Classification of Joseph L. Jorizzo

A working classification of necrotizing vasculitis based on size of the affected vessel is proposed. The classification proposed by Gilliam and Fink in 1976 is a basis for the curren proposal. A revised working classification of vasculitis is presented. Small vessel necrotizing vasculitis and larger vessel necrotizing vasculitis categories are further subdivided. Improved understanding of the basic science aspects of vasculitis will hopefully give rise to a better consensus on the classification of vasculitis. J Invest Dermatol 100:106S–110S, 1993

A considerable portion of the now classic Medical Grand Rounds on SMALL VESSEL NECROTIZING VASCULITIS necrotizing vasculitis presented at The University of Texas Southwestern (NECROTIZING VENULITIS) Medical Center by James W. Gilliam in 1976 dealt with the classification of necrotizing vasculitis. Aspects of this presentation have been The hallmark of small-vessel necrotizing vasculitis is the diagnostic published (Table I) [1]. histopathologic finding of leukocytoclastic vasculitis including endothe- The historical context of Gilliam’s classification is important given the lial cell swelling, neutrophilic invasion of blood-vessel walls, leukocy- confounding array of classification schemas that preceded (and followed!) toclasia (neutrophilic nuclear karyorrhexis), extravasation of erythrocytes, and fibrinoid necrosis of blood vessel walls [14]. This it. The classification of vasculitis remains frustratingly controversial today. Zeek was the first to incorporate a clinicopathologic assessment process has been shown to affect post capillary venules [15,16]. This based on the size of the vessel involved in the inflammatory process in entity has been proposed as a cutaneous model for circulating immune his classification of necrotizing vasculitis in 1952 [2]. Zeek’s schema complex–mediated, neutrophil-induced vessel damage [17]. At the included hypersensitivity arteritis, allergic granulomatosis, Wegener’s same time, it is important to realize that the histologic findings of leuko- granulomatosis, polyarteritis nodosa, and giant cell arteritis [3]. Other cytoclastic vasculitis can occur in settings other than those due to circulating immune complexes such as with septic or less commonly schemas were also proposed [4,5]. with other emboli, with repeated cold injury, next to cutaneous ulcers, or Winkelmann has highlighted issues that can be considered in the development of classification schema of vasculitis, including clinical in associations with other cutaneous insults. classification, systemic versus cutaneous, muscular-vessel versus small- vessel disease, histopathologic features including leukocytoclastic vasculitis Clinical Aspects Although a spectrum of cutaneous necrotizing lesions versus ‘‘lymphocytic vasculitis,’’ and vasculitis showing mixed or granulo- can be seen in patients with small-vessel necrotizing vasculitis, the matous histology [6]. He also reviewed ‘‘laboratory vasculitis’’ in which hallmark lesion is the palpable purpuric papule. These lesions occur in findings obtained during laboratory screening of the patient with vasculitis crops, generally on dependent sites (Fig 1). Lesions are usually less than can be used to develop the classification schema and also etiologic factors, 1 cm in diameter, and they progress from erythema-tous macules to which can be relevant to classification when they are known [6]. purpuric papules, occasionally becoming confluent producing plaques A number of alternative classification systems have been proposed that may ulcerate. Lesions may be moderately symptomatic with pruritus since Gilliam’s Grand Rounds. Most of these have similarities with or pain. Associated, mild, dependent edema can also be symptomatic. Gilliam’s proposed classification, while each proponent has struggled Serum sickness–like signs and symptoms such as arthralgias, arthritis, with various issues raised by Winkelmann [7–12]. Particularly disturbing myalgias, and fever are often associated. are the recently published American College of Rheumatology (ACR) Similar clinicopathologic lesions may occur in internal locations also, criteria for the classification of vasculitis [12]. Although the attempt to presumably due to circulating immune complex–mediated vessel damage develop diagnostic criteria by analyzing clinical variables in a large at those sites. Classic manifestations/locations include proteinuria and/or patient population and then testing these criteria in other patient hematuria/kidney glomeruli; focal or diffuse, central or peripheral populations is laudable, common sense is sometimes sacrificed in favor neurologic manifestations/nervous system; polyarthritis/synovia; abdom- of criteria that are simply reproducible. Particularly obvious problems are inal pain and/or bleeding/gastrointestinal tract; pleuritis and pleural the attempt to codify the histologic findings of small-vessel (‘‘hypersensi- effusion/pleura; signs and symptoms of pericardial effusion/pericardium; tivity’’) vasculitis. Fourteen biopsy criteria are listed! The use of concepts and other manifestations [13,17]. such as ‘‘maculopapular rash,’’ ‘‘medication at onset,’’ and ‘‘eosinophils Most subgroups of small-vessel necrotizing vasculitis listed in Table II on biopsy’’ as criteria seem particularly inappropriate to many are characterized by the types of lesions listed above. Adult patients with dermatologists, as does an entirely separate classification for Henoch- IgA-associated small-vessel necrotizing venulitis (Henoch-Schonlein Schonlein [12]. Table II illustrates the ACR criteria ‘‘selected for purpura) have, in addition, been noted to have distinctive plaque-like the diagnosis of hypersensitivity vasculitis,’’ which corresponds to small- lesions in a livedoid pattern [18]. vessel necrotizing vasculitis. It is easy to criticize, however; the is characterized by wheals, the individual lesions development of a working classification that is clinically relevant, is of which persist for more than 24 h. Classic lesions burn more than itch workable by various specialists, and addresses clinical features, vessel and leave residual purpura after resolution. Lesions are distributed size, histopathologic features, laboratory features, and underlying causes randomly rather than on dependent sites [19]. of vasculitis is a goal that remains elusive. An attempt at classification Erythema elavatum diutinum is characterized by erythematous that represents an update of the classification presented by Gilliam is yellowish-brown plaques that classically occur over the knuckles or presented (see Table III). Small-vessel necrotizing vasculitis is empha- elbows. Lesions are usually chronic [20]. sized in the discussion that follows. Nodular vasculitis is characterized by distinct nodules that represent a suppurative affecting primarily the calves. A deep incisional biopsy is required to confirm the clinical diagnosis [21]. This entity, often considered with small-vessel necrotizing vasculitis, is perhaps best classified with larger-vessel disease. Department of Dermatology, Bowman Gray School of Medicine, Winston- Rheumatoid nodules are subcutaneous, firm nodules that, like Salem, North Carolina, USA erythema elevatum diutinum, affect pressure sites [22]. The histologic Reprint requests to: Dr. Joseph L. Jorizzo, Department of Dermatology, findings reveal palisading granuloma formation, a feature that has Bowman Gray School of Medicine, Wake Forest University, Medical Center recently been seen in association with leukocytoclastic vasculitis in Boulevard, Winston-Salem, NC ‘‘rheumatoid papules’’[23].

0022-202X/93/$06.00 Copyright & 1993 by The Society for Investigative Dermatology, Inc.

106S VOL. 100, NO. 1, SUPPLEMENT, JANUARY 1993 CLASSIFICATION OF VASCULITIS 107S

Table I. Classification of Necrotizing Vasculitides by Table III. Proposed Working Classification of Gilliam and Fink Presented at Medical Grand Rounds Vasculitis on September 9, 1976 at University of Texas I. Small-vessel necrotizing vasculitis Southwestern Medical Center A. Necrotizing venulitis I. Leukocytoclastic Vasculitis (hypersensitivity angiitis or allergic vasculitis) B. Henoch-Scholein purpura A. Schonlein-Henoch purpura C. Essential mixed cryoglobulinemia B. Hypocomplementemic vasculitis D. Waldenstom’s hypergammaglobulinemic purpura C. Essential mixed cryoglobulinemia E. Associated with collagen vascular disease D. Other disease-related dermal vasculitides F. Urticarial vasculitis G. Erythema elevatum diutinum

II. Rheumatic Vasculitis H. Rheumatoid nodules A. Systemic lupus erythematosus I. Reactive leprosy B. Rheumatoid vasculitis J. Septic vasculitis C. Scleroderma D. Dermatomyositis II. Larger-vessel necrotizing vasculitis E. Acute rheumatic fever A. Polyarteritis nodosa 1. Benign cutaneous form

III. Granulomatous Vasculitis 2. Systemic form A. Churg and Strauss allergic granulomatous angiitis B. Granulomatous vasculitis B. Wegener’s granulomatosis 1. Wegener’s granulomatosis C. Limited Wegener’s 2. Allergic granulomatosis 3. lymphomatoid granulomatosis

IV. Polyarteritis Nodosa C. Giant cell arteritis A. Classic type 1. Temporal arteritis B. Limited type (skin and muscle) 2. Takayasu’s disease C. Hepatitis B antigen associated vasculitis D. Larger-vessel vasculitis with collagen vascular disease D. Vasculitis in drug addicts E. Nodular vasculitis E. Vasculitis following serous otitis media

V. Giant Cell Arteritis Lesions of septic vasculitis tend to be acrally located (e.g., finger-tips) A. Temporal arteritis and may occasionally be wedge shaped. They may be papulopustular. B. Polymyalgia rheumatica Lesions are generally not as numerous as those in the patient with the ‘‘usual variety’’ of small-vessel necrotizing vasculitis [24]. C. Takayasu’s disease Histopathologic Aspects Histopathologic features of small-vessel necro- tizing vasculitis are characterized as leukocytoclastic vasculitis as 1 described above [25]. Immunoreactants (IgG, IgM, IgA, C3,C4,C and Cq) and fibrin can inconsistently be demonstrated in dermal vessel on direct immunofluorescence microscopy, although this finding is Table II. 1900 American College of Rheumatology non-specific and is not of much use clinically [13]. The same can Criteria For Hypersensitivity Vasculitis (Traditional be concluded about the ‘‘histamine trap test’’ originally described a by Braverman and Yen in which lesions are induced by intra- Format) dermal histamine injection [15]. Immunoelectron microscopic studies 1. Age at disease onset 416 years have demonstrated that the post-capillary venule is the site of path- ology in this disease and immunoreactants are demonstrable in dermal 2. Medication at disease onset vessels [26]. 3. Palpable purpura The characteristic histopathologic features of small-vessel necrotizing vasculitis are transient. Therefore, confirmation of the clinical diagnosis 4. Maculopapular rash histopathologically can be difficult. Old lesions (older than 24–48h) or 5. Biopsy including arteriole and venule with histologic changes showing treated lesions no longer show the required changes of leukocytoclastic granulocytes in a perivascular or extravascular location vasculitis, but rather show non-specific lymphocytic perivascular changes [17]. The failure to appreciate that vasculitic lesions have aAt least three of five criteria must be present. The presence of three of five ‘‘lifespans’’ and the tendency to view a pathology report as an criteria was associated with a specificity of 83.9% and a sensitivity of interpretation of a static event have, in my view, led to much of the 71.0% [12]. confusion that exists in classifications of vasculitis based on histopatho- logy, including some of the confusion in the new ACR criteria [12]. 108S JORIZZO THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Figure 1. Palpable purpuric papules in an acral distribution suggested a Figure 2. Cutaneous ulceration in a pattern suggestive of larger vessel diagnosis of small-vessel necrotizing vasculitis. Biopsy of a lesion revealed the vasculitis in a patient who proved to have systemic polyarteritis nodosa. confirmatory finding of leukocytoclastic vasculitis. LARGER VESSEL VASCULITIS Polyarteritis Nodosa — Systemic Form Systemic polyarteritis nodosa is a Patient Evaluation A three-stage approach to evaluation of the patient multisystem disease that can be life threatening. Cutaneous lesions occur in with suspected small-vessel necrotizing vasculitis can be employed. The only one-fifth to one-half of patients, with small-vessel type (palpable physician must confirm the diagnosis histologically, determine the extent purpura) lesions being the most common manifestation [29]. These lesions of the disease process, and search for underlying disease. may occur due to a ‘‘spillover’’ of circulating immune complexes into post- Confirmation of the clinical diagnosis histologically is complicated by capillary venules. This is at least part of the reason for the early confusion in the tendency of patients to present to the dermatologist with older lesions classification of vasculitis with failure to distinguish small-vessel necrotizing and/or after aggressive systemic therapy. A commitment to eventual histo- vasculitis and polyarteritis nodosa. The more diagnostic cutaneous lesions logic confirmation and patience are necessary to ‘‘catch the right lesion at of which suggest larger vessel (e.g., muscular artery) involvement on the right time’’ to demonstrate leukocytoclastic vasculitis histologically. clinical examination are large ‘‘punctate’’ cutaneous ulcers, digital Systemic manifestations are not uncommon in the patient presenting gangrene, or livedo reticularis with ulcerating nodules (Fig 2). to the dermatologist. The wide array of signs, symptoms, and possible Systemic involvement can include renal disease with arterial target organs for circulating immune complex – mediated injury have hypertension, which occurs in three-fourths of patients and is the been reviewed. A complete history and physical examination as well as primary cause of death in patients with polyarteritis nodosa [30]. screening laboratory tests are required for patients with small-vessel Dysrythmias, cardiac failure, and cardiac infarction may also prove fatal necrotizing vasculitis. The dermatologist may often wish to work in [31]. Ocular, gastrointestinal, central and peripheral nervous system, and conjunction with the patient’s primary-care physician or an appropriate arthritic complications are the most frequent other manifestations. pediatric or medical subspecialist to achieve this end. Evaluation should Panarteritis of muscular arteries with secondary aneurysmal changes be directed at the systems that can be affected in this disease. Urinalysis are the typical histologic features [32,33]. Not only are the ‘‘lesions and renal function testing are particularly relevant. with lifespans’’ issues discussed above relevant, but histopathologic The underlying cause of small-vessel necrotizing vasculitis is detected confirmation of the diagnosis of polyarteritis nodosa is further compli- in only 39–61% of patients [13]. One should realize that absolute proof of cated by the reduced accessibility of muscular arteries to skin biopsy, by etiology for a given agent is difficult. Even if immunoblotting techniques the occurrence of the diagnostic lesion proximal to the site of cutaneous identify a specific antigen in association with circulating immune infarction, and by the urgency of need for treatment. Arteriographic complexes in the circulation and the same antigen is detected by demonstration of aneurismal changes in renal or mesenteric arteries can immunoperoxidase or other techniques in tissue, cause and effect is not be diagnostic if histologic confirmation is not possible. unequivocally proved. Rather than memorizing a list of implicated Most of the underlying causes outlined for small-vessel necrotizing etiologic agents, it might be easiest to think of possible causes as falling vasculitis are also relevant for polyarteritis nodosa. Hepatitis B might be a into three categories: drugs, infectious agents, or diseases associated with particularly relevant cause [34]. immune complexes. Examples of implicated drugs include aspirin, Therapy with systemic corticosteroids only improved the 5-year penicillin, thiazides, and sulfonamides [13]. Examples of the most accepted survival in this disease to 50%. Cyclophosphamide therapy has greatly associated infectious etiologic agents include streptococcal species, improved 5-year survival to the 70–90% range. Hepatitis B, and Mycobacterium tuberculosis [13]. Disease associated with immune complexes is a designation to include conditions such as Polyarteritis Nodosa – Benign Cutaneous Form A benign cutaneous form various malignancies, collagen vascular diseases (especially systemic lupus of polyarteritis nodosa characterized by painful, ulcerating cutaneous erythematosus, childhood dermatomyositis, and rheumatoid arthritis), nodules surrounding a necrotizing livedo reticularis pattern has been inflammatory bowel disease, and chronic active hepatitis [13]. described [35]. Lesions occur primarily on the extremities. Histopathologic A discussion of the therapeutic approach to the patient with small- findings in the skin are identical to those seen in the systemic form of vessel necrotizing vasculitis is beyond the scope of this review. No polyarteritis nodosa [36]. Although the disease is not life threatening, systemic or topical therapy has been subjected to the scrutiny of a systemic therapy is often undertaken due to the painful nature of the lesions. prospective placebo-controlled, double-blind study. The disease may The incidence and exact relationship of benign cutaneous polyarteritis follow an acute, chronic, or relapsing course [27] and may be limited to nodosa to the systemic form of the disease await further clarification. the skin without progression to systemic disease [28]. Cutaneous disease alone may be left untreated or agents such as oral antibiotics, colchicine, Granulomatous Vasculitis — Wegener’s Granulomatosis Wegener’s or sulfones may be used. Treatment for systemic involvement can include granulomatosis is a rare, multisystem disease characterized by a systemic corticosteroids (single dose, split dose, or pulse regimen), low- necrotizing granulomatous vasculitis. The upper respiratory tract and dose weekly methotrexate, azathioprine, cyclophosphamide, or even kidneys are primary sites of involvement [37]. The classic cutaneous cyclosporine. lesions are pyoderma gangrenosum-like lesions that may occur anywhere VOL. 100, NO. 1, SUPPLEMENT, JANUARY 1993 CLASSIFICATION OF VASCULITIS 109S

but are particularly suggestive of the diagnosis when located in a periorificial distribution [38,39]. Palpable purpuric lesions are also Table IV. Selected Other Vessel-Based Inflammatory common, as they are in polyarteritis nodosa. These lesions result from Dermatoses post-capillary venular vasculitis. I. Neutrophilic vascular reactions Systemic involvement is often heralded by necrotizing granulo- matous lesions of the upper respiratory tract. The nose, nasopharynx, A. Sweet’s syndrome tongue, trachea, and bronchi may be affected. Focal necrotizing B. Pustular vasculitis glomerulonephritis with extra glomerular granulomas is another classic feature. Antineutrophil cytoplasmic antibody may have a special role in 1. Behcet’s disease diagnosis [40]. 2. Bowel-associated dermatosis arthritis syndrome Survival prior to recent therapeutic advances was as low as 10% at 2 years. Newer regimens using cyclophosphamide and prednisone have 3. Idiopathic type resulted in up to 90% 5-year survival rates and to apparent cures [37]. C. Not all centers support quite such high success rates [41]. D. Other Granulomatous Vasculitis — Allergic Granulomatosis of Churg and Strauss Churg and Strauss separated allergic granulomatosis from 1. Familial Mediterranean fever polyarteritis nodosa in the early 1950s. Patients usually have a history 2. Selected disseminated infections of chronic asthma. They develop pulmonary infiltrates and a peripheral blood eosinophilia that may be in the 10–20% range. Small arteries and E. Pyoderma gangrenosum venules are affected by a vasculitis and palisading granulomas surround necrotic areas of connective tissue. Classically, involvement of two or more non-pulmonary organs is II. Lymphocytic vascular reactions required for diagnosis. Cutaneous findings usually include lesions A. Erythema multiforme associated with larger-vessel vasculitis such as cutaneous ulcers and subcutaneous nodules but, as with the other larger-vessel vasculitides, B. Chilblains (pernio) palpable purpura due to post-capillary venular involvement can also be seen. Up to 70% of patients have cutaneous lesions [42,43]. C. Pityriasis lichenoides acuta (PLEVA) Systemic corticosteroids are a mainstay of therapy. A second im- D. Some infections munosuppressive agent may be required [42,43]. The prognosis for untreated patients is generally better than that for polyarteritis nodosa or E. Some insect bite reactions Wegener’s granulomatosis. F. Annular erythemas Granulomatous Vasculitis — Lymphomatoid Granulomatosis Lympho- G. Pigmented purpuric eruptions matoid granulomatosis is a systemic disorder that represents an H. Other angioinvasive lymphohistiocytic process that involves the lungs but can affect virtually any organ, especially the central nervous system, kidneys, and the skin. The skin may be affected in 20% of patients [44,45]. The diagnosis can be confirmed with skin biopsy. Atypical cells may show bizarre cytologic features. Cyclophosphamide and prednisone may produce long-term remission [46]. A significant percentage of patients of rheumatoid arthritis [51], systemic lupus erythematosus [52], and develop widespread lymphoma. juvenile dermatomyositis [53].

Giant Cell Arteritis — Temporal Arteritis Large or medium-sized arteritis Nodular Vasculitis Nodular vasculitis was originally called erythema in the temporal region are the most common site for giant cell arteritis, induratum. Patients develop red, indurated plaques on the lower legs. which can be unilateral or bilateral. Elderly Caucasian women are primarily Older lesions may suppurate. Vasculitis of a subcutaneous artery or affected. Fever, headache, polymyalgia rheumatica, anemia, and elevated vein is found in the center of an area of lobular panniculitis. Although erythrocyte sedimentation rate are common features [47]. The classic initially described in patients with tuberculosis, a host of underlying cutaneous lesion is scalp -ation [48]. Retinal arteritis can lead to causes including drugs, infections, or diseases associated with immune blindness. The histopatho-logic features include a panarteritis with multi- complexes are now considered as possible underlying causes of nodular nucleated giant cells. Systemic corticosteroid therapy is often required. vasculitis [54].

Giant Cell Arteritis — Takayasu’s Disease Takayasu’s arteritis is a chronic VASCULITIS-RELATED SYNDROMES arteritis that affects the aorta and its main branches. Systemic features may Selected other vessel-based inflammatory dermatoses sometimes con- be widespread and depend on the location and severity of involvement of fused with vasculitis are listed in Table IV. The designation vasculitis the vascular bed that is affected [49]. Cutaneous lesions include palpable should not be applied to these conditions despite inflammation of purpura, ulcers, or pyoderma gangrenosum-like lesions [50]. Granuloma- vessels, which characterizes these conditions histologically. tous arteritis followed by fibrosis and stenosis is seen histologically. Systemic prednisone (often with a second immunosuppressive agent) is the principle therapy. Surgical treatment may also be required. SUMMARY The classification of vasculitis remains controversial in 1991, with Vasculitis in Patients with Collagen Vascular Diseases A thorough various authors struggling with how to incorporate histopathologic discussion of vasculitis in collagen vascular diseases is beyond the scope features, size of affected blood vessels, etiology, and other factors in their of this review. These diseases are possible underlying causes of small- classification schemas. Dr. James Gilliam was a significant player in the vessel necrotizing vasculitis as discussed above. Larger vessel involve- attempt to classify vasculitis. We can hope that a new generation of basic ment may be suggested clinically by large cutaneous ulcers, digital and clinical investigators, many influenced by Jim Gilliam, can achieve a gangrene, necrosing livedo reticularis, or pyoderma gangrenosum–like better understanding of the pathogenesis of various vasculitis-related lesions. Other causes of peripheral gangrene and the other cutaneous syndromes and that this understanding will facilitate future classification. findings mentioned must be excluded. Emboli of various types, sludging syndromes (e.g., cryoglobulins or macroglobulins), and vasospasm must be excluded in patients with collagen vascular disorders who develop these cutaneous findings before a diagnosis of large-vessel vasculitis is REFERENCES accepted. Histologic confirmation of the diagnosis of vasculitis should 1. Gilliam JN, Smiley JD: Cutaneous necrotizing vasculitis and related always be sought. Larger vessel vasculitis is a particularly relevant feature disorders. Ann Allergy 37:328–329, 1976 110S JORIZZO THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

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