Cutaneous vasculitis: Relationship to systemic disease and therapy

Cutaneous Vasculitis: to Systemic Disease

Jeffrey P. Cden, Fu4.C.P.

M.D.,

Professor of Medichie (Dermatology) Chief, Division of Dermatology Department of Medicine University of Lmhville Jmhille , Kentucky

Jeffrey P. Callen, M.D., is professor and chief, Division of Dermatology, at the University of Louisville. He is a Fellow of the American College of Physicians, American College of Rheumatology, and the American Academy of Dermatology and is Editor-in-chief of Advances in Dermatology and PaoLuEMs IN D~~~~m~~~~,aswellas section editor for Arthritis and Rheumatism. He is on the editorial or advisory boards of Practical Reviews in Dermatology Journal of the American Academy of Dermatology, Dermatology Digest, and the Journal of the Eumpean Academy of Dermatology and Venereology. Dr. Callen is the author of more than 300 scientific publications, including books and book chapters, original investigations, review articles, case reports, editorials, and abstracts. He has lectured extensively on a variety of dermatologic topics in the United States and abroad. Research areas of interest to Dr. Callen include treatment of dermatomyositis and its relationship to malignancy, cutaneous vasculitis and its relationship to systemic illness, and aspects of dermatology related to internal medicine. 50

Relationship and Therapy

Cutaneous vasculitis is a marker of systemic disease. It may represent the sole manifestation of the disease process or may be considered merely a minor feature of a lifethreatening vasculitic syndrome. Some of the confusion in the classification of vasculitis exists because of the features that are shared by so-called specific syndromes. For example, when one considers patients with paraproteinemia, it is evident that a variety of the vasculitic syndromes can occur in these patients and that the paraprotein may be a manifestation of an associated collagen-vascular disease. Similarly, the patient with hypersensitivity vasculitis may manifest the full gamut of a systemic vasculitis including gastrointestinal bleeding and nephritis. Therefore, when approactig the patient in whom cutaneous disease is a feature, one should consider the full array of vasculitic syndromes, and all organ systems that are potentially affected should be thoroughly evaluated. It appears that the syndrome with which each patient has been diagnosed remains stable. In other words, the patient with chronic cutaneous (small-vessel) vasculitis seems to have involvement of only the skin, even with long-term follow-up. The pathogenesis of cutaneous vasculitis, at least in part, has been linked to the presence of immune complexes in the circulation, which can become deposited in the tissues. However! additional factors including endothelial abnormalities, cytokines, and direct effects of inflammatory cells can also be invoked in this complex cascade of events. Although corticosteroids seem to be effective in most vasculitic syndromes, the doses required often result in steroid-related side effects. Thus, it has been a goal in each vasculitic syndrome to find agents that are effective and’potentially less toxic than corticosteroids. Immunosuppressive or cytotoxic agents have also demonstrated their effectiveness, but long-term use may result in a greater potential for a secondary malignancy. other agents to be considered for patients with vasculitis are antihistamines, antimalarials, dapson8 and sulfonamides, and colchicine. (CLEW PROBL DERMAML 1993; 5xl5-80)

Definitions Vasculitis is a general term that refers to inflammation involving the blood vessels.’ The term does not specify the type of inflammation or the size of the vessel involved.’ The skin is an organ that is well supplied with vasculature and frequently develops manifestations of vasculitis. Often the skin serves as the Curr

Probl

Dermatol,

March/April

1993

initial organ upon which vasculitis is manifest, with involvement of the small- to medium-sized vessels that supply nutrients to the skin. Although there are times when the only recognizable organ system involved is the skin, cutaneous vasculitis rep&ems a systemic disease process because it has been clearly linked to the presence of circulating immune complexes. The term leukocytoclastic vasculitis (LCV) is used to describe a process that is recognized within a biopsy specimen.3 The features that are observed include fibrinoid necrosis of the vessel walls, with infiltration of polymorphonuclear neutrophils (PMNs), some of which are disrupted, resulting in the presence of nuclear debris within the tissue. The reaction pattern is commonly represented clinically as palpable purpura (Fig 1), and thus the term LCV has often been used as a diagnostic or clinical term describing a small-vessel cutaneous vasculitis. Unfortunately, the pathologic process is not specific and can be observed in a variety of vasculitic syndromes, including those that have severe associated systemic disease and processes in the skin that are not vasculitic in their nature, such as insect bites. Furthermore, similar histopathologic changes can occur in the related conditions known as “neutrophilic dermatoses” in which massive infiltration with PMNs occurs in the absence of vascular wall involvement. The conditions that are considered within this spectrum are also at times associated with circulating immune complexes and include the entities of Sweet’s syndrome, pyoderma gangrenosum, and a condition termed “pustular” vasculitis by Jori~zo.~ With the

exception of pustular vasculitis, these disorders will not be discussed further in this monograph. Hypersensitivity vasculilis (HSV) is a term that was perhaps introduced by Pearl M. Zeek, a pathologist, in the late 1940s. Zeek and her coworkers were struggling with the many overlapping features that they observed in patients with vasculitis.’ Their work provided the first classification system and began the separation of hypersensitivity vasculitis (angiitis) from rheumatic vasculitis, polyarteritis (periarteritis) nodosa, granulomatous vasculitis, and large-vessel vasculitis (Table 1). The definition of HSV in general refers to a clinicopathologic process that is manifest as leukocytoclastic vasculitis of the postcapillary venule and often includes the observation that the condition was precipitated by a drug or other substance. However, this term has also been used to describe those patients in whom the disease is an idiopathic, small-vessel cutaneous LCV? Some authors have used this term to include patients with palpable purpura associated with abnormal proteins (e.g., cryoglobulinemia, hyperglobulinemia, etc.), with a variety of infections, with a variety of “autoimmune” disorders, or with malignancy (paraneoplastic vasculitis). HSV is historically differentiated from Henoch-Schonlein purpura; however, in several recent reports, it is evident that these two entities are at times difficult to distinguish. Henoch-Schiinlein purpura (HSP) was first described by Schiinlein in 1837 and then by Henoch in 1868. Schonlein described a patient with a purpuric rash, arthritis, and an abnormal urine sediment.7 Henoch described four patients with a purpuric rash, colicky abdominal pain, and bloody diarrhea.8 Subsequently, HSP was defined as a syndrome that combines the tetrad of palpable arthritis, gastrointestinal involvement, purpura, and nephritis.’ It is recognized that not all patients will manifest involvement of all four of the organ systems. Also, it appears that HSP is much more common in childhood, but can occur during adulthood.” During recent years it has also been recognized that these patients, whether adults or children, will have IgA immune complexes in the circulation or deposited within the skin or kidneys.‘l However, it is not necessary that the patient possess these immune complexes to be diagnosed

Table 1. Zeek’s Classification

FIG 1. Palpable Cur-r Probl

Dermatol,

March/April

purpura 1993

of Vasculitis

Hypersensitivity vasculitis Allergic granulomatosis Rheumatic arteritis Periarteritis nodosa Giant cell arteritis 51

with HSP; age aside, it is often difficult to separate HSV from HSP. Urticaria as a manifestation of vasculitis was perhaps first described by McDuffie et al. in 1973.1’ It has become known as urticarial vasculitis N.U. and is represented by the occurrence of chronic urticaria-like lesions that on biopsy reveal the pattern of leukocytoclastic vasculitis. Patients with UV differ from patients with “garden-variety” urticaria in the duration of their lesions, the occurrence of a residual ecchymosis, and the risk of an underlying systemic collagen vascular disease. Erythema elevatum diutinum (EED) is a rare cutaneous form of vasculitis that was first described by Radcliffe-Cracker and Williams in 1894?3 The disease is characterized by lesions that are relatively fixed and occur on the extensor surfaces, often overlying the joints. Although EED is clinically distinct, it is represented by a LCV. Polyarteritis nodosa (PAN) is an inflammatory necrotizing vasculopathy involving small and medium-sized arterioles and arteries in multiple organs and, as such, it is associated with a wide variety of manifestations. The American College of Rheumatology (ACR) has developed criteria for the classification of PAN (Table 2).14 The criteria seem to be useful in the clinical setting; however, some patients with other vasculitides may be inappropriately diagnosed as PAN. There am patients who develop a disease that involves only the cutaneous surface yet histopathologically, they demonstrate inflammation of the small- or medium-sized arteries with polymorphonuclear leukocytesl’ These patients often possess only two criteria for the classification of PAN, that is, livedo reticularis and the biopsy confirmation. They rarely have or develop Table 2. 1990 American College of Rheumatology Criteria for the Classification of Polyarteritis Nodosa* Unexplained weight loss of 4 or more kg Livedo reticular% Testicular pain or tenderness Myalgia, weakness, or leg tenderness Mononeuropathy or polyneuropathy Diastolic blood pressure of 90 mm Hg or more Elevated blood urea nitrogen (>40 mg/dL) or creatinine (>1.5 mgdL1 B viral infection 8. Serologic evidence of hepatitis 9. Arteriogram revealing aneurysms or occlusions not resulting from another cause 10. Biopsy of a small- or medium-sized artery containing polymorphonuclear neutrophils 1. 2. 3. 4. 5. 6. 7.

*According to the ACR committee, a patient who has 3 01’ more ot these 10 criteria, in the absence of another cause, is said to have polyarteritis. The application of these criteria results in a sensitivity of 82.2% and a specificity of 86.6%.

systemic vasculitic disease. A diagnosis of cutaneous polyarteritis nodosa (CPAN) seems reasonable in this subset; however, therapy is different for these patients than for those with systemic involvement . Granulomatous vasculitis takes at least two forms -Wegener’s granulomatosis (WG) and ChurgStrauss syndrome (CSS). WG is often considered to be a triad in which the upper airway, the lower airway, and the kidneys are involved with a granulomatous inflammation, vasculitis, or both. The diagnosis is confirmed when four criteria are present (1990 ACR classification system): nasal or oral inabnormal chest roentgenographic flammation, findings (nodules, fixed infiltrate, or cavitating lesions), an abnormal urinary sediment (hematuria or red blood cell casts), and granulomatous inflammation on biopsy.16 In 198.5 a report from van der Woude et all’ described the high sensitivity of the antineutrophil cytoplasmic autoantibodies (ANCAsl for WG and correlated the titer of the ANCA with disease activity. However, the presence of an ANCA is not among the criteria for the classification of WG. Perhaps in the next revision of these criteria, an ANCA will be part of the classification. CSS, or allergic granulomatosis and angiitis, is a disorder characterized by hypereosinophilia and systemic vasculitis occurring in patients with asthma, allergic rhinitis, or both. The 1990 ACR criteria developed to classify a patient as having CSS involve the presence of at least four of the following six criteria: asthma, eosinophilia (>lO%), mono- or polyneuropathy, nonfixed pulmonary infiltrates, paranasal sinus abnormality, and extravascular eosinophils.18 A possible third form of granulomatous vasculitis is lymphomatoid granulomatosis (LYG). This entity was described by Liebow et all3 in 1972 as an angiocentric and angiodestructive lymphoreticular proliferative and granulomatous disease that primarily involves the lungs. This disease is distinct and possibly is intermediate between WG and a malignant lymphoma. Most of the patients do progress to develop a malignant lymphoma, in which case their prognosis is guarded. Polyangiitis overlap syndrome (POS) was first described in 1986 by Leavitt and Fauci.” They reported 10 patients who had features that overlapped a variety of the traditional vasculitic syndromes. It is unclear where in the 1990 ACR classification schema these patients would fit. In fact, the schema did not consider this group of patients as a distinct clinicopathologic entity. Large-vessel vasculitis comprises giant cell or temporal arteritis and Takayasu’s arteritis. In general, these conditions only rarely have cutaneous Curr

Probl

Dermatol,

March/April

1993

findings; therefore, they will not be dealt with further in this monograph. History

of Vasculitic

Syndromes

*

Often single case reports or small series of patients have served as the initial description of what later has been recognized as a distinct vasculitic syndrome. The description of Henoch-Schdnlein purpura or anaphylactoid purpura is credited to Schonlein, who in 1837 described a patient with a purpuric rash, arthritis, and an abnormal urine sediment,7 and to Henoch, who in 1868 described four patients with a purpuric rash, colicky abdominal pain, and bloody diarrhea.’ Urticarial vasculitis was first described by McDuffie et al.*’ in four patients who had chronic urticarial lesions, arthritis, gastrointestinal distress, mild renal disease, circulating immune complexes, and hypocomplementemia. Soter et al.‘* later clearly recognized this phenomenon as a distinctive manifestation of cutaneous vasculitis. EED was first described in 1894 by Radcliffe-Cracker and Williams.13 Kussmaul and Maie? reported a case of systemic necrotizing vasculitis in 1866 and named the disease periarteritis nodosa. In 1939, Rackermann and Greenez3 noted that individuals with “allergic” diseases formed a distinct subset of patients with polyarteritis nodosa. Subsequently, Churg and Straussz4 in 1951 described the precise pathologic features of this clinical entity. Also in 1939, Wegene?’ first distinguished the process that subsequently has borne his name. In 1985 it was first recognized that Wegener’s granulomatosis was associated with an antibody directed against intracytoplasmic antigens of neutrophils.*7 This autoantibody has subsequently become known as antineutrophil cytoplasmic antibody. In 1972, the entity of lymphomatoid granulomatosis was described by Liebow et all9 and distinguished from the other granulomatous pulmonary vasculitides because of its distinctive histopathologv and its association with lymphoma. Perhaps the most recent clinicopathologic entity to be described is known as the polyangiitis overlap syndrome. Although Leavitt and Fauci” initially provided a rational argument for the existence of this distinct syndrome, others may wish to subclassify each of their cases as a variant of one of the standard vasculitides. Classification

Before Zeek began to publish her studies on polyarteritis, there was not an accepted method of classifying the vasculitides. She and her colleagues Curr

Probl

Dermatol,

March/April

1993

were the first to recognize that hypersensitivity vasculitis should be separated from polyarteritis nodosa on the basis of morphologic differences and histopathologic differences. Through the years until 1990, each investigator has devised a classification system that was either a modification of that devised by Zeekz6 (Table 3) or was an attempt to use a totally different system” (Table 4). In 1990, the ACR published the results of an extensive prospective analysis of data gathered from multiple centers” (Table 5). It analyzed the data in an attempt to develop a set of criteria that clinical investigators could apply to be certain that the cases they were including or excluding from a study would have some uniformity. From an analysis of the published report, it appears that the ACR began with the premise that the major subclasses suggested by Zeek were truly separable entities. The inclusion of a patient within one category is, therefore, based on a previous diagnostic classification system. Not surprisingly, the ACR report confirmed the distinction between the entities it set out to distinguish. In terms of cutaneous disease, the ACR set of diagnoses does not adequately reflect the experience in a dermatologic office. Palpable purpura or other forms of cutaneous vasculitis may occur in patients with many of the forms of vasculitis within the traditional and modified classification systems. Specifically, LCV of the skin is observed in HSV, HSP, some Table 3. Classification

of Necrotizing

Vasculitis’

1. Leukocytoclastic hypersensitivity or allergic vasculitis A. Henoch-Schdnlein purpura B. Hypocomplementemic (urticarial) vasculitis C. Vasculitis associated with a paraprotein D. Special forms of dermal vasculitides 2. Vasculitis associated with the rheumatic diseases A. Systemic lupus erythematosus B. Rheumatoid arthritis C. Scleruderma D. Dermatomyositis 3. Granulomatous vasculitis A. Allergic granulomatous angiitis of Churg-Strauss B. Wegener’s granulomatosis C. Lymphomatoid granulomatosis 4. Polyarteritis nodosa (medium-sized vessel) A. Classic type B. Cutaneous disease C. Associated with hepatitis B antigen D. Vasculitis in drug addicts 5. Large-vessel vasculitis (giant cell arteritis) A. Temporal arteritis B. Polymyalgia rheumatica C. Takayasu’s disease *Modified from Gilliam JN, Smiley JD: Cutaneous necmtizing vasculitis and related disorders. Ann Allergy 1976; 37:328-339. 83

Table 4. An Alte_mative Classification

System for Vasculitis’

A. Infectious angiitis 1. Spirochete associated (syphilis, Borrelia, etc.) 2. Mycobacterial, bacterial, mycoplasma .b 3. Fungal 4. Viral 5. Rickettsial 6. Pmtozoal B. Noninfectious angiitis 1. Involving predominantly large vessels a. Takayasu arteritis b. Granulomatous (giant cell) arteritis (1) Temporal arteritis and extracranial giant cell arteritis (2) Disseminated visceral granulomatous arteritis (3) Granulomatous angiitis of the central nervous system c. Arteritis of rheumatic diseases 2. Involving predominantly medium-sized and small vessels a. Thromboangiitis obliterans (Buerger’s disease) b. Polyarteritis (periarteritis) nodosa (PAN) (1) Classic PAN (2) Cutaneous PAN (3) Microscopic PAN (4) Infantile PAN (5) Kawasaki’s disease c. Pathergic-allergic granulomatosis (1) Wegener’s grarmlomatosis (2) Churg-Strauss syndrome (allergic granulomatous angiitis) (3) Necmtizing sarcoid granulomatosis (4) Lymphomatoid granulomatosis d. Vasculitis of collagen-vascular disease, including rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, inflammatory myopathies, relapsing polychondritis, Sjogren’s syndrome, Behcet’s syndrome, Cogan’s syndrome e. Vasculitis associated with inflammatory bowel disease 3. Involving predominantly small blood vessels (hypersensitivity angiitis; synonym: leukocytoclastic vasculitis) a. Serum sickness b. Henoch-Schbnlein purpura c. Drug-induced vasculitis d. Mixed cryoglobulinemia e. Hypocomplementemic (urticarial) vasculitis f. Paraneoplastic vasculitis g. Vasculitis associated with deficiency of the second component of complement h. Associated with cystic fibrosis i. Organ transplant vasculitis j. Familial Mediterranean fever k. Atrophie blanche (segmental hyalinizing vasculitis) C. Vasculitis simulators 1. Radiation-induced vasculopathy 2. Vasculopathy of antiphospholipid antibody syndrome 3. Ehlers-Danlos syndrome 4. Sweet’s syndrome (acute febrile neutrophilic dermatosis) 5. Chronic ergotism 6. Embolic phenomena: athemmatous, cholesterol, endocarditis, atrial myxoma 7. Degos disease (malignant atrophic papulosis) 8. Cryofibrinogenemia *Modified from 1992; 19:83-89.

Lie JT: Vasculitis,

1815 to 1991: Classification

and diagnostic

specificity.

Curr

J Rheumatol

Probl

Dermatol,

March/April

1993

Table 5. System Proposed by-the 1990 American College of Rheumatology Subcommittee on Criteria for the Classification of Vasculitis* Hypersensitivity vasculitis Henoch-Schonlein purpura Polyarteritis nodosa Wegener’s granulomatosis Allergic augiomatosis of Churg-Strauss Giant cell angiitis ‘Fmm Hunder GG, Arend WP, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Aheum 1990; 33:1065-1129.

patients with PAN, some patients with WG or CSS, and many patients with the polyangiitis overlap syndrome, if this condition actually exists. Thus, from the viewpoint of the dermatologist, the classification of vasculitis is very different (Table 6). FIG 2. Palpable purpura.

Cutaneous Lesions of Leukocytoclastic Vasculilis Sams et al.,3 in their classic article on cutaneous vasculitis, documented their observation that the lesions of vasculitis are dynamic. The lesions are often polymorphic, yet at some stage they are purpuric and are palpable. The early stages of development may be characterized by macular purpura, whereas older lesions can become nodular, vesiculobullous, necrotic, or ulcerative. Other authors have suggested that palpable purpura, vesiculobullous lesions, or both are representative of smallvessel involvement, whereas nodules, ulcers, and infarctive lesions occur as a reflection of involvement of the medium-sized vessels.” The classic and most typical cutaneous lesion observed in patients with leukocytoclastic vasculitis is palpable purpura (Fig 2). This lesion varies from bright red to purple, and, in contrast to lesions representative of thrombocytopenia or of capillaritis, the lesion of vasculitis is papular rather than macular. The lesions of LCV vary in size from 1 mm to plaques that are several centimeters in diameter. The lesions are often distributed on dependent surfaces such as the legs or the back, with symmetry almost always present. As the lesions resolve, an ecchymotic appearance often remains, but scar formation is rare. In general, the lesions of leukocytoclastic vasculitis are asymptomatic, but if they ulcerate or form nodules, pain may be present. Resolution of the lesions of palpable purpura rarely results in scar formation and usually there is no visible or palpable residual. Piette and Stone3’ have suggested that the lesions of adult patients with @&associated vascnlitis have a distinctive appearCurr

Probl

Dermatol,

March/April

1993

ante with multifocal areas of hemorrhage or superficial necrosis within the lesion, and a livedoid or retiform background. Urticaria-like lesions may be a manifestation of leukocytoclastic vasculitis. The patient with this type of lesion generally has a chronic course, and the lesions are clinically different than those of “garden-variety” urticaria.31 Urticarial vasculitic lesions tend to last longer than those of nonvasculitic urticaria. This can be measured by asking the patient to encircle one or more lesions of recent onset and then note the time to resolution. In patients with urticarial vasculitis, the lesions tend to last for more than 6 hours, and are often present for more than 24 hours, whereas those of nonvasculitic urticaria are of short duration, lasting less than 4 hours. Furthermore, the lesions of urticarial vasculitis frequently resolve with a residual ecchymosis or pigmentation, whereas with nonvasculitic urticaria there is no residual evidence of the lesion’s location. Urticarial vasculitic lesions are also said to be less pruritic, with the patient often complaining of a burning sensation or pain. Finally, patients with vasculitic urticaria often have symptoms of accompanying diseases or systemic organ involvement. Vesicles and bullae can be seen in patients with more severe inflammation of the vessels of the skin (Fig 3). The vesicular lesions tend to arise on purpuric skin, and thus are often hemorrhagic. In patients with bullous lesions, the separation is generally found at the dermal-epidermal junction, but the exact level of the split has not been characterized. The mechanism of the blister formation is believed to be tissue ischemia. The presence of this type of lesion is seemingly not indicative of the type 65

Table 6. Leukocytoclastic and Associated Conditions

Vasculitis

(LCV): Diiferential

Diagnosis

I. Entities that are manifest by palpable purpura and LCV histopathologically: Idiopathic Henoch-Schonlein purpura @&lated LCV) Non-IgA vasculitis Acute hemorrhagic edema of infancy Infectious: Any infection can be associated; the following are perhaps more common: Otitis media streptococcus Meningococcemia Hepatitis B Gonococcemia Influenza Mononucleosis Human immunodeficiency VkUS

Systemic

disease: Lupus erythematosus Rheumatoid arthritis Dermatomyositis

Sjogren’s

syndrome

Scleroderma Inflammatory bowel disease Wegener’s granulomatosis Cystic fibrosis

Chronic active hepatitis Paraproteinemia Malignancy (‘paraneoplastic vasculitis”): Hodgkin’s disease Leukemia and lymphoma Solid tumors Multiple myeloma Drugs and chemicals: Any drug can be associated; the following are perhaps more common: Sulfonamides Penicillin Allopurinol Quinidine Propyhhiouracil Food additives II. Entities that demonstrate LCV histopathologically but may not exhibit palpable purpura: Hypocomplementemic hnticarial~ vasculitis Dego’s disease Erythema elevatum diutinum III. Entities that may demonstrate palpable purpura but are not LCV histopathologically: Disseminated Antiphospholipid intravascular antibody coagulopathy syndrome Purpura fulmlnans Embolic phenomenon: Bacterial endocarditis Coumarin necrosis Atheroemboli Cryofibrinogenemia Cholesterol emboli Atrophie blanche (livedoid Left atrial myxoma vasculitis)

Curr

Pmbl

Lkrmatol,

MarchApriI

1993

+.

FIG 5. Ulceration of the skin in a patient with vasculitis.

FIG 3. Vesiculobullous lesions with purpura in a patient with leukocytoclastic vasculitis.

of association, nor is it seemingly correlated with the size of the vessels involved. Resolution of the lesions results in erosions, and thus in the patients I have observed, scarring has not been a residual. Necrosis, ulceration, or both may also occur in patients with cutaneous vasculitis (Figs 4 and 5). Usually the necrosis occurs in relation to the intensity of the inflammatory reaction within the vessels, which results in a vascular compromise caused by the interruption of the normal blood flow. Although ulceration and necrosis can occur in patients with involvement of the small dermal vessels, its presence often signifies involvement of larger vessels. In particular, when nodules are present along with a livedo reticularis and ulcerations (Fig 61, the vessel involved is often the medium-sized arteriole in the deep dermis or at the subcutaneous-dermal margin. Another pattern that may occur in patients with vasculitis is small purpuric lesions, a livedo re-

FIG 4. Cutaneous palpable purpura with necrosis in a patient with vasculitis. Cur-r Pdd

Dermatol,

March/April

1993

ticularis, and small ulcerations that heal with stellate ivory white scars (Fig 7). This pattern has been termed atrophie blanche, livedoid vasculitis, or segmental hyalinizing vasculitis. Although some patients with this pattern have demonstrable leukocytoclastic vasculitis, others do not have vasculitis. It has been my contention that the clinical lesions are at the end stage of the vasculitic process, and, thus because of the timing of the sampling, a vasculitic histopathology may not be evident. Systemic

Involvement

Regardless of the syndrome or specific disease entity, systemic involvement is possible and the or gan systems involved are perhaps those with the richest supply of vessels. Table 7 provides a tabulation of the common manifestations of vasculitis in each organ system. Patients with small-vessel (leukocytoclasticl vasculitis of the skin Qmlromes

FIG 6. Livedo reticularis with leg ulceration. 67

FIG 7, A AND B. which

healed

Livedo at a later date

reticularis and small ulcerations with stellate, ivory-colored scars

such as HSV or HSP) may not develop any of these symptoms. However, in each entity a full gamut of systemic involvement is possible in any individual. Patients with granulomatous vasculitides tend to have disease in the respiratory system, whereas polyarteritis nodosa tends to involve the kidneys and nervous systems. Some of the confusion that accompanies the concept of vasculitis is caused by the overlap of clinical manifestations from one “specific” entity to another.

Histopathologic

Findings

Several questions about the histopathologic findings in patients with cutaneous vasculitis are important. First, what is the histopathologic correlate of the cutaneous disease? Second, is it always necessary to con&m the diagnosis of vasculitis by tissue examination? Third, is the process, as viewed under the microscope, dynamic? The term “vasculitis” simply means inflammation within the vessels. It is not specific regarding the nature of the infiltrate. The use of this general term can lead to confusion because there is a histopathologic entity known as reactive “perivasculitis,” which is also not representative of a specific clini-

cal process,

but is represented

(Fig 8) classically demonstrates endothelial swelling of the postcapillary venules, eosinophilic fibrin deposition within and around the vessels walls (iibrinoid necrosis), neutrophilic infiltration of the vessel walls, extravasation of erythrocytes (hemorrhage), and fragmentation of neutrophils (leukocytoclasis or nuclear dust) .32,33 Several investigators have studied the nature of the inflammatory infiltrate in patients with cutaneous vasculitis. From these investigations, two theories have evolved. One theory suggests that the process is dynamic, changing with time from a neutrophil-predominant process to a mononuclear-predominant process.34 The other theory suggests that there are two distinct clinical-pathologic entities that represent inflammatory vascular disease (vasculitisl, one in which the neutrophil is the predominant cell invading the vessel wall (these cases have been defined as those in which there are >5% neutrophils present), and

by a perivascular

cuffing with a sparse lymphohistiocytic infiltrate. Patients with this “perivasculitis” are not clinically representative of patients with diseases associated with immune complexes. Thus, these patients are not part of the spectrum of cutaneous vasculitis. Histopathologically, leukocytoclastic vasculitis 58

(A), (9).

FIG 8.

Histopathologic

changes Curr

of leukocytoclastic Probl

Dermatol,

vasculitis. March/April

1993

Table 7. Svstemic Involvement Cutaneous

involvement:

in Vasculitis

Palpable purpura Urticarial lesions Vesiculobullous lesions+ Necrosis Ulceration Livedo reticularis

Musculoskeletal involvement:

Arthralgias Arthritis Myalgias Myositis

Renal involvement:

Hematuria Proteinuria (nephrotic syndrome) Renal insufficiency Hypertension

Gastrointestinal involvement:

Colicky pain Hemorrhage (bloody diarrhea, melena) Ulceration Perforation

Pulmonary

Infiltrates Pleuritis and/or pleural etisions Nodules (solid or cavitating) Asthma

Neurologic

Cardiac

involvement:

involvement:

Motor or sensory neuropathy Cephalafgia Diplopia Stroke Mononeuritis multiplex Myocarditis Pericarditis Coronary artery vasculitis

involvement:

Miscellaneous:

Fever/constitutional symptoms Pancreatitis

the other in which mononuclear cells predominate .35,36 Another issue relates to whether or not there is a need for tissue documentation of the vasculitic process. It is my opinion that documentation of the histopathology in the skin is almost always necessary. There are many conditions in which purpura can be present, but the pathologic process is not that of an inflammatory vasculopathy. The diagnosis of embolic phenomena such as atheromatous emboli, cholesterol emboli, or left atrial myxoma Curr

Probl

Dermatol,

March/April

1993

can be suggested on examination of the skin biopsy, Similarly, patients with cryoglobulinemia, cryofibrinogenemia, and antiphospholipid antibody syndrome have a noninflammatory vasculopathy characterized by amorphous proteinaceous material within the vessels. Unfortunately, not all cases will demonstrate the characteristic histopathologic findings. In these patients, I prefer to take a biopsy of another lesion, perhaps one of recent onset, before initiating therapy. Additionally, there are instances in which the pathologist returns a report with a diagnosis of vasculitis when the clinician was not suspecting the diagnosis. In this case, it is necessary to re-examine the patient before the final clinical diagnosis is established, because there are many diseases of the skin in which inflammation surrounding the blood vessels may occur but which do not represent an immune complex-mediated vasculopathy (e.g., insect bite reactions, granuloma faciale, or infections that are vessel based). If there is a suggestion that vasculitis should not be suspected clinically, reassessment and perhaps rebiopsy should occur. Vasculitic

Syndromes

Hypersensitivity

Vasculitis

The concept of a separate entity known as “hypersensitivity vasculitis” (HSV), also known as allergic angiitis, leukocytoclastic vasculitis, and smallvessel vasculitis, was first developed by Zeek et al. in EMS5 This concept was based on observations that a distinct group of patients exist in whom the disease follows the administration of a drug or other antigenic substance (serum sickness in the 1940s) and in which the disease involves primarily the small blood vessels in the skin.37 Ta-

Table 8. Common Drugs and Other Agents Implicated as Causes of Hypersensitivity Vasculitis Nonsteroidal anti-inflammatory drugs: aspirin, naproxen, phenylbutazone Antibiotics: penicillins, sulfonamides, tetracycline, erythromycin, gentamicin, zovirudine Thiazides Propylthyouracil Allopurinol Phenothiazines Diphenylhydantoin Potassium iodide Vaccines Herbicides Insecticides Foods and food additives (tartrazine) Inhalants 59

ble 8 lists some of the morecommon drugs (Liss WA, Wolverton SE: personal communication, November 15, 1992) and other agents that have been implicated as causes of HSV. In addition to drugs, food, and food additives, inhalants should be cenr sidered as a potential cause of HSV in selected patients.42 Tenacti and Novey4’ documented that fumes containing behenic acid from heat-activated photocopy paper were responsible for the development of HSV in a patient. Furthermore, it has been noted that the HSV is similar to a process that can be experimentally induced in animals following sensitization with a variety of antigensP3 Unfortunately, the distinctiveness of this entity has been called into question by the observations that both the clinical and the histopathologic changes that characterize HSV may be found in the absence of an identifiable antigenic source, and may also occur in other vasculitic syndromes such as HenochSchiinlein purpura, polyarteritis nodosa, ChurgStrauss syndrome, Wegener’s~granulomatosis, and polyangiitis. Furthermore, although the early reports of HSV emphasized the cutaneous disease and the usual benign course, recent studies have clearly documented the potential for systemic involvement,44-46 as well as the potential for deathP’ The concept of HSV as a specific entity has endured and is probably useful clinically because it defines a relatively benign subset of vasculitis. Therefore, the authors of the 1990 ACR criteria elected to include this entity among their seven clinical entities.& Unfortunately, 15 of the 21 criteria they selected for examination related to the histopathologic changes found on the biopsy. As can be recognized from the discussion above, this approach would most likely not take into account the dynamic nature of the infiltrate. Furthermore, on the “short” list of final criteria was the age of the patient (>16 years for HSV vs <16 years for HSP). In subsequent studies of the same individuals used to create the criteria for HSV and HSP, the only clear difference is the age of onset?’ Despite the shortcomings of the ACR criteria, the concept of HSV as a distinct entity remains somewhat reasonable; however, patients classified as having HSV still require careful assessment to establish that the cutaneous vasculitis is not part of another vasculitic syndrome. The ACR defined two methods of classification, a traditional format and a tree format. The sensitivity and specificity of both formats varied slightly, and many cases of other vasculitic syndromes could be misclassified as HSV (roughly 10% to 15% of the total patients examined, and specifically 30% of the patients with HSP). According to the criteria developed, the patient is said to have HSV if three of the following five criteria are 80

present: 1) age at disease onset >16 years, 2) medication that may be a precipitating factor taken at the onset of symptoms, 3) palpable purpura“slightly elevated purpuric rash over one or more areas of the skin; does not blanch with pressure and is not related to thrombocytopenia,” 4 maculopapular rash--“flat and raised lesions of various sizes over one or more areas of the skin,” and 5) histopathologic findings of granulocytes in a perivascular or extravascular location. With use of these criteria, it is evident to the practicing dermatologist that most of the patients that we diagnose as having LCV will be able to be classified as HSV; however, patients with polyarteritis nodosa, granulomatous vasculitis who have palpable purpura will be misclassified, and furthermore, patients with nonvessel-based neutrophilic inflammatory dermatoses such as acute febrile neutrophilic dermatosis (Sweet’s syndrome) may also be misclassified. Therefore, this classification schema is only of partial use. Presumed HSV must still be differentiated from other forms of vasculitis and from other dermatoses, and the practitioner must consider a variety of potential etiologic agents or associated conditions other than drugs, serum, or other ingestares. HSV is generally manifest by the appearance of palpable purpura, most commonly on the lower extremities below the knees (Fig 9). The disease is usually symmetrical and may be exacerbated by prolonged dependence of the legs. In addition, patients who are confined to bed will manifest lesions on dependent surfaces such as the buttocks and

FIG 9. Palpable purpura of hypersensitivity vasculitis. This patient developed vasculitis after the administration of a cephalosporin tibiotic. Cur-r Pr-abl

Dermatol,

March/April

an-

1993

FIG 10. Lesions

on the buttocks

in a patient

with

hypersensitivity

FIG 12. Generalized

palpable

purpura

can

occasionally

occur.

vasculitis.

back (Fig 10). Lesions also may occur in areas of trauma (pather@ or under tight-fitting clothing. Intertriginous areas may be spared, perhaps because of a warmer environment (Fig 11). Although the lesions are most frequent on dependent surfaces, at times the disease may be generalized (Fig 12) and may even involve the mucosal surfaces (Fig 13). The lesions of HSV are usually asymptomatic, but occasionally patients may have burning or itching. The lesions tend to occur in crops and often begin as a macular erythema, macular purpura, or urticarial papules (Fig 14) that progress to palpable purpura (Fig 15). Sams et al3 suggested that the development of the clinical lesion is dynamic, often beginning as nonpalpable purpura that eventually becomes palpable. Further, they suggested that in “later stages, some lesions become nodular, bullous, infarctive and ulcerative.” Most often the pa-

FIG 11. Sparing taneous Curr

of the intertriginous

surfaces

Dermatol,

with cu-

FIG 13. Mucosal

vasculitis. Pmbl

in a patient

tient has only one type of lesion, which fades as reparative processes begin. There are patients who have nodules, bullae, ulcers, necrosis, and/or livedo reticularis in combination with palpable purpura or as a sole manifestation of small-vessel vasculitis. Most patients with these additional findings will be classified with another vasculitic syndrome despite the finding of leukocytoclastic vasculitis on histopathologic examination. The purpuric lesions of vasculitis are characterized by smooth, discrete papules with relatively uniform lesional hemorrhage. Recently, Piette and Stone3’ attempted to distinguish IgA-related palpable purpura from other forms of leukocytoclastic vasculitis. They described a distinct pattern of IgAassociated cutaneous vasculitis in which the lesions were superficial purpuric plaques with multifocal areas of hemorrhage and necrosis arranged in a retiform pattern (Fig 16). It is important to recognize this form of cutaneous small-vessel vasculitis because of the association of IgA cutaneous vasculitis with IgA nephropathy. To date, the work of Piette and Stone has not been reconfirmed. Systemic involvement in patients with HSV is not uncommon, but its frequency has not been clearly determined. In a recent review of 58 patients with

Mar&April

1993

lesion

of leukocytoclastic

vasculitis 61

FIG 14.

Initial

urticarial

lesions

in a patient

with

FIG 16. Retiform

leukocytoclastic

plaques

in a patient

with

IgA-associated

vascu-

vasculitis.

litis.

HSV by W. A. Liss and S. E. Wolverton (written communication, November l-5,1992), 19 of 44 (43%) had renal involvement, 13 of 44 (32%) had arthralgias, but only 9% had liver or lung involvement, 5% had gastrointestinal involvement, and only 2% had central nervous system or cardiac involvement. Further, constitutional symptoms such as fever and myalgias were present in 20% and ll%, respectively. Rechallenge resulted in confirmation that a drug was involved in 13 of their patients. Haber et al?’ also have performed a similar review with frequencies of internal involvement at approximately the same level. The course of HSV is highly variable. The disease duration has ranged from 1 day to 10 months. In those patients in whom the skin is the sole manifestation of the disease process and there is an easily identified and removable antigen, the duration of the disease is usually short (
the offending substance. In the setting of systemic involvement, the course is often prolonged and death may occur in about one third of the patients. Mullick et aL3’ have suggested that the presence of widespread cutaneous disease correlates with the severity of internal involvement and the potential for death.

FIG 15. Three ical palpable 62

days purpura.

later,

the patient

in Fig 14 has developed

typ-

Henoch-Schblein

Purpura

A syndrome manifest by acute purpura and arthritis was first described by Schonlein in 1837. In 1874, Henoch noted a similar syndrome that included nephritis and colicky abdominal pain. Subsequently, this syndrome has become known as Henoch-Schonlein purpura (HSP), and also as anaphylactoid purpura and purpura urticans. This syndrome was not separated from HSV in Zeek’s classification schema. Also, Gilliam and Smile? included this syndrome within their category of hypersensitivity vasculitis. Only with the recent ACR classification has HSP been separated as a distinct entity.51 HSP was initially recognized in children, but there are adults who have identical features. The syndrome includes purpura, nephritis, arthritis, and gastrointestinal involvement. The disease is usually acute in its onset and often follows an upper respiratory tract infection, particularly streptococcal pharyngitis. By definition, children are more frequently affected than adults, and HSP is more frequent in men. Also, the disease appears to have a seasonal variation with a peak ‘during the winter. The incidence of HSP in the 2- to 14-year-old population has been estimated to be 14 per 100,000 per year?’ Skin lesions are one of the defining features of HSP. The rash may begin as macular erythema or urticaria but in a very short time period, the eruption becomes purpuric. The lower extremities and Curr

Probl

Dermatol,

March/April

1993

buttocks are the most common sites for skin lesions (Fig 17). Other vasculitic syndromes, meningococcemia, bacterial endocarditis, and Rocky Mountain spotted fever should be included in the differential diagnosis of HSP. Most often, purpura is pa& of the presenting manifestations, but in some cases, arthritis, abdominal symptoms, or both may precede the rash by as much as a few weeks. The joints are involved in 60% to 90% of patients with HSP. Perhaps joint involvement is less frequent in adults with HSP than in children. Arthritis, arthralgias, or both occur most often in the knees and ankles, but the wrists and elbows may also be involved. The joints of the pelvic and shoulder girdle are almost never affected, and the small joints of the hands and feet are rarely affected. Physical examination of the joints reveals periarticular edema without joint effusions. Warmth or tenderness is not usually found. With resolution of the process, there is no permanent damage to the affected joints. Gastrointestinal involvement occurs in about 50% to 70% of the patients. The most common symptom is colicky abdominal pain, which may be accompanied by vomiting. Bloody diarrhea or melena occurs in about 50% of the affected individuals. In some patients, the symptoms are so severe that they mimic an acute abdomen. Bowel involvement may be complicated by perforation or intussusception. The involvement of the bowel is caused by a vasculitis of the small vessels in the submucosa, with resultant edema and hemorrhage of the bowel

spite complete resolution of the acute process, long-term follow-up studies have demonstrated that subsequent pregnancies are more frequently complicated by hypertension, and that the frequency of hypertension or renal insufficiency is higher than that for the general population?4 Manifestations of HSP may also occur in other organ systems. Individual reports of associated asthma, hemoptysis, myocarditis, hepatomegaly, seizures, hemiparesis, subarachnoid hemorrhage, parotitis, orchitis, adrenal necrosis with resultant Addison’s disease, and pancreatitis have appeared in the literature.55 HSP must be differentiated from other vasculitic syndromes. In adults, the distinction from HSV may be impossible in the absence of immunofluorescence microscopy?6 In children, other causes such as systemic lupus erythematosus or polyarteritis nodosa should be considered. When the disease is manifest first by colicky abdominal pain, appendicitis must be considered. In the typical case of HSP, the only laboratory tests that need to be routinely performed are those that assess for the presence of renal involvement. Where the diagnosis is in doubt, histologic confirmation of a small-vessel vasculitis can be easily accomplished via a skin biopsy. In adults with presumed HSP, the demonstration of IgA deposition in the cutaneous vessels is diagnostic. Increases in serum levels of IgA occur in some patients with HSP, and in a recent study, Saulsbufl demonstrated that the increase was caused by IgAl.

Wdl.

Renal involvement in HSP occurs in 20% to 100% of the patients. The manifestations of renal involvement include hematuria, proteinuria, hypertension, and impaired renal function. The involvement may be transient and minor, or may result in progressive renal insufficiency. The histopathologic and immunopathologic findings are identical to those of Berger’s disease or IgA nephropathy.53 De-

FIG 17. Curr

Probl

Henoch-Schdnlein Dermatol,

March/April

purpura. 1993

Cutaneous Vasculitis as Part of Another Disease Process

Rheumatic

Inflammatory vasculopathy is a relatively frequent process associated with the group of disorders often referred to as “collagen-vascular diseases.r58 Among these diseases, vasculitis is a common occurrence in patients with rheumatoid arthritis, lupus erythematosus, and Sjogren’s syndrome; occurs in some patients with mixed connective tissue disease and relapsing polychondritis; and is rare among patients with scleroderma and inflammatory myopathy. A variety of vascular complications occur in patients with rheumatoid arthritis from the more mundane capillaritis to severe, life-threatening systemic vasculitis.5gt ‘O The rheumatoid nodule, which is histopathologically a palisading necrobiotic granuloma, may start as an inflammatory vasculitis. In addition, Smith et a161 have described a condition that they term “rheumatoid papules.” This entity is characterized by small erythematous papules which, on histologic examination, reveal a 63

palisading granuloma and leukocytoclastic vasculitis. The nomenclature associated with the inflammatory vasculopathy that occurs in patients with rheumatoid arthritis is controversial and often confusing. Some authors will diagnose rheumatoid vas-* culitis in patients who have rheumatoid arthritis with small-vessel vasculitis; others reserve this term for patients with ‘serious” vasculitis that involves the small arteries of the digits, nerves, and mesentery. Vollertsen and Conn6’ have divided the vasculopathies associated with rheumatoid arthritis into three categories: 1) vascular involvement as part of the pathogenesis of rheumatoid arthritis, 2) isolated digital vasculitis, and 3) the syndrome of clinical rheumatoid vasculitis. The latter can be subdivided into patients who demonstrate systemic rheumatoid vasculitis and those in whom the vasculitis is localized primarily to the skin. The patient with serious vasculitis frequently has an active arthritis with rheumatoid nodules and high levels of rheumatoid factor. These patients will have digital infarcts, leg ulcers, and/or palpable purpura. Involvement of the mesenteric vessels or coronary arteries can be associated with the more severe and life-threatening consequences. In contrast, there exist patients with rheumatoid arthritis whose inflammatory vessel disease involves only the small cutaneous vessels. It has not been clearly delineated how many of these patients have secondary Sjogren’s syndrome, a condition that would be expected to be associated with vasculitis of the small vessels. These patients tend to have elevated levels of rheumatoid factor, but they often have a more protracted course that is not complicated by neuropathy or arteritis of the viscera. Lupus erythematosus (LE) is a disease with protean manifestations. Systemic lupus erythematosus is associated with the presence of immune complexes in the circulation. It has, thus, been presumed that the LE-associated vasculitis is a manifestation of these circulating immune complexes. However, although many of the patients with LE have circulating immune complexes, only some will have vasculitid. The types of vasculitic disease manifest in LE are similar to those seen in rheumatoid arthritis in that vessels of any size may be affected. In patients with large-vessel disease, serious and potentially life-threatening consequences can occur, whereas patients who have small-vessel vasculitis have a milder process. Also, secondary Sjogren’s syndrome can complicate LE, and few if any of the studies of L&associated vasculitis have controlled for the presence of Sjogren’s syndrome. In addition, urticarial lesions can complicate LE and often represent vasculitis.63 The presence of 64

clinically recognizable vasculitis in patients with LE, regardless of the size of the involved vessel, signifies active disease and has been associated with a poorer prognosis. The gravest prognosis is associated with involvement of the larger vessels and with digital gangrene and nail fold infarcts. Another issue in the patient with LE is the presence of antiphospholipid antibodies. Although these antibodies are associated with a vasculopathy, there is no evidence to suggest that it is an inflammatory lesion; rather, the vasculopathy is seemingly a thrombotic process. Sjogren’s syndrome may be either a primary disease process or a secondary phenomenon to another connective tissue disease such as rheumatoid arthritis or lupus erythematosus. It is characterized by keratoconjunctivitis sicca and xerostomia. Tests such as the Schirmer’s test, the rose bengal dye test, slit lamp examination, and biopsy of the minor salivary glands are useful for confirmation of the clinical suspicion of Sjogren’s syndrome. Alexander and Provost36 have suggested that there are two distinct patterns to the vasculopathy that is associated with Sjogren’s syndrome, and further, that these patterns correlate with the risk of hypocomplementemia, serologic hyperreactivity, and central nervous system disease. The two patterns that have been suggested are one that is rich in neutrophils and one in which there is mononuclear destruction of the vessel. This concept of two distinct patterns has been challenged by the observation that the character of the infiltrate changes with time in patients who have serial biopsies. Nevertheless, the vasculitic lesions that occur in Sjiigren’s syndrome most often involve the skin and are manifest as a palpable purpura, or occasionally, as urticarial lesions. In the many reports published by the group from Johns Hopkins, it appears that the vasculopathy is a marker of more serious internal disease that is not necessarily vasculitic in nature. However, there are a few reports in which the patient with Sjiigren’s-associated vasculitis has had serious systemic vasculitic complicationsW Cutaneous Vasculitis as Manifestation of Paraproteinemia Paraproteins are abnormal proteins that appear in the serum in association with a variety of disorders. The paraproteins may be of several types, including cryoglobulins, macroglobulins, and gamma heavy chains. In addition, there are patients in whom the abnormality is the level of the proteins, and these patients may be termed hyperglobulinemit. Regardless of the type of abnormality, there is a common group of associated diseases that inCur-r Probl

Dermatol,

March/April

X493

eludes lymphoproliferative disorders, collagenvascular diseases, and infectious diseases65 (Table 9). The skin disease found with these abnormal proteins is commonly characterized by purpura, livedo reticularis, urticaria, and/or ulceration. Hismcathologic evaluation of patients with abnormal proteins commonly reveals either a vasculitis or a noninflammatory hyaline thrombosis within the vessel. Cryoglobulins are serum immunoglobulins that precipitate when the serum is cooled. There are three major types of cryoglobulinemia: type I is a monoclonal immunoglobulin and usually occurs in patients with a lymphoproliferative disease, in particular, multiple myeloma; type II is a mixed cryoglobulin consisting of both monoclonal and polyclonal elements; and type III is polyclonal. Types II and III occur in conjunction with collagen-vascular diseases and infections,66 although one third of the patients with type II or III cryoglobulinemia do not have an associated disorder and are thus termed to have essential cryoglobulinemia.67 The clinical features of patients with cryoglobulinemia frequently occur as a result of inflammation or occlusion of the small vessels.= The skin lesions in these patients include both palpable and macular purpura (Fig 181, leg “ulcers, urticaria-like lesions, livedo reticularis, acrocyanosis, and digital gangrene. Raynaud’s disease is also a common finding. Systemic disease is frequent and includes peripheral neuropathy, arthralgias, renal disease (proteinuria, azotemia, and/or hypertension), as well as hepatic dysfunction, hepatosplenomegaly, intestinal vasculitis, and coronary vasculitis. Because many of these patients have either a collagen-vascular disease or hepatitis, the symptoms that occur are not surprising. Furthermore, the other areas involved and types of involvement are reminiscent of disease observed in idiopathic Tddble 9. Some Underlying

Diseases in Patients

Paraproteins Lymphoproliferative disorders Multiple myeloma Chronic lymphocytic leukemia Lymphoma Autoimmune diseases Collagen-vascular diseases: lupus rheumatoid arthritis SjGgren’s syndrome Behqet’s disease Infectious diseases Hepatitis B and C Mononucleosis Cytomegalovkus Bacterial endocarditis Curr

Pmbl

Lkmatol,

MardU~rill993

erythematosus,

with

FIG 18. Vasculitis associated with cryoglobulinemia. Neal Fenske, M.D., Tampa, Florida.)

(Courtesy of

forms of vasculitis (e.g., hypersensitivity vasculitis). In my opinion, the major reasons to distinguish this group of patients are the potential recognition of an associated lymphoproliferative disease and that therapy aimed at stopping the production of the cryoglobulin is warranted. Waldenstr6m6’ first described hyperglobulinemit purpura in 1943 as a distinct syndrome consisting of recurrent episodes of purpura, elevated levels of gamma globulin, an elevated erythrocyte sedimentation rate, and a mild anemia. This entity may be a primary process or may be secondary to an associated condition such as Sjiigren’s syndrome, lupus erythematosus, thyroiditis, sarcoidosis, rheumatoid arthritis, thymoma, or myeloma~70,71 Histopathologic evaluation of the skin lesions has identified either a leukocytoclastic vasculitis or a mononuclear perivascular infiltrate. In the patient described by Hudson and Callen,” repeated biopsies were performed, and only when the earliest lesions were sampled were we able to demonstrate the leukocytoclastic vasculitis. Thus, it seems that this entity has direct parallels with the type of vasculopathy that occurs in patients with Sjogren’s syndrome. Recognition of hyperglobulinemit purpura, similar to that of cryoglobulinassociated vasculitis, should lead the physician toward associated conditions, in particular Sjiigren’s syndrome. Therapy with corticosteroids, immunosuppressives, or both is usually necessary. Schnitzler’s syndrome, or chronic urticaria with macroglobulinemia, is another vasculitic syndrome associated with a paraprotein.73’ 74 It was first described by Schnitzler and colleagues in 1974 and 66

was proposed to be an entity-distinct from Waldensttim’s macroglobulinemia.75 This is a rare syndrome with fewer than 20 cases reported in the literature. The syndrome is characterized by chronic urticaria, fever, an elevated erythrocyte sedimer@ation rate, a monoclonal IgM (most often kappa) paraprotein, and urinary Bence Jones protein. About half of the patients have had bone pain and anemia, but neither myeloma nor lymphoma seemingly complicates the course. A recent report has documented the presence of an I&A paraprotein in 4 of 13 patients with erythema elevatum diutinum, a chronic form of cutaneous vasculitis76 (see below). Additional single case reports have demonstrated IgG kappa paraprotein, and myeloma in patients with EED. In the report of Wilkinson et al.,77 two of the patients had IgA kappa, whereas while one had IgA lambda. Similarly, the investigators at the Mayo Clinic76 found that 5 of their 13 patients with EED had a paraprotein-IgA in all 5, but IgM also in 2. Furthermore, this group pointed out that routine serum protein electrophoresis failed to identify any of these patients, and suggested that in patients with EED, testing with immunoelectrophoresis be part of the routine evaluation.

Paraneoplastic

Vasculitis

Neoplasia has been associated with a wide spectrum of vasculitic syndromes (Table 10). The most frequent associations include polyarteritis nodosa with hairy cell leukemia and cutaneous smallvessel vasculitis (leukocytoclastic vasculitis) with a variety of lymphoproliferative disorders, as well as adenocarcinomas. Occasionally, these associations are truly paraneoplastic; in other words, they are recognized concurrently and follow a parallel course. Unfortunately, there are no adequate stud-

Table 10. Malignanc.y-Associated

Vasculopathies

Cutaneous (small-vessel) vasculitis and Henoch-SchGnlein purpura Polyarteritis nodosa: Systemic Cutaneous Cryoglobulinemia (and other paraproteinemias) Digital necrosis and Raynaud’s disease Embolic phenomena: Atriai myxoma Nonbacterial thrombotic endocarditis Thrombotic processes: Superficial migratory thrombophlebitis Antiphospholipid antibody syndrome Deep venous thrombosis 66

ies that document the frequency of neoplasia in patients with vasculitis, and in one large communitybased study of 82 patients, none were found to have an associated malignancy.44 This contrasts with data from SBnchez-Guerrero et al.78 in which they found 11 cases of paraneoplastic vasculitis among their 222 patients with vasculitis, and the data of Schroeter et aL7’ from the Mayo Clinic in which there were 4 such cases among 26 patients. Hairy cell leukemia is a rare entity characterized by fatigue, fever, recurrent infections, pancytopenia, and splenomegaly. In the circulation, the bone marrow, and the spleen, the characteristic mononuclear cell with prominent cytoplasmic projections can be found. Because of the prominent projections, these cells have been termed “hairy” cells. Systemic polyarteritis nodosa has been the primary form of vasculitis reported in patients with hairy cell leukemia.80,81 However,at least one patient with a small-vessel vasculitis has been reported.‘la In general, the vasculitic syndrome appears after the diagnosis of the leukemia, and the course is not parallel. Thus, it seems that the vasculitic syndrome is a complication of the leukemic process. The pathogenesis of the association is not known. Theories such as an abnormal handling of immune complexes, the ability of the hairy cell to synthesize immunoglobulins, the presence of a common antigen on the hairy cell and the endothelial cell, and the direct tissue invasion by the hairy cell have been proposed, but there are no strong data to support any of these theories. Clinically, the vasculitis does not differ from non-hairy-cell-associated PAN. One major issue relates to the therapy for the vasculitis, because treatments normally used for PAN may result in a worsening of the pancytopenia, an increase in the risk of infection, or both. The prognosis in this group of patients is guarded, and death usually occurs secondary to the complications of the leukemia rather than to the vascu-litis. PAN has been also associated with a variety of other lymphoreticular malignancies. Furthermore, there are several individual cases in which cutaneous PAN has been reported with lymphoreticular malignancy. In these reports, as was the case with the association of hairy cell leukemia and PAN, there does not appear to be a clear paraneoplastic relationship of the malignancy and the vasculitis. Small-vessel vasculitis has also been reported to occur in patients with malignancy.” In these patients, lymphoreticular malignancies predominate, but there are numerous reports of solid tumors in patients with small-vessel vasculitis of the skin. SBnchez-Guerrero et aL7’ describe 11 patients with vasculitis

and

neoplasia; Curr

4 had Probl

solid

Dermatol,

tumors, March/April

and

i’

1993

had a variety of lymphomas, leukemias, or preleukemias. Of their 11 patients, 9 had disease that was limited to the skin; in 4 of these patients, the appearance of the vasculitis was associated with the recognition of the tumor (1 case) or reco@tipn of tumor recurrence (3 cases). It was not clear in their report whether there was a response to tumor therapy in the patients with active malignancy and vasculitis. Specifically, they stated that only 2 of their 11 patients required therapy for vasculitis. Fain et alF3 reported 14 patients with vasculitis and neoplasia in whom small-vessel vasculitis accounted for 8 of the patients: 1 had a bronchogenic squamous cell carcinoma, whereas the other 7 had a variety of hematologic disorders including 3 with multiple myeloma, 3 with refractory anemia with sideroblasts, and 1 with leukemia. The vasculitis occurred concurrently in two patients, before the recognition of the malignancy in three patients, and 2% to 4% years after the neoplasia in three patients. Most of their patients responded to therapy with corticosteroids, and it was unclear whether tumor therapy had an effect on the vasculitis. In another study from France, Beylot et al.- reported their experience with 12 patients with leukocytoclastic vasculitis and hematologic malignancies: 4 of their patients had myelodysplastic syndromes, 1 had angioimmunoblastic lymphadenopathy, 1 had a granulocytic sarcoma, 4 had various leukemias, and 2 had lymphomas. The vasculitis occurred shortly before the diagnosis of the hematologic process in four patients, 4 and 12 months before the neoplasia in two patients, and at some point during the course in the remaining six patients. Castro et al.,= in a study of 62 patients with myelodysplastic syndromes, found 7 with cutaneous vasculitis. This report did not detail the relationship of the two processes, but in several of their patients, skin disease improved or resolved despite the continued presence of the myelodysplastic disease. Two similar groups of six and four patients with myelodysplasias and cutaneous vasculitis have also been reported from Great Britain.86’ ” FinalIy, there are single case reports of erythema elevatum diutinum with myelodysplasia,88 livedoid vasculitis with leukemia,8g and urticarial vasculitis with colonic adenocarcinoma.so Enough reports of the association of cutaneous vasculitis with hematologic disorders exist that it seems reasonable to assess each vasculitic patient for the presence of hematologic malignancy; therefore, the presence of anemia, thrombocytopenia, leukopenia, or leukocytosis must be carefully evaluated. The issue of the relationship of cutaneous vasculitis and solid tumors is questionable. Limited numbers of reports, and the lack of a paraneoplasCur-r

Pmbl

Dermatol,

March/April

1993

tic course in all but a few patients, obviate the need for an extensive evaluation for malignancy. Other possible relationships between vasculitic syndromes and neoplasia have appeared in the literature. Malignancy is a part of the disease process in lymphomatoid granulomatosis. Paraproteinassociated vasculitis is frequently complicated by neoplasia. Recently, vasculitis has been reported as a complication of therapy for malignancy including chemotherapeutic agents, bone marrow transplantation with immunosuppression,‘l and radiotherapy. Conversely, acute myelocytic leukemia has been reported as a consequence of cytotoxic therapy of a patient with PAN.g2 FinaIly, there are patients with malignancy who first appear with a clinical picture that simulates a vasculitic syndrome. Urticarial

Vasculitis

Urticarial vasculitis is a disease characterized clinically by urticarial lesions and histopathologicalIy by leukocytoclastic vasculitis. This disorder was perhaps first clearly distinguished as an entity by McDuffie et al?2 when they reported ‘. . . four patients with recurrent attacks of erythematous urticarial and hemorrhagic skin lesions associated with synovitis and sometimes abdominal distress.” Two of their four patients also had glomerulonephritis, and all four had hypocomplementemia. For this entity, they coined the term “hypocomplementemic urticarial vasculitis.” Since the original description, it has become recognized that some patients with urticaria have vasculitis in the absence of hypocomplementemia; about one fifth of patients with urticarial vasculitis will have significant pulmonary diseaseg3; when urticaria occurs in patients with collagen vascular diseases, leukocytoclastic vasculitis is the usual histopathologic correlate, and the urticarial vasculitic lesions usually correlate with active systemic inflammatory disease94-s6; urticarial vasculitis also may occur in patients with hepatitis-associated vasculitis, paraneoplastic vasculitis, and paraprotein-associated vasculitis”; and almost all of the patients have longstanding chronic urticaria. Clinically, urticarial vasculitis is distinguished from routine urticaria by lesions that are painful or burning rather than pruritic, last more than 24 hours, and resolve with purpura or bruising?’ Histopathologically, the lesions should be represented by leukocytoclastic vasculitis with fibrinoid necrosis and leukocytoclasis. These changes should be distinguished from the nonvascuhtic processes of neutrophilic urticaria and urticaria with diffuse dermal neutrophilia. Both of these conditions have been described by Winkelmann and his col67

leagues” at the Mayo Clinic. These two conditions do not seem to be associated with the risk of internal disease or hypocomplementemia that may occur in some patients with urticarial vasculitis. However, it is not clear from their studies if repeat&l biopsies were taken, nor is it stated how old the lesions were that had had biopsies. Thus, it is possible that these entities are benign variants of urticarial vasculitis. Laboratory evaluation other than an increased erythrocyte sedimentation rate and abnormal complement levels is usually unremarkable with the exception of abnormalities that would be found with an associated disease process, such as a positive antinuclear antibody test in patients with lupus erythematosus. In a recent analysis of 72 patients with urtlcarial vasculitis, Mehmgan et alloo found that only 23 of the 68 tested patients had an elevated sedimentation rate. Thus, although an elevated sedimentation rate is more often present in patients with urticaria who have vasculitis, a normal rate does not rule out the presence of vasculitis. Similarly, only 23 of 65 patients had a depressed total hemolytic complement (CH,,), only 18 had a decreased C3 level, and only 6 had a decreased C4 level. Abnormal urinary sediments correlated with the presence of nephritis. Tests of lung function revealed abnormalities in those with associated chronic obstructive pulmonary disease. Mehregan et al. also analyzed the differences between those patients with hypocomplementemia and those with normocomplementemia. They found that those with hypocomplementemia had a significantly higher frequency of residual pmpura, arthralgias, abdominal pain, chronic obstructive pulmonary disease, and deposition of immunoglobulin or C3 in blood vessels or the basement membrane zone. Acute Hemorrhagic

Edema of Infancy

Acute hemorrhagic edema of infancy is a rare form of leukocytoclastic vasculitis that occurs in infants below 2 years of age?“, lo2 It has an acute onset, often following an upper respiratory tract infection, drug ingestion, or both. The rash begins as urticarial plaques but rapidly becomes intensely purpuric, and fever and generalized edema are common features. This disorder may simulate purpura fulminans or disseminated intravascular coagulopathy. Acute hemorrhagic edema of infancy has been distinguished from Henoch-Schiinlein purpura on the basis of both clinical and immunologic grounds. Patients with acute hemorrhagic edema of infancy demonstrate IgM within the dermal vessels rather than IgA, which is observed in es

HSP. The process of acute hemorrhagic edema of infancy is benign and self-limited without residua. Erythema

Elevatum Diutinum

Erythema elevatum diutinum is an unusual form of cutaneous vasculitis characterized by persistent erythematous, violaceous and/or yellow papules, plaques, and nodules1o3 Wig 19). The lesions often occur over bony prominences, are most often on acral or extensor skin surfaces, and am distributed symmetrically. Occasionally the patients may have arthralgias, but other systemic manifestations of vasculitis am absent. The disease is of unknown cause, but some of the patients with erythema elevatum diutinum have a paraprotein, usually IgA, but occasionally IgM (see preceding discussion). This particular vasculitic disease appears to respond poorly to all therapies other than oral dapsone or equivalent agents. Pustular

Vasculitis

Jorizzo et al4 coined the term “pustular vasculitis” to describe the neutrophilic lesions that occur in patients with bowel bypass surgery, inflammatory bowel disease, blind loop syndromes, and BehGet’s disease. These patients manifest similar cutaneous and systemic abnormalities, which include pustular lesions (Fig 201, erythematous plaques that simulate acute febrile neutrophilic dermatosis (Sweet’s syndrome), erythema nodosum-like lesions, or pyoderma gangrenosum-like lesions, in conjunction with polyarthritis, fever, and myalgias. Although the initial reports described a leukocytoelastic vasculitis, it has become evident that this process is not one in which the vessel walls are destroyed. Thus, it might be best to consider this entity under the lesions that simulate vasculitis.

FIG 19. Erythema M.D.,

Baltimore,

elevatum Maryland.)

diutinum.

Curr

Pmbl

(Courtesy

Dermatol,

of Evan

March/April

Farmer,

1993

Table 11. Associated Conditions in Patients with Polyarteritis Nodosa Infections: Hepatitis B Serous otitis media Streptococcal infection

Endocarditis Human immunodeficiency Collagen-vascular diseases: Lupus erythematosus Rheumatoid arthritis

virus

Relapsing polychondritis Other: FIG 20. Pustular vasculitis in a patient with Behcet’s disease.

Cutaneous Polyarteritis Nodosa and Cutaneous Lesions in Patients with Polyarteritis Nodosa Polyarteritis nodosa is a disease of small- and medium-sized vessels and usualIy is related to immune complexes. Recently, PAN, like Wegener’s granulomatosis, has been associated with the presence of antineutrophil cytoplasmic autoantibodies (ANCAl. The history of polyarteritis nodosa is interesting; most of the entities discussed in this monograph were at one time diiferentiated from PAN. Since the initial description in 1866, the following entities have been separated: Wegener’s granulomatosis in 1936, hypersensitivity vasculitis in 1942, allergic granulomatosis in 1951, Kawasaki’s disease in 1967, and microscopic PAN in 1985. Thus, PAN has evolved as a diagnosis of exclusion when a multisystem necrotizing vasculitis cannot fit into one of the presently recognized vasculitic syndromes .lo4 Polyarteritis nodosa exists in at least three forms: classic PAN, microscopic PAN, and cutaneous PAN. Classic PAM-Classic PAN is a multisystem disease that has a sign&ant associated morbidity and potential mortality if untreated. It occurs in middle age and is more common in men (2 : 11. Patients frequently have constitutional symptoms at the onset including fever, malaise, and weight loss. Neuropathy, headache, or other neurologic symptoms are common at the onset of the disease, with mononeuritis multiplex the characteristic neurologic finding. Abdominal pain is also a common manifestation. The cause of PAN is not known, but it may occur in conjunction with a variety of other disorders including infections and collagen-vascular diseases (Table 111. The skin is a rare manifestation on initial evaluation (4%); however, 40% to 50% of patients with PAN will eventually have cutaneous disease. Because the disease affects small arterioles, the characteristic cutaneous lesions are nodules, ulcers, Cur-r

Pmbl

Dematol,

March/April

1993

Parapmteinemia Inflammatory bowel Hairy cell leukemia

disease

and livedo reticularis.

However,

and urticarial

may occur

lesions

palpable

purpura

in patients

with

PAN. Digital necrosis may also occur in PAN (Fig 211. Systemic features of PAN are by definition common. The kidney is involved in 70% of patients, and renal failure or its complications are the cause of death in 50% of the patients who succumb to this disease. Hypertension is common and can be related to renal disease or vascular involvement of the renal arteries. Peripheral neuropathy occurs in 50% of patients, and nerve biopsy may serve as a good source for tissue diagnosis. Gastrointestinal vascuIitis with infarction occurs in about 40% of patients and is another major source of death.*” Cardiac involvement occurs in about 30% of patients with PAN, but lung involvement is uncommon. If lung involvement is seen, the diagnosis of Wegener’s granulomatosis or allergic granulomatosis should be strongly considered. The diagnosis of PAN is suspected in the patient with multisystem disease in whom necrotizing vasculitis of a small or medium-sized artery or typical

FIG 21. Digital necrosis in a patient with systemic necrotizing vasculitis. 63

radiographic abnormalities are observed. There is no diagnostic test available for classic PAN, but many patients will have a positive ANCA. The ACR has developed criteria for classification which at times may be helpful in diagnosis; however, ri@d use of these criteria in a clinical setting is discour-’ aged. Tissue can be obtained from the skin, muscle, testis, sural nerve, or rectum to aid in the diagnosis. Another useful diagnostic procedure is an arteriogram, which can demonstrate multiple fusiform aneurysms or occlusions. In an appropriate setting, the angiogram can establish a diagnosis in up to 80% of cases. However, a negative study does not exclude the diagnosis.

Microscopic

P&V.-Microscopic PAN is a systemic vasculitis affecting small vessels with an associated focal and segmental necrotizing glomerulonephritis.lo6 As is the case with classic PAN, other recognized vasculitic syndromes must be excluded. The distinction from classic PAN seems to be the lack of aneurysms and the propensity to involve smaller vessels. Skin involvement is seen in 30% to 40% of patients with microscopic PAN and is similar in its manifestations to that observed in classic PAN. Microscopic PAN is associated with antimyeloperoxidase antibodies, which am actually one type of ANCA-the peripheral pattern, or p-ANCA. Cutaneous PAN, Cutaneous PAN differs from classic PAN by the lack of severe systemic disease.lo7’ lo8 Although cutaneous PAN is thought to be a localized vasculitic process, systemic features such as fever, neuropathy, myalgias, arthralgias, and arthritis occur in up to half of the patients.*0s’110 In addition, some patients have associated systemic diseases including inflammatory bowel diseases (both Crohn’s and ulcerative colitis), hepatitis B infection, and parapmteinemia.111-113 The prognosis for patients with cutaneous PAN is good, but a chronic course is common.

Cutaneous Manifestations of Wegener’s Granulomatosis and Churg-Strauss Syndrome Classic Wegener’s granulomatosis is characterized by the triad of necrotizing granulomas of the upper and/or lower respiratory tracts, focal glomerulonephritis, and varying degrees of systemic vasculitis.114 Limited Wegener’s granulomatosis occurs when only the respiratory tract is affected. Cutaneous disease occurs in about half the patients with Wegener’s granulomatosis. The lesions can be palpable purpura, papules, nodules, necrosis, or ulcers. *14-116 Histopathologically, the lesions of the skin are either a small-vessel vasculitis or a granu70

lomatous vasculitis. Cutaneous disease is a rare initial manifestation and does not usually correlate with disease activity. In a recent report of three patients with Wegener’s granulomatosis, Mangold and Callen117 found that the cutaneous disease was a key factor in the recognition of the disease in one patient, and in the other two, it was associated with disease exacerbation. ANCA appears to be a useful test in following patients with Wegener’s granulomatosis, but it is not diagnostic because of its occurrence in other systemic vasculitic syndromes .ll’ Without treatment, death is common. Churg-Strauss syndrome is a disorder characterized by systemic vasculitis in association with hypereosinophilia, asthma, and allergic rhinitis.l” Pulmonary involvement is almost always present in CSS and is usually represented by asthma, transient pulmonary infiltrates, or both. The other systemic findings are similar in frequency to that observed in PAN. Cutaneous lesions occur in about half the patients with CSS and are similar to those described for Wegener’s granulomatosis.“’

Polyangiitis

Overlap Syndrome

In 1977, deShazo et al.lzl reported a patient with systemic vasculitis who had “coexistent large and small-vessel involvement.” Later Leavitt and Fauci” reported their findings in 10 patients who had features of systemic vasculitis that could not be classified into one of the well-defined vasculitic syndromes. They coined the term “polyangiitis overlap syndrome” for this group. Skin lesions were present in 9 of their 10 patients, some of whom had smallvessel vasculitis. In fact, this type of presentation is not uncommon, since dermatologists who follow patients with systemic vasculitides such as Wegener’s granulomatosis or polyarteritis nodosa observe that the cutaneous lesions are often leukocytoclastic (small-vessel) vasculitis.“” lz3 Vasculitis

Simulators

Because the primary therapy for vasculitic syndromes is corticosteroids with or without immunosuppressive and/or cytotoxic drugs, it is important to be certain that the process is truly an inflammatory vasculopathy and/or not one of the diseases

that can simulate

the clinical manifestations.

There

are a variety of common and rare disorders that can simulate the cutaneous as well as the systemic manifestations of vasculitis.124 Palpable purpura is a common manifestation of cutaneous leukocytoclastic (small-vessel) vasculitis. Purpura can also occur in patients who have nonCur-r Probl

Dermatol,

March/April

1993

inflammatory manifestations of cryoglobulinemia or other paraproteinemia. In this case, the histopathologic e xamination of the skin will reveal a proteinaceous material within the vessel lumina. A similar histopathologic picture may also b& obsewed in patients with antiphospholipid antibodieslz5., however, these patients will often have ulcer ation of the skin, particularly the lower legs, in addition to purpura (Fig 221. Patients with embolic phenomena may also develop palpable purpura. Emboli from left atrial myxoma, from valvular vegetations in patients with bacterial or fungal endocarditis, from valvular vegetations in the antiphospholipid antibody syndrome, or from cholesterol containing atheromatous plaques may result in cutaneous (Fig 23) as well as systemic signs similar to those of vasculitis.‘z6-*31 Patients with oxalosis can form crystals that deposit within the vessels and with renal simulate palpable purpura.132 Patients failure who have cutaneous calciphylaxis can also develop necrotic purpuric lesions caused by calcium deposition in vessels (Fig 24). Leg ulceration is another common manifestation of vasculitis. The most frequent cutaneous manifestation of the antiphospholipid antibody is the leg ulcer, often with a surrounding’pattern that suggests livedo reticularis. It is unclear whether the antibody that these patients possess is of pathogenic importance or merely serves as a marker of the disease. In these patients, therapy is directed at a correction of the hypercoagulable state, and, thus, therapies such as aspirin, Persantine, Coumadin and/or heparin have been used successfully. Necrosis of the fingertips or toes can occur in se-

FIG 22.

Leg

ulceration

in a patient

with

antibod-

23.

J’robl

Dermatol,

March/April

1993

Reticulated

purpura

in a patient

with

atheromatous

em-

boli.

vere cases of vasculitis. It can also occur in patients with Baynaud’s disease, embolic syndromes (see above), antiphospholipid antibody syndrome, severe atherosclerotic vascular disease, or thromboangiitis obliterans (Buerger’s disease). Buerger’s disease is of unknown etiology in which there is occlusion of the small arteries and veins leading to pain and changes of ischemia of the distal digits.133 It has been associated with excess cigarette smoking. Therapy includes vasodilating agents in addition to antiplatelet agents. Atrophie blanche (also known as segmental hyalinizing vasculitis, livedoid vasculitis, or livedo reticularis with summer ulceration) is a cutaneous disease characterized by petechial or purpuric lesions, livedo reticularis, and small ulcerations that heal with stellate, ivory-colored scars occurring on the lower extremities.‘34’135 This is an idiopathic condition. Histopathologic examination generally reveals a noninflammatory occlusive vasculopathy. Although in some patients the earliest lesions may be a leukocytoclastic vasculitis, the late lesions rarely, if ever, demonstrate inflammation. Several reports have found that these patients have abnormalities suggesting a hypercoagulable state such as

FIG 24. Cutaneous phylaxis

ies. Cut-r

antiphospholipid

RG

from

acute

necrosis and ulceration renal failure.

in a patient

with calci-

71

elevated levels of fibrinopeptide A,136 defective release of tissue plasminogen activator,13’ or increased levels of plasminogen activator inhibitor.13’ A similar clinical and histopathologic picture may be observed in patients with antiphospholipid a@-. tibodies or cryofibrinogenemia.13s Thus, tests such as anticardiolipin antibody, lupus anticoagulant (activated partial thromboplastin time), and cryofibrinogen should be ordered in patients who have clinical findings of livedoid vasculitis. Therapy of livedoid vasculitis is directed at a correction of the hypercoagulable state. In a recent report, Klein and Pittelkow138 found that intravenous recombinant tissue plasminogen activator was effective in five of six patients. In patients with cryofibrinogenemia, Falanga et al.14’ found that oral stanazolol, an anabolic steroid, was effective in most patients.

Pathogenesis

Current evidence suggests that leukocytoclastic vasculitis, whether of the small or medium-sized vessels, is an immune complex disorder.141-144 It is presumed that antibodies are formed to some antigen and that these bind and form circulating immune complexes. Most vasculitides are caused by IgG or IgM immune complexes, but HenochSchonlein purpura is caused by IgA immune complexes. Soluble immune complexes that are not removed by filtration through the kidneys or by the reticuloendothelial system can become lodged between the endothelial cells of the vessel wall. This process can be exacerbated by vasoactive amines, specitically histamine, which can dilate the vessel, creating spaces between endothelial cells within which the circulating immune complexes can lodge. This observation can be used clinically to reproduce lesions. Once lodged, the circulating immune complexes can activate complement via the classical pathway. This results in the release of chemotactic factors, in particular C5a, which attracts the formation of the membrane attack complex, which in turn may damage the endothelial cells directly. The cytokine C5a specifically attracts polymorphonuclear leukocytes, releases their lysosomal enzymes, and causes tissue destruction with resultant edema and hemorrhage. The destruction of the tissue is eventually cleared with recruitment of mononuclear cells. Thus, in this dynamic process, the polymorphonuclear leukocyte precedes the mononuclear cell. Although there is evidence to support the immune complex theory, other data suggest that vasculitis is more complex and that immune complexes may not be the primary problem. Savage,145 72

in a recent review, discussed the role of immune complexes and direct damage from cells involved in inflammation, the role of the endothelial cell as a target for injury as well as a contributor to injury, the interaction of the coagulation pathway,146 the role of platelet and platelet-derived factors, and the role of cytokines in the immunopathogenesis of vasculitic syndromes. There is perhaps a central role for the mast cell and basophils that are located in close proximity to the postcapillary venule (one of the presumed targets of vessel damage).147 At a minimum, mast cells may be involved in the production of cytokines, which serve as chemoattractants for other inflammatory cells. They also release factors that cause vasodilation which, in vivo, has been linked to trapping of immune complexes within the vessel walls. Similarly, monocytes, macrophages, and lymphocytes may be involved through the release of cytokines. In addition to immunopathologic factors, several nonimmunologic factors are involved in the expression of disease. Increased hydrostatic pressure predisposes certain areas of involvement, explaining the observation that vasculitis is more common on the legs and buttocks. Fibrinolytic activity may also be abnormal in some patients.

Evaluation

Because significant morbidity can result from systemic involvement in patients with cutaneous vasculitis, an exacting evaluation of the patient should be done to rule out or define the type and severity of systemic involvement (Table 12). Evaluation of a patient suspected of having cutaneous small-vessel vasculitis should be guided by knowledge of possible etiologic agents, underlying disease associations, and the differential diagnosis of the most common clinical manifestations, that is, palpable purpura, urticaria, and leg ulceration. Evaluation should include a thorough history and physical examination with attention to possible etiologic agents, ingestants, infections, and associated symptomatology. Once a skin biopsy has confirmed the diagnosis of leukocytoclastic vasculitis, laboratory studies should include, at the minimum, a complete blood count, urinalysis, cryoglobulins, serum protein electrophoresis, hepatitis B surface antigen, antinuclear antibody, anti-R0 @S-A) antibody, total hemolytic complement, chest roentgenogram, and an assessment of renal function. This testing is waived in the patient with an obvious cause for acute vasculitis, for example, a drug-related case. Also, in patients in whom systemic vasculitic synCurr

Probl

Dermatol,

March/April

1993

Table 12. Evaluation

of Patients

with Cutaneous

Vasculitis 1. History: Infections? Drug ingestion? History of one of the “associated” disorders? Systemic symptoms? 2. Physical examination: General appearance T&e of skin lesion 3. Skin biopsy: Immunofluorescence is optional, perhaps useful when IgA disease is being considered 4. Laboratory studies: Necessary: Complete blood count Urinalysis, tests of renal function Chest x-ray examination Tests for collagen vascular diseases - antinuclear antibody, anti-R0 @S-A), rheumatoid factor, etc. Hepatitis B surface antigen Tests for paraproteins, cryoglobulins, cryofibrinogens, etc. When appropriate or under special circumstances: Total hemolytic complement Circulating immune complexes Sedimentation rate Anticardiolipin antibody Antineutrophil cytoplasmic antibody (p-ANCA and/or c-ANCA) von Willebrand (factor VIII1 antigen Blood cultures

dromes are being considered, tests such as the ANCA may be diagnostically helpful. In addition, in patients in whom the diagnosis of @A-associated vasculitis is being considered, direct immunofluorescence biopsy of an early lesion can aid in confirmation of this immunopathologic entity. This test is generally unnecessary in children with HSP, but may help in adults with presumed HSP. The recommended battery of laboratory studies, roentgenograms, serologic tests, and cutaneous biopsy is nonspecific for systemic involvement. Such studies serve only as a guide to rule out systemic vasculitis. In other words, if the laboratory screen is normal, further invasive studies to uncover systemic involvement are probably unwarranted. In a recent study, 40 consecutive patients with suspected systemic vasculitis were assessed by sequential testing.la First, screening laboratory vaIues were obtained and, depending on the results, the investigation progressed with so-called safe tests (e.g., skin, muscle, rectal biopsies). These were followed by “invasive” tests such as arteriography, and kidney or lung biopsies, if indicated. No single Cur-r Probl

Dermatol,

March/April

1993

laboratory test was found to adequately predict systemic involvement. Skin biopsy, rectal biopsy, and arteriography were found to be insensitive, nonspecific, and of poor predictive value. Muscle biopsy was the most valuable safe procedure. Based on their findings, the authors offer the following diagnostic approach to the patient with possible systemic vasculitis. If the diagnosis of systemic disease is still being considered after the initial screening, three options are available: 1) sural nerve electrophysiology followed by biopsy if abnormal, 2) muscle biopsy, and 3) open lung biopsy if pulmonary disease is prominent. If the diagnosis remains unconfirmed after these studies and the patient has an abnormal “active” urinary sediment, percutaneous renal biopsy should be considered. If the urine sediment is negative, other studies such as testicular biopsy and visceral angiography can be considered. In addition, in another recent study, a variety of autoantibodies and factors released by damaged endothelial cells were analyzed for their predictive value in the diagnosis of systemic vasculitis?4s Of the four tests analyzed, (ANCA, anticardiolipin antibody, von Willebrand factor antigen, and fibronectin), only the ANCA was specific. Although the other tests were often abnormal (highly sensitive), they were not specific.

Management

The therapy of cutaneous vasculitis depends on whether or not there is clinical evidence of systemic disease, the severity of the cutaneous disease, and the severity of the systemic disease. The patient with severe systemic necrotizing vasculitis should be treated rapidly and aggressively with systemic corticosteroids and an immunosuppressive Pulsed therapy with either methyl%ent*150’ 151 prednisolone or cyclophosphamide can result in rapid control of the disease. Plasma exchange and cryofihration also have been beneficial for individual patients.15” 153 However, in the patient with chronic cutaneous vasculitis without clinically apparent systemic involvement, each therapeutic agent should be evaluated for the possible risks versus benefits.154 The patient with chronic cutaneous vasculitis tends to be frustrated and frequently desires therapy for symptomatic relief or cosmetic reasons. In some cases, small recurrent purpuric lesions with superficial ulceration can compromise the patient’s ability to work, and in this instance, effective therapy that can allow the patient to become functional is warranted. In patients with acute disease such as Henoch-SchGnlein purpura, it may not be nec73

essary to treat other than symptomatically. In a recent report, Saulsbury155 documented that the use of systemic corticosteroids did not prevent the delayed development of nephritis. It is important to identify and remove any offelM: ing antigen that may be present. In addition, underlying diseases that have specific therapies should be treated. Some examples are the identitication of an ingestant, such as a drug, food, or food additive, that can be removed. Lunardi et al.156 reported successful use of an elimination diet in five patients with hypersensitivity vasculitis. They had patients on a S-week elimination diet followed by open and blinded food and food-additive challenges. They identified benzoates, tartrazines (21, eggs (21, beans W, potatoes (11, and chicken (11 as the cause of vasculitis in these patients. Interestingly, three of their patients had a documented lowering of the level of circulating immune com-

plexes after the diet. Some patients

will have their

“paraneoplastic” vasculitis resolve on removal of their tumor. Two of my patients, one with an adenocarcinoma and one with a pheochromocytoma, 15’ had resolution of their cutaneous vasculitis with tumor resection. Patients with paraproteinemia may be good candidates for an immunosuppressive agent to suppress the formation of the abnormal protein. Patients with erythema elevatum diutinum seem to respond extremely well to oral dapsone. Finally, patients with a cryofibrinogen

may respond zolol.140

to thrombolytic

Patients without ated phenomenon

agents such as stano-

an identifiable who require

cause or associtherapy can be

treated with a variety of agents. A therapeutic der can be designed

quentially tive agent

mechanism

from which

selected until is located.‘5s

for cutaneous

therapy

an appropriate Because

lad-

can be se-

and effec-

the postulated

vasculitis

involves

im-

mune complex-mediated disease, complement activation, chemotaxis of polymorphonuclear leukocytes, lysosomal release and resultant cell destruction, and modulation of the process by vasoactive substances, agents that interfere with any of these processes may be beneficial. Although agents such as antihistamines, nonsteroidal anti-inflammatory agents, antimalarials, oral potassium iodide, and sulfones have been reported to be effective in individual cases, they have not been uniformly effective in my patients. Corticosteroids, if given in a high enough dosage, are almost always effective. Colchitine is effective for 75% to 80% of patients with cutaneous vasculitis. Immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, or cyclosporine are also often effective. A progression of therapies has been suggested for the 74

patient with urticarial vasculitis similar to that shown in Fig 25. As with other small-vessel vasculitic syndromes, individual reports suggest benefit from a variety of agents. If possible, I prefer to avoid the use of systemic corticosteroids in this group of patients. Doses that are effective invariably lead to side effects, and the patients require prolonged therapy. Patients with urticarial vascuhtis are often bothered by the burning or itching of the lesions. The patients should be treated first with antihistamines. Hl antagonists can be combined with H2 antagonists, but I have found that the doses required are often greater than those that cause drowsiness. In some cases, the use of doxepin HCl, which has effects on both Hl and H2 receptors, is effective. The newer, nonsedating agents, such as terbeniIine or astemizole, can be used during waking hours, and a soporific agent can be given before retiring. In patients with chronic, cutaneous, nonurticarial leukocytoclastic vasculitis, oral colchicine, given at a dose of 0.6 mg twice daily, is often selected as

Hydroxychloroquine

1 Add Azathioprine

1

FIG 25. A possible therapeutic ladder for the treatment of the patient with cutaneous vasculitis. (Reproduced with permission from Berg RE, Kantor GR, Bergfeld WF: Urticarial vasculitis. Int J Dermatol 1988; 27:468-472.) Curr

Pmbl

Dermatol,

March/April

1393

an initial therapy.160-162 Xolchicine is an alkaloid that is known to inhibit polymorphonuclear leukocyte chemotaxis, block lysosomal formation, and stabilize lysosomal membranes. These factors are believed to be involved in the pathogenesis@ leukocytoclastic vasculitis, and thus, this agent perhaps blocks the end response of the immune complex disease. About 80% of patients treated with colchicine will respond, as judged by the disappearance of lesions and absence of new lesions. In most cases in which response occurs, if the colchitine is stopped, the disease returns, and with reinstitution of the therapy, the clinical signs are again suppressed. The onset of action is rapid, usually occurring within the first 4 to 7 days; if no response is noted by 2 weeks, the therapy should be considered a failure. In addition to the cutaneous benefits, arthralgias and arthritis may respond to colchicine. However, no changes are noted in circulating immune complex levels or abnormalities of proteins. This therapy is reserved for patients who lack severe systemic involvement. Colchicine is generally well tolerated and can be used for long periods of time. Toxicity is most frequently gastrointestinal, but long-term use should not be undertaken in potentially pregnant women, and blood counts should be monitored periodically. Although corticosteroids can be used to stop progression of disease when it is acute or for severe systemic involvement, their use in chronic, nonlifethreatening leukocytoclastic vasculitis is often complicated by multiple side effects. For this reason, immunosuppressive agents can be used as corticosteroid-sparing agents. Cyclophosphamide has been selected in many cases as the agent of choice, specifically, for severe necrotizing vasculitis or Wegener’s granulomatosis. Recently, Jorizzo et al.163 have reported the use of low-dose methotrexate as a corticosteroid-sparing agent for cutaneous polyarteritis nodosa. In their three patients, 7.5 to 15 mg given orally once weekly led to control of disease and cessation of oral corticosteroids. In addition, Hoffman et al.lw recently reported their results with methotrexate in 29 patients with Wegener’s granulomatosis. They administered weekly methotrexate either orally or intramuscularly in doses of 15 to 25 mg in combination with oral prednisone 1 mgkg per day. Remission was induced in 76% of their patients, a rate comparable to that for cyclophosphamide-treated patients without the toxicity associated with that therapy. Azathioprine has been reported to be effective in patients with a variety of vasculitic syndromes. In a recent report from our group, five of six patients with chronic, recalcitrant, cutaneous leukocytoCur-r

Pmbl

Dermatol,

March/April

1993

elastic vasculitis responded to oral azathioprine in a dose of 150 mg per day.165 The onset of action is delayed, often for 3 to 8 weeks. Corticosteroid dosage in our patients was able to be lowered or stopped. Side effects in these patients have been minimal, but several patients have developed verrucae (warts). Heurkens et al.‘66 also have used azathioprine for the treatment of patients with rheumatoid arthritis complicated by vasculitis. They found that this therapy was effective for patients with severe systemic vasculitis. They divided their patients with only cutaneous vasculitis into two groups: one received prednisone plus azathioprine, and the other continued the existing antirheumatic therapy without addition of prednisone or azathioprine. Although both groups improved during an l&month period, there were few statistical differences between them. They concluded that prednisone and azathioprine were not indicated for patients with only cutaneous vasculitis. However, when one carefully reviews their data, it is evident that of the 8 treated patients, only 1 had active disease at 18 months, whereas of the 11 “untreated” patients, 5 had active cutaneous disease. Furthermore, the issue of morbidity is not addressed in their report. Often healing of even small ulcerations results in an improved quality of life for the patient with cutaneous vasculitis. Thus, the benefits versus the risks of azathioprine therapy must be carefully assessed in each patient. A wide variety of agents have been used effectively in individual cases. These include hydroxychloroquine or gold for urticarial vasculitis,167P ‘6~ heparin or pentoxifylline for livedoid vasculitis,‘6sp 170 trimethoprim/sulfamethoxazole for Wegener’s granulomatosis,‘71 and potassium iodide for various cutaneous vasculitides.“’ Acknowledgment I thank Dr. Carol L. Kulp-Shorten for her helpful editorial suggestions, and Ms. Sandy Lie for her secretarial support. REFERENCES 1. Callen JP: Cutaneous vasculitis and its relationship to systemic disease. Disease-a-Month 1981; 283-48. 2. Churg A, Churg J: Systemic Vasculitis. New York, Igaku-

Shoin Medical Publishers, Inc, 1991. 3. Ssms WM Jr, Thorne EG, Small P, et al: Leukocytoclastic vascditis. Arch DermatollS76; 112219-226. 4. Jorizzo JL, Solomon AB, Zanolli MD, Leshin B: Neutrophihc vascular reactions. J Am Acad Dennatol 1988; 19983-1005. 5. Zeek PM, Smith LC, Wector JC: Studies on perivasculitis nodosa. III. The di@erentiation between the vascu75

6.

7. 8. 9. 10. 11. 12. 13. 14.

15. 16.

17.

18.

19. 20. 21. 22.

23. 24. 25.

26. 76

lar lesions of periarteritis nodo_sa and hypersensitivity. Am J Path01 1948; 24:889-917. Swerlick RA, Lawley TJ: Small-vessel vasculitis and cutaneous vasculitis, in Churg A, Churg J teds): Systemic Vasculitis. New York, Igaku-Shoin Medical Publishers, * Inc., 1991:193-201. SchGnlein JL: Allegemeine and specielle Pathologie und Therapie, ed 3, vol 2. He&au, Germany, LiteraturComptoir, 1837:48. Henoch EH: Ueber eine eigenthumliche Form von Purpura. Berl Klin Wochenschr 1874;11:641- 643. Saulsbury F: Henoch-Sch6nlein purpura. Pediatr Dermat01 1984; 1:195-201. Ilan Y, Naparstek Y: Schtinlein-Henoch purpura in adults and children. Semin Arthritis Rheum 1991; 21:103-109. Kauffmann RH, Herrmann WA, Mejier CJLM, et al: Circulating IgA-immune complexes in Henoch-SchBnlein purpura. Am J Med 1980; 69?359-866. McDuffie FC, Sams WM Jr, Maldonado JE, et al: Hypocomplementemia with cutaneous vasculitis and arthritis. Mayo Cfin Proc 1973; 48340-348. Radcliffe-Cracker H, Williams C: Erythema elevatum diutinum. Br J Dermatol 1894; 6:1-9. Lightfoot RW Jr, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Polyarteritis nodosa. Arthritis Rheum 1990; 333088-1093. D&-Perez JL, Winkelmann RK: Cutaneous periarteritis nodosa. Arch Dermatol 1974; 110:4b7-414. Leavitt RY, Fauci AS, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33:1101-1107. van der Woude TJ, Rasmussen N, Lobatto S, et al: Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985; 1:425-429. Masi AT, Hunder GG, Lie JT, et al: The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss Syndrome (Allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33:1094-1100. Liebow AA, Carrington CRB, Friedman PJ: Lymphomatoid granulomatosis. Hum Path01 1972; 3:457-558. Leavitt RY, Fauci AS: Polyangiitis overlap syndrome. Am J Med 1986; 81:79-85. Soter NA, Austen KF, Gigli I: Urticaria and arthralgias as manifestations of necrutizing angiitis (vasculitis). J Invest Dermatol 1974; 63~485-490. Kussmaul A, Maier R: Uber eine bischer nicht beschreibene eigethii mliche Arterien Krankung, die mit Morbus Brightii und rapid fortschreitender allegmeiner Muskellghmung einhergeht. Dtsch Arch K/in Med 1866; 1:484-517. Rackermann FM, Greene EJ: Periarteritis nodosa and asthma. Trans Assoc Am Physicians 1939; 54:112-118. Churg J, Strauss L: Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Path01 1951; 27277-301. Wegener F: LJber eine eigenartige rhinogene granulomatose mit besonderer Beteiligung des arteriensysterns und der Nieren. Beitr Path01 Anat 1939; 102:3768. Gilliam JN, Smiley JD: Cutaneous necrotizing vasculi-

tis and related disorders. Ann Allergy 1976; 37:328-339. 27. Lie JT: Vasculitis, 1815 to 1991: Classification and diagnostic specificity. J Rheumatol 1992; 19:83-89. 28. Hunder GG, Arend WP, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Vasculitis. Arthritis Rheum 1990; 33:1065-1144. 29. Fan PT, Davis JA, Somer T, et al: A clinical approach to systemic vasculitis. Semin Arthritis Rheumatol 1980; 9248-302. 30. Piette WW, Stone MS: A cutaneous sign of IgAassociated small dermal vessel leukocytoclastic vasculitis in adults (Henoch-ScMnlein purpura). Arch Dermatol 1989;12553-56. 31. Monroe EW, Schulz CI, Maize JC, Jordon RE: Vasculitis in chronic urticaria: An immunopathologic study. J InvestDermatol1981;76:103-107. 32. Hodge SJ, Callen JP, Ekenstam E: Cutaneous leukocytoclastic vasculitis: Correlation of histopathological changes with clinical severity and course. J Cutan Path01 1987; 14279-284. 33. Sanchez NP, Van Hale HM, Su WPD: Clinical and histopathologic spectrum of necrotizing vasculitis. Arch Dermatoll985; 121220-224. 34. Zax RH, Hodge SJ, Callen JP: Cutaneous leukocytoclastic vasculitis: Serial histopathologic evaluation demonstrates the dynamic nature of the infiltrate. Arch Dermatol 1990;126:69-72. 35. Soter NA, Mihm MC Jr, Gigli I, et al: Two distinct cellular patterns in cutaneous necrotizing angiitis. J InvestDermatol1976;66:344-350. 36. Alexander E, Provost TI? SjGgren’s syndrome.Arch Dermatol 1987;123:801-810. 37. McCombs RP: Systemic “allergic” vasculitis. JAMA 1965; 194:1059-1064. 38. Mullick FG, McAllister HA, Wagner BM, Fenoglio JJ: Drug related vasculitis. Hum Path01 1979;10:313-325. 39. Micha&lsson G, Pettersson L, Juhlin L: Purpura caused by food and drug additives. Arch Dermatol 1974; 109:49-52. 40. Veien NK, Krugdahl A: Cutaneous vasculitis induced by food additives. Acta Derm Venereol &o&h) 1990; 71:73-74. 41. Arias JA, Santana C, Vizcaina, et al: Vasculitis po hipersensibilidad: antiisis de 60 pacientes. Rev Clin Esp 1989; 185:187-190. 42. Tencati JR, Novey HS: Hypersensitivity angiitis caused by fumes l?om heat-activated photocopy paper. Ann Intern Med 1983; 98:320-322. 43. Cream JJ, Bryceson ADM, Ryder G: Disappearance of immunoglobulin and complement from the Arthus reaction and its relevance to studies of vasculitis in man. BrJDermatol1971;84:106-109. 44. af Ekenstam E, Callen JP: Cutaneous leukocytoclastic vasculitis. Arch Dermatol 1984; 120:484-489. 45. Winkelmann RK, Ditto WB: Cutaneous and visceral syndromes of necrutizing or “allergic” angiitis: A study of 38 cases. Medicine 1964; 43:59-89. 46. Handel DW, Roenigk HH Jr, Shainoff J, Deodhar S: Necrotizing vasculitis. Arch Dermatol 1975; 111:847-852. 47. Yermakov VM, Hitti IF, Sutton AL: Necrotizing vasculitis associated with diphenylhydantoin: Two fatal cases. Hum Path01 1983;13:182-184. 48. Calabrese LH, Michel BA, Bloch DA, et al: The AmeriCm-r

ProblDermatol,

March/April

1993

can College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum 1990; 33:1108-1113. 49. Michel BA, Hunder GG, Bloch DA, Calabrese L: Hypersensitivity vasculitis and Henoch-Sch6nlein pu ura: A comparison between the 2 disorders. J Rh x matol 1992; 19:721-728. 50. Haber MM, Marboe CC, Fenoglio JJ Jr: Vasculitis in drug reactions and serum sickness, in Churg A, Churg J (eds): Systemic Vasculitis. New York, Igaku-Shoin Medical Publishers, Inc., 1991:305-313. 51. Mills JA, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Henoch-SchBnlein purpura. Arthritis Rheum 1990; 33:1114-1121. 52. Farley TA, Gillespie S, Rasoulpour M, et al: Epidemiology of a cluster of Henoch-Schijnlein purpura. Am J Dis Child 1989; 143:798-803. 53. Hall RP, Stachura I, Cason J, et al: &A-containing circulating immune complexes in patients with nephmpathy. Am J Med 1983; 74:56-63. 54. Goldstein AR, White RHR, Akuse R, Chantler C: Longterm follow-up of childhood Henoch-Schiinlein nephritis. Lancet 1992; 339280-282. 55. White RHR: Henoch-ScMnlein purpura, in Churg J teds): Systemic Vasculitis. Churg A, New York, IgakuShoin Medical Publishers, Inc., 1991203-217. 56. Van Hale HM, Gibson LE, S&meter AL: HenochSchijnlein vasculitis: Direct immunofluorescence study of uninvolved skin. J Am Acad Dermatol 1986; 15:665670. 57. Saulsbury FT: Heavy and light chain composition of serum IgA and IgA rheumatoid factor in HenochSchijnlein purpura. Arthritis Rheum 1992; 35:1377-1380. 58. Lakhanpal S, Conn DL, Lie JT: Clinical and prognostic significance of vasculitis as an early manifestation of connective tissue disease syndromes. Ann Intern Med 1984; 103 :743- 748. 59. Jorizzo JL, Gonzalez EB, Apisarthanarax P, Daniels JC: Pigmented purpuric eruption in a patient with rheumatoid arthritis.Arch Intern Med 1982; 1422184-2185. 60. Scott DGI, Bacon PA, Tribe CR: Systemic rheumatoid vasculitis: A clinical and laboratory study of 50 cases. Medicine 1981; 60288-297. 61. Smith ML, Jorizzo JL, Semble E, et al: Rheumatoid papules: Lesions showing features of vasculitis and palisading granuloma. J Am Acad Dermatol 1989; 20:348352. 62. Vollertsen RS, Conn DL: Vasculitis associated with rheumatoid arthritis. Rheum Dis Clin North Am 1990; 16:445-461. 63. O’Loughlin S, Schmeter AL, Jordon RE: Chronic urticaria-like lesions in systemic lupus erythematosus. Arch Dermatoll978; 114:879-883. 64. Aizawa Y, Zawadzki ZA, Micolonghi TS, et al: Vasculitis and Sjiigren’s syndrome with IgA-IgG cryoglobulinemia terminating in immunoblastic sarcoma. Am J Med 1979; 67:160-165. 65. Churg J: Cryoglobulinemic vasculitis, Churg A, Churg J teds): in Systemic Vasculitis. New York, Igaku-Shoin Medical Publishers, Inc., 1991293-304. 66. Lawley TJ, Gorevic PD, Hamburger MI, et al: Multiple types of immune complexes in patients with mixed Curr

Probl

Dermatol,

March/April

1993

cryoglobulinemia. J Invest Dennatol 1980; 75297-301. 67. Gorevic PD, Kassab HJ, Kohn R, et al: Mixed cryoglobulinemia: Clinical aspects and long-term follow-up of 40 patients. Am J Med 1980; 69287-308. 68. Cohen SJ, Pittelkow MR, Su WPD: Cutaneous manifestations of cryoglobulinemia: Clinical and histopathologic study of seventy-two patients. J Am Acad Dermato/ 1991; 2521-27. 69. Waldenstriim J: Clinical methods for the detection of hyperpmteinemia and their practical, diagnostic value. Nord Med 1943; 20:2288-2295. 70. Finder KA, McCollough ML, Dixon SL, et al: Hypergammaglobulinemic purpura of Waldenstrijm. J Am Acad Dermatol 1990; 23:669-676. 71. Ferreim JE, Pasarin G, Quesada R, Gould E: Benign hypergammaglobulinemic purpura of Waldenstriim associated with Sjiigren’s syndrome. Am J Med 1986; 81:734- 740. 72. Hudson CP, Callen JP: Cutaneous leukocytoclastic vasculitis with hyperglobulinemia and splenomegaly. Arch Dermatoll984; 120:1224-1226. 73. Janier M, Bonvalet D, Blanc MF, et al: Chronic urticaria and macmglobulinemia (Schnitzler’s syndrome). J Am Acad Dermatoll989; 20206-211. 74. Berdy SS, Bloch KJ: Schnitzler’s syndrome: A broader clinical spectrum. JAllergy Clin Immunoll991; 87:849854. 75. Schnitzler L, Schubert B, Boasson M, et al: Urticaire chmnique, lesions osseuses, macmglobulinemie IgM: Maladie de Waldensttim? Bull Sot Fr Dermatol Syphil 1974; 81:363. 76. Yiannias JA, El-Azhary R, Gibson LE: Erythema elevaturn diutinum: A clinical and histopathologic study of 13 patients. J Am Acad Dermatol 1992; 26:38-44. 77. Wilkinson SM, English JSC, Smith NP, et al: Erythema elevatum diutinum: A clinicopathological study. Clin Epxp Dermatol 1992; 17:87-93. 78. SBnchez-Guerrem J, GutiBrrez-Ureiia S, Vidaller A, et al: Vasculitis as a paraneoplastic syndrome. Report of 11 cases and review of the literature. J Rheumatol 1990; 17:1458-1462. 79. Schmeter AL, Copeman PWM, Jordon RE, et al: Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch Dermatol 1971; 104254-259. 80. Komadina KH, Houk RW: Polyarteritis nodosa presenting as recurrent pneumonia following splenectomy for hairy-cell leukemia. Semin Arthritis Rheum 1989; 18252-257. 81. Weinstein A: Systemic vasculitis and hairy cell leukemia. J Rheumatol 1982; 9:349-350. Sla. Spann CR, CaBen JP, Yam LT, Apgar JT: Cutaneous leukocytoclastic vasculitis complicating hairy cell leukemia. Arch Dermatol 1986; 122:1057-1059. 82. Longley S, Caldwell JR, Panush RS: Paraneoplastic vasculitis. Am J Med 1986; 80:1027-1030. 83. Fain 0, Guillevin L, Kaplan G, et al: Vascularites et n6oplasies. Ann Med Interne 1991; 142:486-504. 84. Beylot J, Malou M, Doutre MS, et al: Vascularites leucocytoclasiques et hemopathies malignes. Rev Med Interne 1989; 10:509-514. 85. Castro M, Conn DL, Su WPD, Garton JP: Rheumatic manifestations in myelodysplastic syndromes. J Rheumatol 1991; 18:721- 727. 86. Green AR, Shuttleworth D, Bowen DT, Bentley DP: Cu77

taneous vascuIitis in patients @th myelodysplasia. Br J Haematol 1990; 74364- 370. 87. PagIiuca A, Higgins E, Samson D, et aI: ProdmmaI cutaneous vasculitis in myelodysplastic syndromes. Br J Haematol 1990; 74:444-446. 88. Queipo de LIano MP, Yerba M, Cabrera R, et al: Mye&- . dysplastic syndrome in association with erythema elevatum diutinum. J Rheumatol 1992; 19:1005. 89. Sadick NS, AlIen SL: Atmphie blanche in chronic myelogenous leukemia. Cutis 1988; 42206-209. SO. Lewis JE: Urticarial vasculitis occurring in association with visceral malignancy. Acta Derm Venereal 1990;

70345-347. 91. Seiden MV, O’Donnell WJ, Weinblatt M, Licht J: Vasculitis with recurrent pulmonary hemorrhage in a longterm smvivor after autologous bone marrow transplantation. Bone Marrow Tram 1990; 6345-347. 92. Es&ante A, Kaufman RL, Beardmore TD: Acute myelocytic leukemia after the use of cyclophosphamide in the treatment of polyarteritis nodosa. J Rheumatol 1989; 16:1147-1149. 93. Schwartz HR, McDufEe FC, Black LF, et aI: Hypocomplementemic urticarial vasculitis: Association with chronic obstructive pulmonary disease. Mayo Clin Proc 1982; 57231-238. 94. Asherson RA, Sontheimer R: Urticarial vascuIitis and syndromes in association with connective tissue diseases.Ann Rheum Dis 1991; 50:743-744. 95. Pmvost ‘IT, Zone JJ, Synkowski D, et al: Unusual cutaneous manifestations of systemic lubus erythematosus: I. Urticaria-like lesions. Correlation with clinical and serological abnormalities. J Invest Dermato/ 1980;

75:495-499. 96. Asherson RA, D’Cruz D, Stephens

97. 98. 99. 100. 101.

CJM, et aI: UrticariaI vascuIitis in a connective tissue disease clinic: Patterns, presentations and treatment. Semin Arthritis Rheum 1991; 20285-296. Yasue T, Yasue A: Urticarial vasculitis with circulating immune complexes and mixed cryoglobulins: Studies of pathogenesis. J Dermatof 1987; 14597-603. Callen JP, KaIbfleisch S: UrticariaI vasculitis: A report of nine cases and review of the literature. Br J DermatoI 1982; 107%7- 94. Winkelmann RK, Wilson-Jones E, Smith NP, et al: Neutmphihc urticaria. Acta Derm Venereol 1988; 68:129- 133. Mehregan DR, HaII MJ, Gibson LE: UrticariaI vasculitis: A histopathologic and clinical review of 72 cases. J Am Acad Dermatol 1992; 26:441-448. Sara&r Y, Tinaztepe K, AdaIiogIu G, Tuncer A: Acute hemomhagic edema of infancy @HEI)-A variant of Henoch-Schiinlein purpura or a distinct clinical entity?

J Allergy Clin Immunol 1990; 86:473-483. 102. Legrain V, L.ejean S, Tdieb A, et al: Infantile acute hemorrhagic edema of the skin: Study of ten cases. J Am Acad Dermatol 1991; 24:17-22. 103. Katz SI, Gallin JI, Hertz KC, et al: Erythema elevatum diutinum: Skin and systemic manifestations, immunologic studies, and successful treatment with dapsone. Medicine 1977; 56:443-455. 104. Rosen S, FaIk RJ, Jennette JC: Polyarteritis nodosa, including microscopic form and renal vasculitis, in Churg A, Churg J (eds): Systemic Vasculitis. New York, Igaku-Shoin Medical Publishers, Inc., 199157-77. 78

105. Lopez LR, Schocket AL, Stanford RE, et al: Gastmintestinal involvement in leukocytoclastic vasculitis and polytieritis nodosa. J RheumatollS80; 7677-684. 106. Hommas PB, David-Bajar KM, Fitzpatrick JE, et aI: Microscopic polyarteritis. Arch DermatollSS2; 128:12231228. 107. Chen KR: Cutaneous polyarteritis nodosa: A clinical and histopathological study of 20 cases. J Dermatol 1989; 16:429-442. 108. Moreland LW, BaII GV: Cutaneous polyarteritis nodosa. Am J Med 1990; 88:426-430. 109. Mekori YA, Awai LE, Weidel JD, KohIer PF: Cutaneous polyarteritis nodosa associated with rapidly pmgressive arthritis. Arthritis Rheum 1984; 27574-578. 110. Dewar CL, Bellamy N: Necrotizing mesenteric vasculitis after longstanding cutaneous poIyarteritis nodosa. J RheumatollSS2; 19:1308-1311. 111. Gudbjiimsson B, H8Rgren R: Cutaneous polyarteritis nodosa associated with Crohn’s disease. J Rheumatol 1990; 17:386-390. 112. Chiu G, Rajapakse CNA: Cutaneous polyarteritis nodosa and ulcerative colitis. J Rheumatol 1191; 18:769770. 113. Van de Pette JEW, Jan& JM, Wilton JMA, MacDonald DM: Cutaneous periarteritis nodosa. Arch Dermatol 1984; l20:109-111. 114. Hoffman GS, Kerr GS, Leavitt RY, et aI: Wegener granuIomatosis: An anaIysis of 158 patients. Ann Intern Med 1992; 116:488-498. 115. Hu CH, O’Loughlin S, Winkehnann RK: Cutaneous manifestations of Wegener gramdomatosis. Arch Dermato1 1977; 113~175-182. 116. Franc& C, Huong DLT, Piette JC, et al: Dennatological manifestations of Wegener’s granuIomatosis. Arthritis Rheum 1992; 35:S165. 117. Mangold MC, CaIlen JP: Cutaneous leukocytoclastic vascuIitis associated with active Wegener’s gramdomatosis. J Am Acad DermatollSS2; 26579-584. 118. Specks U, WheatIey CL, McDonald TJ, et al: Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener’s granulomatosis. Mayo Clin Proc 1989;

6428-36. 119. Lanham JG, EIkon KB, Pusey CD, Hughes GR: Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg-Strauss syndrome. Medicine 1984; 6365-81. 120. F’inan MC, Winkehnann RK: The cutaneous extravascular necmtizing granuloma (Churg-Strauss granuloma) and systemic disease: A review of 27 cases. Medicine 1983; 62:142-158. 121. deShazo RD, Levinson AI, Lawless OJ, Weisbaum G: Systemic vasculitis with coexistent large and smaU vessel involvement. JAMA 1977; 238:X&%0-1942. 122. Pischel KD, ZvaifIer NJ: Simultaneous occurrence of polyarteritis nodosa and leukocytoclastic vasculitis. J RheumatollS84; 1X42-544. 123. Mousa ARM, Marafie AA, Dajani AI: Cutaneous necmtizing vasculitis complicating Takayasu’s arteritis with a review of cutaneous manifestations. J Rheumatol 1985; 12807-610. 124. Lie JT: Vasculitis simulators and vasculitis look-al&es. Curr Opin Rheumatol 1992; 4:47-55. 125. Asherson RA, JacobeIIi S, Rosenberg H, et al: Skin nodules and macules resembling vasculitis in the antiCurr

Pmbl

Dermatol,

MarchApril

1993

126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144.

145. 146. 147.

phospholipid syndrome--A report of two cases. C/in E,xp Dermato! 1992; 17266-269. Boussen K, MoaIla M, Blondeau P, et aI: Embolization of cardiac myxomas masquerading as polyarteritis nodosa. J Rheumatoll991; 18283-285. Goette DK: Unilateral palpable purpura. Ar&Dermato1 1981; 117:430-431. Falanga V, Fine MJ, Kapoor WN: The cutaneous manifestations of cholesterol crystal embolization.Arch Dermatoll986; 122:1194-1198. Turakhia AK, Khan MA: Splinter hemorrhages as a possible clinical manifestation of cholesterol crystal emboIization. J Rheumatol 1990; 17:1083-1086. Rubenfeld S, Min KW: Leukocytoclastic angiitis in subacute bacterial endocarditis. Arch Dermatol 1977; 113:1073-1074. CappiaRo RA, Espinoza LR, AIeIman H, et al: Cholesterol embolism: A pseudovasculitic syndrome. Semin Arthritis Rheum 1989; 18240-246. Greer KE, Cooper PH, Campbell F, Westervelt FB: Primary oxalosis with livedo reticularis. Arch Dermatol 1980; 116213-214. O’Dell JR, Linder J, Markin RS, Moore GF: Thromboangiitis obliterans IBuerger’s disease) and smokeless tobacco. Arthritis Rheum 1987; 30:1054- 1056. Schroeter AL, Diaz-Perez JL, Winkelmann RK, Jordon RE: Livedo vasculitis (the vascuhtis of atrophie blanche). Arch Dermatol 1975; 111:188-193. Millstone LM, Braverman IM, Lucky P, Fleckman P: Classification and therapy of atrophie blanche. Arch Dermatol 1983;119:963-969. McCaImont CS, McCaImont TH, Jorizzo JL, et al: Livedo vascubtis: Vascubtis of thrombotic vasculopathy? Clin Ew Dermatoll992; 17:4-S. Pizzo SV, Murray JC, Gonias SL: Atrophie blanche. Arch Dermatoll986; 110:571-579. Klein KL, Pittelkow MR: Tissue plasminogen activator for treatment of Iivedoid vasculitis. Mayo Clin Proc 1992; 67:923-933. Beightler E, Diven DG, Sanchez RL, Solomon AR: Thrombotic vasculopathy associated with cryofibrinogenemia. JAm Acad Dermatol 1991; 24~342-345. FaIanga V, Kirsner RS, Eaglstein WH, et aI: StanozoIoI in treatment of leg ulcers due to cryofibrinogenemia. Lancet 1991; 338347-348. Mackel SE, Jordon RE: Leukocytoclastic vasculitis. Arch Dermatoll982; 118296-301. Giangiacomo J, Tsai CC: DermaI and glomerular deposition of &A in anaphylactoid purpura. Am J Dis Child 1977; 131:981-3. Kammer GM, Soter NA, Schur PH: Circulating immune complexes in patients with necrotizing vasculitis. Clin Immunol Immunopathol 1980; 15:658-670. Braverman IM, Yen A: Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic angiitis. J Invest Dermatol 1975; 64:105-112. Savage COS: Pathogenesis of systemic vasculitis, in Churg A, Churg J feds): Systemic Vasculitis. New York, Igaku-Shoin Medical Publishers, Inc., 1991:7-30. Jordan JM, Allen NB, Pizo SV: Defective release of tissue plasminogen activator in systemic and cutaneous vasculitis. Am J Med 1987; 82:397-400. Tosca N, Stratigos JD: Possible pathogenic mechanisms

Cm-r Probl

Dermatoi,

March/April

1993

148. 149.

150. 151. 152. 153.

154. 155. 156. 157. 158. 159. 160. 161. 162. 163.

164.

165.

166.

in allergic cutaneous vasculitis. Int J Dermatol 1988; 27:291-296. Dahlberg PJ, Lockhart JM, Overholt EL: Diagnostic studies for systemic necrotizing vasculitis. Arch Intern Med 1989; 149:161- 165. Bliel L, Manger B, Winkler TH, et aI: The role of antineutrophil cytoplasm antibodies, anticardiolipin antibodies, von WiRebrand factor antigen, and fibronectin for the diagnosis of systemic vasculitis. J Rheumatol 1991; 18:1199-1206. Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. NEnglJMed 1979;301235-258. Scott DGI, Bacon PA: Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 1984; 76:377-3&L Turner AN, Whittaker S, Banks I, et aI: Plasma exchange in refractory cutaneous vasculitis. Br J Dermatol 1990; 122:41-45. Sawada K, SegaI AM, MaIchesky PS, et al: Rapid improvement in a patient with leukocytoclastic vasculitis with secondary mixed cryoglobulinemia treated with cryoiihration. J Rheumatoll991; 18:91-94. Cupps TR, Springer RM, Fauci AS: Chronic, recurrent small-vessel cutaneous vasculitis. JAMA 1982; 247:1994-1998. Saulsbury FT: Corticosteroid therapy does not prevent nephritis in Henoch-SchonIein purpura. Arthritis Rheum 1992;35Sl89. Lunardi C, Bambara LM, Biasi D, et ah Elimination diet in the treatment of selected patients with hypersensitivity vasculitis. C/in E~rp Rheumatol 1992; 10:131-135. CaIlen JP: Cutaneous leukocytoclastic vasculitis in a patient with an adenocarcinoma of the colon. J Rheumatot 1987; 14:386-389. Kulp-Shorten CL, Rhodes RH, Peterson H, CaRen JP: Cutaneous vasculitis associated with pheochmmocytoma. Arthritis Rheum 1990; 33:1852-X%6. Berg RE, Kantor GR: Urticarial vasculitis. Int J Dermato/ 1988;27:468-472. Hazen PG, Michel B: Management of necmtizing vasculitis with colchicine. Arch Dermatol 1979; 115:13031306. CaBen JP: Colchicine is effective in controlling chronic cutaneous leukocytoclastic vasculitis. J Am Acad Dermatol1985;13:193-200. Wiles JC, Hansen RC, Lynch PJ: Urticarial vasculitis treated with colchicine. Arch Dermatol 1985; 121:802805. Jorizzo JL, White WL, Wise CM, et al: Low-dose weekly methotrexate for unusual neutmphibc vascular reactions: Cutaneous polyarteritis and Behcet’s disease. J Am Acad Dermatoll991; 24973-978. Hoffman GS, Leavitt RY, Kerr GS, Fauci AS: The treatment of Wegener’s granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992; 35:1322-1329. CaRen JP, Spencer LV, Burruss JB, Holtman J: Azathioprine: An effective, corticosteroid sparing therapy for patients with recalcitrant cutaneous lupus erythematosus or with recalcitrant cutaneous leukocytoclastic vascuhtis. Arch Dermatol 1991; 1271515-522. Heurkens AHM, Westedt ML, Breedveld FC: Prednisone plus azathioprine treatment in patients with rheuma7!l

toid arthritis complicated by vasculitis. Arch Intern Med 1991; 151:2249-2254. 167. Lopez LR, Davis KC, Kohler PF, Schocket AL: The hypocomplementemic urticarial-vasculitis syndrome: Therapeutic response to hydroxychlomquine. JAllrgy C/in Immunol 1984; 73:600-603. 168. Handfield-Jones SE, Greaves MW: Urticarial vasculitisresponse to gold therapy. J Roy Sot Med 1991; 64:?69. 169. Heine KG, Davis GW: Idiopathic atrophie blanche: Treatment with low-dose heparin.Arch Dermatoll986; 122:855-856.

80

170. Sauer GC: Pentoxifylline (Trental) therapy for the vasculitis of atrophie blanche. Arch Dermatol 1986; 122:380-381. 171. DeRemee RA: The treatment of Wegener’s granulomatosis with trimethoprimsulfamethoxazole: Illusion or vision? Arthritis Rheum 1988; 31:1068-1074. 172. Schulz EJ, Whiting DA: Treatment of erythema nodosum and nodular vasculitis with potassium iodide. Br J Dermatoll976; 94:75- 78.

Curr

Pmbl

Dermatol,

March/April

1993