urticarias and consists of a superficial and deep infiltrate of lymphocytes and eosinophils in a perivascular location. The infiltrate is often wedge shaped. Interstitial eosinophils may also be present, and in lesions of less than 24 hours’ duration there are also some neutrophils. There is variable subepidermal edema. In angioedema , the edema and vascular dilatation involve the deep dermis and/or subcutis, although in the hereditary form there is usually no infiltrate of inflammatory cells. It is also quite mild in other forms of the disease. In Schnitzler's syndrome, there are often neutrophils in the dermal infiltrate in a perivascular location mimicking a neutrophilic urticaria. Monoclonal IgM and its autoantibody deposit in the epidermis and at the dermoepidermal junction in the region of the anchoring fibrils. One case of cholinergic urticaria associated with hypohidrosis showed partial occlusion of the intraepidermal portion of an eccrine sweat duct by keratinous material, with proximal ductal dilatation and periductal lymphocytic infiltration.

Differential diagnosis

When urticarial lesions show perivascular lymphocytic infiltrates, the differential diagnosis can be quite broad and includes polymorphic light eruption, drug-induced exanthem, arthropod reaction, viral exanthem, and id reaction. Although the presence of eosinophils often narrows the focus somewhat to drug or arthropod reaction, clearly eosinophils appear in urticaria due to a variety of factors, including (as noted previously) delayed pressure, and they may be entirely absent in reactions to arthropods or drugs. The finding of diffuse neutrophils with mild perivascular inflammation also raises the possibility of cellulitis or erysipelas; bacteria are typically difficult to identify in tissue sections of those lesions. Neutrophilic urticarias usually lack the other features commonly associated with true vasculitis: endothelial swelling, leukocytoclasis, extravasated erythrocytes, and fibrin deposition. If those features are found in varying combinations, one should suspect urticarial vasculitis. Direct immunofluorescence may then be helpful in that vasculitic lesions show immunoglobulin and complement deposition in vessel walls. A recently described group of disorders termed neutrophilic urticarial dermatosis can also display leukocytoclasia; disorders showing these changes include SLE, Still's disease (juvenile rheumatoid arthritis), and Schnitzler's syndrome. Spongiotic changes should ordinarily argue against a diagnosis of urticaria, unless another process can be invoked (e.g., superimposed allergic contact dermatitis or secondary eczematization of an urticarial lesion). In addition, both papular urticaria and urticarial dermatitis may show spongiosis. A variety of other dermatoses may well have an urticaria-like dermal component and yet not represent a primary form of urticaria. A variant of follicular mucinosis has been described that has clinical resemblances to urticaria but characteristic features of follicular mucinosis on biopsy.

Clinical manifestations

Leukocytoclastic vasculitis usually presents with erythematous macules or palpable purpura, with a predilection for dependent parts, particularly the lower parts of the legs. Other lesions that may be present include hemorrhagic vesicles and bullae, nodules, crusted ulcers, and, less commonly, livedo reticularis, pustules, or annular lesions. Segmental leukocytoclastic vasculitis has accompanied herpes zoster. Nodular angiomatoid lesions have been described in a patient with IgA-λ myeloma. An erythema gyratum repens–like eruption occurred in one patient. Cases with urticarial lesions are classified separately as urticarial vasculitis (see later). Individual lesions vary from 1 mm to several centimeters in diameter. Large lesions are sometimes painful. There may be a single crop of lesions that subside spontaneously after a few weeks or crops of lesions at different stages of evolution that may recur intermittently. Unilateral and localized lesions are rare. Koebnerization is also surprisingly uncommon. Interestingly, a “reverse” Koebner phenomenon has also been described: disappearance of vasculitic lesions where a pressure bandage had been applied to a skin biopsy site.

Extracutaneous manifestations occur in approximately 20% of affected individuals and include arthralgia, myositis, low-grade fever, and malaise. In a retrospective series of 93 adult patients reported in 2006, extracutaneous involvement was found in 39.8% of patients. Less commonly, there are renal, gastrointestinal, pulmonary, or neurological manifestations. Bilateral acute angle closure glaucoma was the presenting feature of a case of systemic leukocytoclastic vasculitis. The severity of the histopathological changes is not predictive of extracutaneous involvement. Many of these cases with systemic manifestations would now be classified as microscopic polyangiitis (polyarteritis) (see p. 265 ), although renal involvement is still associated with cutaneous small vessel vasculitis. There is a low mortality in leukocytoclastic vasculitis; death, when caused by the vasculitis, is related to involvement of systemic vessels. In one study of 160 patients with leukocytoclastic vasculitis, the mortality rate was 1.9%.

Etiology

There are several different etiological groups, although in approximately 40% of cases there is no apparent cause. The recognized groups include infections, drugs and chemicals, cancers, and systemic diseases. In a retrospective study of 93 adult patients (referred to previously), no obvious cause was found in 44.1%. Drugs and infections were the most common cause. Miscellaneous causes include certain arthropod bites, severe atherosclerosis, gallbladder vasculitis, prolonged exercise, some coral ulcers, and coronary artery bypass surgery. Exercise-induced vasculitis can occur in marathon runners, in women after long walks, and in golfers. Sometimes only an urticaria is present. A deep leukocytoclastic vasculitis has been found in cases of lower extremity inflammatory lymphedema, an exquisitely tender condition occurring in otherwise healthy adult military trainees during the first 72 hours of basic training and associated with prolonged standing at attention.

Streptococcal infection of the upper respiratory tract is the most commonly implicated infection. A streptococcal bullous erysipelas has also been associated with a vasculitis. Other infections include influenza, Mycobacterium tuberculosis , M. haemophilum , hepatitis B, herpes simplex, herpes zoster/varicella, human herpesvirus 6 (HHV-6), cytomegalovirus, parvovirus infection, HIV infection, malaria, and scrub typhus, with disseminated intravascular coagulation, caused by Orientia tsutsugamushi . It has followed influenza immunization and envenomation of the brown recluse spider (Loxosceles reclusa).

The drugs that cause vasculitis are listed in Table 9.2 . Chemicals used in industry, drug and food additives, and hyposensitizing antigens are also linked to leukocytoclastic vasculitis. The cancers associated with leukocytoclastic vasculitis include lymphomas (e.g., angioimmunoblastic T-cell lymphoma), diffuse large B-cell lymphoma, myelodysplastic syndrome, mycosis fungoides, hairy cell leukemia, chronic lymphocytic leukemia, multiple myeloma, IgA-λ monoclinal gammopathy, and visceral tumors such as gastric and colonic adenocarcinoma, pleural mesothelioma, squamous cell carcinoma of the lung, and hypernephroma.

The systemic diseases include SLE, dermatomyositis, generalized morphea, mixed connective tissue disease, Behçet's disease, celiac disease, inflammatory bowel disease, cystic fibrosis, Sjögren's disease, subcorneal pustular dermatosis, pyoderma gangrenosum, sarcoidosis, the Wiskott–Aldrich syndrome, and α ₁ -antitrypsin deficiency.

Pathogenesis

The pathogenesis of leukocytoclastic vasculitis involves the deposition of immune complexes in vessel walls with activation of the complement system, particularly the terminal components. This contrasts with microscopic polyangiitis in which immune complexes are often absent. Chemotaxis of neutrophils and injury to vessel walls with exudation of serum, erythrocytes, and fibrin result. Cell adhesion molecules play a critical role in the interaction between the vascular endothelium and leukocytes. These adhesion molecules are likely to be involved in the recruitment of the neutrophils. Mast cells may also play a role. The size of the immune complexes, which depends on the valence of the respective antigen and antibody and their relative concentrations (which is in part determined by the number of binding sites on the antigen), determines the likelihood of their deposition. The complexes most likely to precipitate are those with antigens bearing two to four binding sites and in a concentration approximately equivalent with antibody. These are the largest immune complexes that ordinarily remain soluble.

Various antibodies have been detected in patients with acute vasculitis, including ANCA and IgA class anticardiolipin antibodies. ANCA-positive vasculitis is known to be associated with the antithyroid drug propylthiouracil; both myeloperoxidase ANCA and proteinase-3 ANCA have been reported. In one study, cryoglobulins were found in 25% of cases.

Lymphokines also play an important role in the evolution of the vascular lesions. Interleukins (IL-1, IL-6, and IL-8) are increased in the circulation, as is tumor necrosis factor (TNF). Both TNF and IL-1 may stimulate the endothelium to activate the intrinsic and extrinsic coagulation pathways and reduce its fibrinolytic activity. This may be the explanation for the thrombosis that occurs in vasculitis.

The formation of platelet aggregates appears to play a thus far unrecognized role in cutaneous small vessel vasculitis. In all cases of vasculitis, platelet clumps are associated with diffuse immunostaining of the perivascular stroma with the initiator of platelet aggregation, anti–von Willebrand's factor.

Hemodynamic factors such as turbulence and increased venous pressure, as well as the reduced fibrinolytic activity that occurs in the legs, may explain why localization of lesions to this site is common. Rarely, lesions may develop in areas of previously traumatized skin—the Koebner phenomenon. The size and configuration of the complexes may also determine the class of vessel affected. The size of the affected vessels correlates with the clinical features. For example, involvement of small dermal vessels results in erythema or palpable purpura, whereas lesions in larger arteries may lead to nodules, ulcers, or livedo reticularis. Deep venous involvement results in nodules without ulceration.

Drug- and infection-related vasculitis usually respond to the withdrawal of the drug and the treatment of the infection, respectively. Systemic corticosteroids can be used in severe drug-related cases to hasten the resolution of the disease. In more chronic cases, as seen with some of the tumor-associated and idiopathic vasculitides, other therapy is used, such as dapsone, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, cyclophosphamide, and intravenous immunoglobulin. Rituximab has been used for small vessel vasculitis, particularly the type II mixed cryoglobulinemic vasculitis. Hyperbaric oxygen therapy has been used as a successful adjuvant in vasculitides with nonhealing skin ulcers.

Histopathology

Acute vasculitis is a dynamic process. Accordingly, not all the features described here will necessarily be present at a particular stage in the evolution of the disease. It is best to perform a biopsy on a lesion of 18 to 24 hours’ duration because this will show the most diagnostic features. The changes to be described usually involve the small venules (postcapillary venules) in the dermis, although in severe cases arterioles may also be affected. In the cases associated with lower extremity inflammatory lymphedema in military basic trainees, leukocytoclastic vasculitis involved the deep dermal vascular plexus. Some of the cases involving arterioles would now be classified as microscopic polyangiitis (see p. 265 ). There is infiltration of vessel walls with neutrophils that also extend into the perivascular zone and beyond. These neutrophils undergo degeneration (leukocytoclasis) with the formation of nuclear dust ( Fig. 9.7 ). Nuclear dust is not synonymous with this condition. LeBoit has reviewed the other circumstances in which it can be found. The vessel walls are thickened by the exudate of inflammatory cells and edema fluid. There is also exudation of fibrin (“fibrinoid necrosis”) that often extends into the adjacent perivascular connective tissue. Endothelial cells are usually swollen and some are degenerate. Thrombosis of vessels is sometimes present. The dermis shows variable edema and extravasation of red blood cells.

In some lesions, particularly those of longer duration, eosinophils and lymphocytes are also present, particularly in a perivascular location. Macrophages, which are scattered in the interstitium even in the early stages, show a time-dependent increase. In vasculitis caused by drugs, a mixed inflammatory cell infiltrate of eosinophils, lymphocytes, and occasional neutrophils is commonly seen. The mean eosinophil count per high power field was 5.20 in a series of drug-induced cases and 1.05 in non–drug-induced cases. The vasculitis induced by tamoxifen (discussed previously) was unusual in being localized to the mastectomy scar and right thorax.

In resolving lesions, there is usually only a mild perivascular infiltrate of lymphocytes and some eosinophils. A rare plasma cell may also be present. Perivascular hemophagocytosis is another late feature. A striking feature of late resolving lesions is hypercellularity of the dermis with an increased number of interstitial fibroblasts and histiocytes, giving the appearance of a “busy dermis” ( Fig. 9.8 ). There is sometimes a mild increase in acid mucopolysaccharides imparting a vague “necrobiotic” appearance. These findings on the evolutionary changes in vasculitis are based on a study by the author of five cases of leukocytoclastic vasculitis, biopsied several times over the course of a 2-week period. It was never published.

Uncommonly, the subepidermal edema is so pronounced that vesiculobullous lesions result. Cutaneous infarction, usually involving only the epidermis and upper third of the dermis, may follow thrombosis of affected vessels. Presumptive ischemic changes are not uncommon in sweat glands, even in the absence of infarction. They include apoptosis, necrosis, and basal cell hyperplasia. Rare changes reported in leukocytoclastic vasculitis include epidermal lichenoid changes, subepidermal microabscess formation resembling dermatitis herpetiformis, and intraepidermal vesiculation with acantholytic cells containing vacuolated nuclei. Cytomegalovirus-associated vasculitis can sometimes occur without inclusion body changes.

Although previous studies suggested that direct immunofluorescence is not particularly useful unless performed on lesions less than 6 hours old, studies have found fibrinogen, C3, and IgM in early lesions; albumin, fibrinogen, and IgG in fully developed lesions; and mainly fibrinogen, with some C3, in late lesions. Lesional skin is more often positive than nonlesional skin. Another study found vascular deposits of immunoglobulin in 81% of cases. The presence of immunoglobulin was seen more often in patients who had at least one extracutaneous manifestation. The presence of IgA was a strong predictor of renal disease. E-selectin (ELAM-1) is present early in the course of vasculitis but decreases as the lesion evolves.

Differential diagnosis

The main differential diagnostic problem is the recognition of leukocytoclastic vasculitis when changes are subtle, obscured by dense inflammation, or mimicked (to an extent) by neutrophilic perivascular infiltrates. Diagnosis therefore requires careful inspection of vessel changes, facilitated at times by multiple levels and direct immunofluorescence study. One must also be aware of the phenomenon of “secondary vasculitis” as seen, for example, at the base of ulcers or in heavy neutrophilic dermal infiltrates. In such circumstances, it is worthwhile to evaluate those vessels that are not in the immediate vicinity of an ulcer and to examine for evidence of true vessel injury. Some examples of neutrophilic urticaria, a potential clinical mimic of urticarial vasculitis, can create considerable diagnostic difficulty. This form of urticaria consists of long-standing lesions that are accompanied by pain rather than pruritus. Included are a number of the “physical urticarias”—cholinergic, cold, and delayed pressure urticarias. Neutrophils aggregate around dermal vessels, but leukocytoclasis is not observed, nor is there evidence for endothelial injury or fibrin deposition.

Histopathology

The appearances are usually indistinguishable from those seen in leukocytoclastic vasculitis. IgA, predominantly of the IgA1 subclass, is demonstrable in vessel walls in both involved and uninvolved skin in most cases, provided that the biopsy is taken early in the course of the disease. It has been suggested that the punch biopsy should be taken from the edge of a fresh lesion to maximize the chances of finding IgA deposits. Lesions should be less than 48 hours old. Apoptotic dendrocytes (factor XIIIa positive) were noted around vessels in one case. Johnson et al. found that renal involvement is significantly associated with papillary dermal edema on histopathology and with perivascular C3 deposition on direct immunofluorescence. The latter finding has been supported in another large study, in which it was also found that IgM deposition has an association with articular involvement.

Henoch–Schönlein purpura is not synonymous with IgA-associated vasculitis. Rather, it is one subcategory of it. An IgA vasculitis has been seen, without the usual clinical features of Henoch–Schönlein purpura, in a setting of prior infection, usually of the upper respiratory tract, in granulomatosis with polyangiitis (formerly Wegener's granulomatosis), inflammatory bowel disease, and malignancies. IgA vasculitis and nephropathy have followed Bartonella henselae infection. IgA deposits in superficial dermal vessels have also been reported in patients with evidence of alcohol abuse; the frequency of these deposits apparently does not differ when comparing patients with and without IgA nephritis.

Histopathology

There is a necrotizing, eosinophil-rich vasculitis involving small vessels in the dermis and, sometimes, the subcutis ( Fig. 9.9 ). It involves a smaller class of vessel than Churg–Strauss syndrome. There is marked deposition of eosinophil granule major basic protein in the vessel walls. Dermal infiltration by eosinophils is prominent, but there is little or no leukocytoclasis. The overlying epidermis is often normal, but there may be minor eosinophilic spongiosis.

Dermoscopy has shown spots and purpuric globules (representing damaged superficial dermal vessels with erythrocyte extravasation), with an irregular red-orange background. Such changes can also be seen in other forms of vasculitis.