Cutaneous vasculitis

In this paper the current concepts of cutaneous vasculitis are reviewed, with emphasis on clinical patterns, strict pathologic criteria and mechanisms of injury. A plea is made to classify vasculitis not as syndromes but (a) according to organ involvement (limited cutaneous or complicated multisystem), (b) by cause, (c) by pathologic description and (d) by anatomic depth and type of vessel involvement. Dans actuelle cutanee,

In this paper the current concepts of cutaneous vasculitis are reviewed, with emphasis on clinical patterns, strict pathologic criteria and mechanisms of injury. A plea is made to classify vasculitis not as syndromes but (a) according to organ involvement (limited cutaneous or complicated multisystem), Cutaneous vasculitis can be defined as a number of clinical syndromes that on pathologic examination show destructive and inflammatory changes in blood vessels.

Patliogenesis and clinical features
In the early 1 900s Osler1 first recognized the difficulty of classifying cutaneous vasculitis on the basis of the clinical appearance of the lesions. The dermatologic literature is now flooded with attempts to classify the vasculitic lesions on this basis;2 there is confusing overlap within the classifications, and the list of eponyms and syndrome names is lengthy and not helpful to physician or patient, diagnostically or therapeutically. Vasculitis should be considered in terms of pathologic criteria and mechanism of injury if known. The location of the vessel affected and the severity of the insult are important determinants of the morphologic features of the cutaneous lesions.
Palpable purpura is the hallmark and most diagnostic feature of cutaneous vasculitis.3 Other primary lesions, although less specific, may represent vasculitis of the skin; these include transient erythema, papules, pustules, urticaria, petechiae, vesicles, bullae, necrosis, ulceration, and chronic telangiectasi a, livedo reticularis and atrophic scarring, depending on the severity and duration of damage to the vessel wall. 4 In the absence of palpable purpura clinical diagnosis is extremely difficult and only pathologic examination is confirmatory.
The clinical features reflect local microvascular injury. Whatever the specific cause, if a mild or transient change occurs in the superficial vessels, then erythema or urticaria will result. If these lesions persist for more than 24 hours the clinician should suspect that vasculitis is the underlying problem; inking of the margin of the lesion may be of practical help. When the insult is more prolonged or more severe, vascular permeability increases and papules, vesicles or purpura develop. Itching and stinging of these lesions reflect the superficial location of the affected vessels. As plasma leaks from the vessel, hemoconcentration coupled with endothelial damage can lead to stasis, thrombosis and anoxia. Then, as more of the vascular supply to the skin is compromised, necrosis with or without ulceration can occur. If the vessels of the subcutaneous fat are affected pain is more likely to be present.5 Clinically vasculitis of the cutaneous fat often presents as crops of poorly demarcated, tender nodules.
The primary target vessel is most often the venule. Frequently it is difficult to distinguish arteriole from yenule because of damage and infiltration.6 With local conditions of stasis and gravity these lesions tend to occur on the lower legs and dependent areas of the body. Often after healing there is postinflammatory, yellow-brown pigmentation. In some forms of vasculitis the damage can be so extensive as to cause atrophic scarring with hypopigmentation -atrophie blanche. 7 Involvement of other organs (e.g., peripheral neuropathy, gastrointestinal hemorrhage, hemoptysis and hematuna) associated with skin lesions indicates complicated (multisystem) vasculitis. 5 No clinical feature of cutaneous vasculitis allows the physician to distinguish vasculitis confined to the skin from the complicated form.

Pathologic features
The definitive diagnosis ot vasculitis is made from examination of biopsy specimens. It is very important that biopsy of early lesions be done and, if indicated, several biopsies should be taken to follow the progression of the pathologic process.9 Vasculitis can involve both the superficial and the deep vessels of the skin, so the biopsy specimen must include subcutaneous fat. To ensure adequate depth, surgical wedge biopsy is recommended.
The major pathologic criteria for the diagnosis of cutaneous vasculitis are: 1. Cellular infiltration in the vessel wall.
3. Necrosis associated with inflammatory infiltration. The minor criteria are: 1. Endothelial swelling (with or without proliferation).
2. Extravasation of erythrocytes. 3. Thrombosis in the lumen. Two of the three major criteria should be fulfilled for the diagnosis of vasculitis. Characteristically, cellular infiltration is seen within the vessel wall. The infiltrating cells may be: (a) polymorphonuclear leukocytes, which may undergo fragmentation (leukocytoclasia); (b) lymphocytes or monocytes (macrophages); or (c) monocytes (macrophages) and histiocytes in a granulomatous arrangement, with or without giant cells. Rarely, no cellular infiltrate is seen and hyalinization of the vessel wall occurs. as in livedo vasculitis.10 Fibrinoid, probably an incompletely polymerized form of fibrin, classically is deposited in the vessel wall following endothelial damage. This substance probably helps perpetuate the inflammatory response because of its chernotactic properties, and its presence may mimic necrosis.
The pathologic process is a dynamic one, so biopsy specimens from lesions at different stages in the same patient may show different pathologic features.

Mechanisms of injury
Many theories, both immunologic and nonimmunologic, have been proposed to explain the characteristic changes seen in cutaneous vasculitis. One theory that has some support from experiments with animals is the immune complex theory." Briefly stated, antigen-antibody complexes (immune complexes) in conditions of antigen excess are deposited in the vessel wall. As an example, a drug or its metabolite could be the antigen or hapten. The complexes will fix complement, which is then chemotactic for neutrophils. When the neutrophils try to phagocytose these complexes, proteolytic enzymes, which can damage the vessel wall, are released from the neutrophils. lysosomes. The resultant inflammatory response attracts more neutrophils. Monocytes appear as a second wave of phagocytic cells and remove debris from areas of tissue damage.
Modifying factors are known to be important in this general type of reaction. Smaller complexes (7S-19S) are not phagocytosed easily by the reticuloendothelial system and hence circulate for longer periods and have a greater chance of being deposited in the wall of blood vessels and initiating the vasculitic process. Complement-fixing antibodies are more likely to be the initiators of the inflammation.12 Antibodies that have a greater binding affinity for their corresponding antigen are cleared more readily by the reticuloendothelial system and therefore are less likely to cause inflammation. Genetic factors, such as immune response genes, can influence the amount and type of antibody formed in response to stimulating antigen. It is well known from experiments with animals that a weak antibody response is more likely to cause the development of immune complex disease because of the antigen excess. Physical factors such as external pressure, trauma, peripheral cooling, gravity and dependency all contribute to the tendency for these complexes to localize in the vessels of the lower legs. As well, the superficial venous plexus in the lower legs is more tortuous than in other areas of the body, which predisposes this area to stasis.13 Add to these factors the known increased number of gaps between endothelial cells and the thicker basement membrane of venules in the lower legs and it is not difficult to understand why immune complexes settle in these areas.
This is just one theory of complement activation. Several biologic pathways are well recognized to interact with each other and complement to initiate inflammation14 (e.g., platelet aggregation and fibrinolysis). Investigation One treatable cause that must always be excluded is infection (e.g., gonococcemia, meningococcemia and Rocky Mountain spotted fever). Because of the bewildering variety of causes and associations with cutaneous vasculitis, careful history-taking is important. One should ask about recent infection or drug intake, physical triggers (e.g., cold) and history of chronic illness (e.g., rheumatoid disease).
Hemoglobin concentration, leukocyte and platelet counts and erythrocyte sed-imentation rate (ESR) should be determined. An increase in the ESR may reflect the presence of immune complexes that are not normally identified by protein electrophoresis or immunoelectrophoresis. Serologic testing for cryoglobulins,11 antinuclear factor (ANF) and rheumatoid factor should be done, and measurement of the concentrations of the C3 and C4 components of serum complement is available in most centres. The presence of a paraprotein may be detected by immunoelectrophoresis. Because of recent reports of hepatitis B antigenemia with periarteritis nodosa16 and cutaneous vasculitis, this antigen should be sought when it is indicated. Coagulation and fibrinolytic studies17'18 have been advocated to help determine the pathogenesis of some types of vasculitis (e.g., livedo vasculitis). Thrombocytopenia or depressed serum complement concentration would be evidence of complicated (multisystem) vasculitis. Urinalysis is extremely important in patients with vasculitis to detect possible renal involvement; both analysis of a 24-hour urine collection for protein concentration and creatinine clearance, and simple urinalysis for the presence of casts or hematuria should be done. In patients with persistent proteinuria or abnormal renal sediment renal biopsy may be necessary.
Infectious causes should be investigated with appropriate cultures.
The most important diagnostic procedure is the skin biopsy. The specimen should be sent to the laboratory for regular histologic examination and, when possible, it should be frozen quickly for immunofluorescence to detect the presence of immunoglobulins, fibrin or complement19 within the vessel walls. As procedures become refined it will soon be possible to measure the presence and concentration of immune complexes in peripheral blood. It may be important to freeze samples of serum so that, in the future, serial measurements can assist in management.

Management
Despite intensive investigation, in many cases no cause will be found. Prednisone is reserved for use in cases of cutaneous vasculitis in which other organs are involved or if the cutaneous disease is severe. Immunosuppressive agents such as cyclophosphamide are used in some cases of multisystem vasculitis (e.g., Wegener's granulomatosis). In theory these drugs may aggravate vasculitis by decreasing antibody production. This can lead to a relative antigen excess and an increase in the proportion of immune complexes of low molecular weight, which predispose to vasculitis. A host of other systemic drugs have been used, with variable success, such as dapsone, penicillamine, iodides and heparin. Plasmapheresis has been used in some centres to decrease the concentration of immune complexes.

Classification
The many terms that have been used to describe cutaneous vasculitis and associated syndromes are presented in Table I. We urge that cutaneous vasculitis be classified as follows: 1. By extent of involvement: limited to skin or complicated (multisystem involvement affecting, for example, kidney, lung or nervous system).
4. By anatomic depth and type of vessel affected: superficial dermal yenule, as in Henoch-Sch5nlein purpura, or vein in the subcutaneous fat, as in erythema nodosum, for example.
If every case of cutaneous vasculitis is classified as above, consistent patterns of response may emerge and etiologic or associated factors will be identified within specific subclassifications. This should lead to a rational approach to determining pathogenesis and therapy.

Case reports Case 1
Clinical features: In a 24-year-old woman a severe streptococcal sore throat developed 4 weeks prior to admission to hospital. She was treated with penicillin in appropriate dosage but after 5 days of therapy typical red, tender nodules of erythema nodosum developed on the lower legs. She was admitted to hospital when target lesions of erythema multiforme with bullae appeared on her face and arms (Fig. 1). Acute arthritis was noted, especially of the left elbow.
Clinical impression: Erythema nodosum and erythema multiforme were associated with P-hemolytic streptococcal infection or penicillin therapy, or both.
Pathologic findings: Biopsy specimens from the erythema nodosum lesions (Fig.  2) showed a predominantly lymphohistiocytic infiltration of the septal veins of the subcutaneous fat; in the septa were Miescher's granulomata typical of erythema nodosum. Specimens from the erythema multiforme lesions (Fig. 3) showed vasculitis of the superficial dermal vessels, with a predominantly lymphocytic infiltration and fibrinoid in the vessel walls, and eosinophilic necrosis of the epidermis.
Immunofluorescence: This was not done.
Comment: We classified this case as one of self-limited, complicated (multisystem) vasculitis caused by streptococcal infection or penicillin therapy, or both. The vasculitic process involves lymphohistiocytic infiltration of the septal veins of the subcutanous fat (erythema nodosum) and lymphocytic infiltration of the superficial dermal venules (erythema multiforme).

Case 2
Clinical features: A 64-year-old woman was seen initially in 1970 because of asymptomatic palpable purpuric papules on the legs, buttocks and arms (Fig. 4).
She also complained of arthralgias and fatigue. Subsequently she was found to be anemic and a severe peripheral neuropathy developed. The ESR was elevated, the C4 concentration depressed, the rheumatoid factor titre very high (1:163 840) and the ANF titre positive, with nucleolar and homogeneous patterns at different times. Proteinuria then developed and immune complexes as well as cryoglobulins were detected in her serum. Despite therapy with prednisone in high dosage, chlorambucil and cyclophosphamide, as well as plasmapheresis, her disease process remained active. A renal biopsy specimen showed proliferative glomerulonephritis.
Clinical impression: A complicated, multisystem vasculitis involved skin, kidney and peripheral nervous system, with marked serologic abnormalities and cryoglobulins in the serum (Melcher-Franklin syndrome).
Comment: This case illustrates a severe, progressive, complicated leukocytoclastic vasculitis with cryoglobulin formation involving the superficial dermal vessels.

Case 3
Clinical features: A 33-year-old man complained of progressive, painful erythematous and purpuric papules with crusting, ulceration and swelling on the lower legs and ankles (Fig. 6). A linear, purple, reticulated pattern was noted. He denied any constitutional symptoms or drug intake. Physical findings, apart from the above, were normal. The signs and symptoms tended to flare during the summer and improve during the winter.
Clinical impression: The diagnosis was livedo vasculitis with summer ulcerations.
Pathologic findings: The superficial dermal vessels showed thrombosis and hyalinization. No cellular infiltrate was noted. Fibrinoid was deposited in the vessel walls (Fig. 7).
Immunofluorescence: C3 and IgA were evident in the walls of the superficial dermal vessels, consistent with a diagnosis of vasculitis.
Comment: We classified this case as one of localized vasculitis confined to the skin with no apparent cause. Hyalinization with necrosis and thrombosis was noted in the superficial dermal vessels without cellular infiltration.

Case 4
Clinical features: A 52-year-old man was admitted to hospital with right-sided congestive heart failure. Therapy with digitalis, furosemide and salt restriction was begun. Ten days after admission, purpuric and ecchymotic papules and plaques with bullae were noted, beginning on the ankles and spreading up the legs to include the thighs and buttocks (Fig. 8)  lesions began to involute significantly after 72 hours. Residual macular pigmentation was noted, especially around the ankles. Pathologic findings: The small, superficial dermal vessels showed a predominantly lymphocytic infiltration and extravasation of erythrocytes was prominent. There was some fibrinoid deposition.
Immunofluorescence: This was not done. Comment: We believe that this case illustrates a limited cutaneous vasculitis associated with furosemide therapy. The infiltrating cell was a lymphocyte and only the superficial dermal vessels were involved.

Conclusion
We have attempted in this paper to set forth clinical and pathologic criteria for the diagnosis of cutaneous vasculitis. A strong plea is made for a more logical classification.