Classification of Vasculitis

Transcription

1 106S Classification of Vasculitis 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 necrotizing vasculitis presented at The University of Texas Southwestern Medical Center by James W. Gilliam in 1976 dealt with the classification of necrotizing vasculitis. Aspects of this presentation have been published (Table I) [1]. The historical context of Gilliam s classification is important given the confounding array of classification schemas that preceded (and followed!) it. The classification of vasculitis remains frustratingly controversial today. Zeek was the first to incorporate a clinicopathologic assessment based on the size of the vessel involved in the inflammatory process in his classification of necrotizing vasculitis in 1952 [2]. Zeek s schema included hypersensitivity arteritis, allergic granulomatosis, Wegener s granulomatosis, polyarteritis nodosa, and giant cell arteritis [3]. Other schemas were also proposed [4,5]. Winkelmann has highlighted issues that can be considered in the development of classification schema of vasculitis, including clinical classification, systemic versus cutaneous, muscular-vessel versus smallvessel disease, histopathologic features including leukocytoclastic vasculitis versus lymphocytic vasculitis, and vasculitis showing mixed or granulomatous histology [6]. He also reviewed laboratory vasculitis in which findings obtained during laboratory screening of the patient with vasculitis can be used to develop the classification schema and also etiologic factors, which can be relevant to classification when they are known [6]. A number of alternative classification systems have been proposed since Gilliam s Grand Rounds. Most of these have similarities with Gilliam s proposed classification, while each proponent has struggled with various issues raised by Winkelmann [7 12]. Particularly disturbing are the recently published American College of Rheumatology (ACR) criteria for the classification of vasculitis [12]. Although the attempt to develop diagnostic criteria by analyzing clinical variables in a large patient population and then testing these criteria in other patient populations is laudable, common sense is sometimes sacrificed in favor of criteria that are simply reproducible. Particularly obvious problems are the attempt to codify the histologic findings of small-vessel ( hypersensitivity ) vasculitis. Fourteen biopsy criteria are listed! The use of concepts such as maculopapular rash, medication at onset, and eosinophils on biopsy as criteria seem particularly inappropriate to many dermatologists, as does an entirely separate classification for Henoch- Schonlein purpura [12]. Table II illustrates the ACR criteria selected for the diagnosis of hypersensitivity vasculitis, which corresponds to smallvessel necrotizing vasculitis. It is easy to criticize, however; the development of a working classification that is clinically relevant, is workable by various specialists, and addresses clinical features, vessel size, histopathologic features, laboratory features, and underlying causes of vasculitis is a goal that remains elusive. An attempt at classification that represents an update of the classification presented by Gilliam is presented (see Table III). Small-vessel necrotizing vasculitis is emphasized in the discussion that follows. Department of Dermatology, Bowman Gray School of Medicine, Winston- Salem, North Carolina, USA Reprint requests to: Dr. Joseph L. Jorizzo, Department of Dermatology, Bowman Gray School of Medicine, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC SMALL VESSEL NECROTIZING VASCULITIS (NECROTIZING VENULITIS) The hallmark of small-vessel necrotizing vasculitis is the diagnostic histopathologic finding of leukocytoclastic vasculitis including endothelial cell swelling, neutrophilic invasion of blood-vessel walls, leukocytoclasia (neutrophilic nuclear karyorrhexis), extravasation of erythrocytes, and fibrinoid necrosis of blood vessel walls [14]. This process has been shown to affect post capillary venules [15,16]. This entity has been proposed as a cutaneous model for circulating immune complex mediated, neutrophil-induced vessel damage [17]. At the same time, it is important to realize that the histologic findings of leukocytoclastic vasculitis can occur in settings other than those due to circulating immune complexes such as with septic or less commonly with other emboli, with repeated cold injury, next to cutaneous ulcers, or in associations with other cutaneous insults. Clinical Aspects Although a spectrum of cutaneous necrotizing lesions can be seen in patients with small-vessel necrotizing vasculitis, the hallmark lesion is the palpable purpuric papule. These lesions occur in crops, generally on dependent sites (Fig 1). Lesions are usually less than 1 cm in diameter, and they progress from erythema-tous macules to purpuric papules, occasionally becoming confluent producing plaques that may ulcerate. Lesions may be moderately symptomatic with pruritus or pain. Associated, mild, dependent edema can also be symptomatic. Serum sickness like signs and symptoms such as arthralgias, arthritis, myalgias, and fever are often associated. Similar clinicopathologic lesions may occur in internal locations also, presumably due to circulating immune complex mediated vessel damage at those sites. Classic manifestations/locations include proteinuria and/or hematuria/kidney glomeruli; focal or diffuse, central or peripheral neurologic manifestations/nervous system; polyarthritis/synovia; abdominal pain and/or bleeding/gastrointestinal tract; pleuritis and pleural effusion/pleura; signs and symptoms of pericardial effusion/pericardium; and other manifestations [13,17]. Most subgroups of small-vessel necrotizing vasculitis listed in Table II are characterized by the types of lesions listed above. Adult patients with IgA-associated small-vessel necrotizing venulitis (Henoch-Schonlein purpura) have, in addition, been noted to have distinctive plaque-like lesions in a livedoid pattern [18]. Urticarial vasculitis is characterized by wheals, the individual lesions of which persist for more than 24 h. Classic lesions burn more than itch and leave residual purpura after resolution. Lesions are distributed randomly rather than on dependent sites [19]. Erythema elavatum diutinum is characterized by erythematous yellowish-brown plaques that classically occur over the knuckles or elbows. Lesions are usually chronic [20]. Nodular vasculitis is characterized by distinct nodules that represent a suppurative panniculitis 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. Rheumatoid nodules are subcutaneous, firm nodules that, like erythema elevatum diutinum, affect pressure sites [22]. The histologic findings reveal palisading granuloma formation, a feature that has recently been seen in association with leukocytoclastic vasculitis in rheumatoid papules [23] X/93/$06.00 Copyright & 1993 by The Society for Investigative Dermatology, Inc.

2 VOL. 100, NO. 1, SUPPLEMENT, JANUARY 1993 CLASSIFICATION OF VASCULITIS 107S Table I. Classification of Necrotizing Vasculitides by Gilliam and Fink Presented at Medical Grand Rounds on September 9, 1976 at University of Texas Southwestern Medical Center I. Leukocytoclastic Vasculitis (hypersensitivity angiitis or allergic vasculitis) A. Schonlein-Henoch purpura B. Hypocomplementemic vasculitis C. Essential mixed cryoglobulinemia D. Other disease-related dermal vasculitides II. Rheumatic Vasculitis A. Systemic lupus erythematosus B. Rheumatoid vasculitis C. Scleroderma D. Dermatomyositis E. Acute rheumatic fever III. Granulomatous Vasculitis A. Churg and Strauss allergic granulomatous angiitis B. Wegener s granulomatosis C. Limited Wegener s IV. Polyarteritis Nodosa A. Classic type B. Limited type (skin and muscle) C. Hepatitis B antigen associated vasculitis D. Vasculitis in drug addicts E. Vasculitis following serous otitis media Table III. Proposed Working Classification of Vasculitis I. Small-vessel necrotizing vasculitis A. Necrotizing venulitis B. Henoch-Scholein purpura C. Essential mixed cryoglobulinemia D. Waldenstom s hypergammaglobulinemic purpura E. Associated with collagen vascular disease F. Urticarial vasculitis G. Erythema elevatum diutinum H. Rheumatoid nodules I. Reactive leprosy J. Septic vasculitis II. Larger-vessel necrotizing vasculitis A. Polyarteritis nodosa 1. Benign cutaneous form 2. Systemic form B. Granulomatous vasculitis 1. Wegener s granulomatosis 2. Allergic granulomatosis 3. lymphomatoid granulomatosis C. Giant cell arteritis 1. Temporal arteritis 2. Takayasu s disease D. Larger-vessel vasculitis with collagen vascular disease E. Nodular vasculitis V. Giant Cell Arteritis A. Temporal arteritis B. Polymyalgia rheumatica C. Takayasu s disease Table II American College of Rheumatology Criteria For Hypersensitivity Vasculitis (Traditional Format) a 1. Age at disease onset 416 years 2. Medication at disease onset 3. Palpable purpura 4. Maculopapular rash 5. Biopsy including arteriole and venule with histologic changes showing granulocytes in a perivascular or extravascular location a At least three of five criteria must be present. The presence of three of five criteria was associated with a specificity of 83.9% and a sensitivity of 71.0% [12]. Lesions of septic vasculitis tend to be acrally located (e.g., finger-tips) and may occasionally be wedge shaped. They may be papulopustular. Lesions are generally not as numerous as those in the patient with the usual variety of small-vessel necrotizing vasculitis [24]. Histopathologic Aspects Histopathologic features of small-vessel necrotizing vasculitis are characterized as leukocytoclastic vasculitis as described above [25]. Immunoreactants (IgG, IgM, IgA, C 3,C 4,C 1 and C q ) and fibrin can inconsistently be demonstrated in dermal vessel on direct immunofluorescence microscopy, although this finding is non-specific and is not of much use clinically [13]. The same can be concluded about the histamine trap test originally described by Braverman and Yen in which lesions are induced by intradermal histamine injection [15]. Immunoelectron microscopic studies have demonstrated that the post-capillary venule is the site of pathology in this disease and immunoreactants are demonstrable in dermal vessels [26]. The characteristic histopathologic features of small-vessel necrotizing vasculitis are transient. Therefore, confirmation of the clinical diagnosis histopathologically can be difficult. Old lesions (older than h) or treated lesions no longer show the required changes of leukocytoclastic vasculitis, but rather show non-specific lymphocytic perivascular changes [17]. The failure to appreciate that vasculitic lesions have lifespans and the tendency to view a pathology report as an interpretation of a static event have, in my view, led to much of the confusion that exists in classifications of vasculitis based on histopathology, including some of the confusion in the new ACR criteria [12].

3 108S JORIZZO THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Figure 1. Palpable purpuric papules in an acral distribution suggested a diagnosis of small-vessel necrotizing vasculitis. Biopsy of a lesion revealed the confirmatory finding of leukocytoclastic vasculitis. Patient Evaluation A three-stage approach to evaluation of the patient with suspected small-vessel necrotizing vasculitis can be employed. The physician must confirm the diagnosis histologically, determine the extent of the disease process, and search for underlying disease. Confirmation of the clinical diagnosis histologically is complicated by the tendency of patients to present to the dermatologist with older lesions and/or after aggressive systemic therapy. A commitment to eventual histologic confirmation and patience are necessary to catch the right lesion at the right time to demonstrate leukocytoclastic vasculitis histologically. Systemic manifestations are not uncommon in the patient presenting to the dermatologist. The wide array of signs, symptoms, and possible target organs for circulating immune complex mediated injury have been reviewed. A complete history and physical examination as well as screening laboratory tests are required for patients with small-vessel necrotizing vasculitis. The dermatologist may often wish to work in conjunction with the patient s primary-care physician or an appropriate pediatric or medical subspecialist to achieve this end. Evaluation should be directed at the systems that can be affected in this disease. Urinalysis and renal function testing are particularly relevant. The underlying cause of small-vessel necrotizing vasculitis is detected in only 39 61% of patients [13]. One should realize that absolute proof of etiology for a given agent is difficult. Even if immunoblotting techniques identify a specific antigen in association with circulating immune complexes in the circulation and the same antigen is detected by immunoperoxidase or other techniques in tissue, cause and effect is not unequivocally proved. Rather than memorizing a list of implicated etiologic agents, it might be easiest to think of possible causes as falling into three categories: drugs, infectious agents, or diseases associated with immune complexes. Examples of implicated drugs include aspirin, penicillin, thiazides, and sulfonamides [13]. Examples of the most accepted associated infectious etiologic agents include streptococcal species, Hepatitis B, and Mycobacterium tuberculosis [13]. Disease associated with immune complexes is a designation to include conditions such as various malignancies, collagen vascular diseases (especially systemic lupus erythematosus, childhood dermatomyositis, and rheumatoid arthritis), inflammatory bowel disease, and chronic active hepatitis [13]. A discussion of the therapeutic approach to the patient with smallvessel necrotizing vasculitis is beyond the scope of this review. No systemic or topical therapy has been subjected to the scrutiny of a prospective placebo-controlled, double-blind study. The disease may follow an acute, chronic, or relapsing course [27] and may be limited to the skin without progression to systemic disease [28]. Cutaneous disease alone may be left untreated or agents such as oral antibiotics, colchicine, or sulfones may be used. Treatment for systemic involvement can include systemic corticosteroids (single dose, split dose, or pulse regimen), lowdose weekly methotrexate, azathioprine, cyclophosphamide, or even cyclosporine. Figure 2. Cutaneous ulceration in a pattern suggestive of larger vessel vasculitis in a patient who proved to have systemic polyarteritis nodosa. LARGER VESSEL VASCULITIS Polyarteritis Nodosa Systemic Form Systemic polyarteritis nodosa is a multisystem disease that can be life threatening. Cutaneous lesions occur in only one-fifth to one-half of patients, with small-vessel type (palpable purpura) lesions being the most common manifestation [29]. These lesions may occur due to a spillover of circulating immune complexes into postcapillary venules. This is at least part of the reason for the early confusion in classification of vasculitis with failure to distinguish small-vessel necrotizing vasculitis and polyarteritis nodosa. The more diagnostic cutaneous lesions of which suggest larger vessel (e.g., muscular artery) involvement on clinical examination are large punctate cutaneous ulcers, digital gangrene, or livedo reticularis with ulcerating nodules (Fig 2). Systemic involvement can include renal disease with arterial hypertension, which occurs in three-fourths of patients and is the primary cause of death in patients with polyarteritis nodosa [30]. Dysrythmias, cardiac failure, and cardiac infarction may also prove fatal [31]. Ocular, gastrointestinal, central and peripheral nervous system, and arthritic complications are the most frequent other manifestations. Panarteritis of muscular arteries with secondary aneurysmal changes are the typical histologic features [32,33]. Not only are the lesions with lifespans issues discussed above relevant, but histopathologic confirmation of the diagnosis of polyarteritis nodosa is further complicated by the reduced accessibility of muscular arteries to skin biopsy, by the occurrence of the diagnostic lesion proximal to the site of cutaneous infarction, and by the urgency of need for treatment. Arteriographic demonstration of aneurismal changes in renal or mesenteric arteries can be diagnostic if histologic confirmation is not possible. Most of the underlying causes outlined for small-vessel necrotizing vasculitis are also relevant for polyarteritis nodosa. Hepatitis B might be a particularly relevant cause [34]. Therapy with systemic corticosteroids only improved the 5-year survival in this disease to 50%. Cyclophosphamide therapy has greatly improved 5-year survival to the 70 90% range. Polyarteritis Nodosa Benign Cutaneous Form A benign cutaneous form of polyarteritis nodosa characterized by painful, ulcerating cutaneous nodules surrounding a necrotizing livedo reticularis pattern has been described [35]. Lesions occur primarily on the extremities. Histopathologic findings in the skin are identical to those seen in the systemic form of polyarteritis nodosa [36]. Although the disease is not life threatening, systemic therapy is often undertaken due to the painful nature of the lesions. The incidence and exact relationship of benign cutaneous polyarteritis nodosa to the systemic form of the disease await further clarification. Granulomatous Vasculitis Wegener s Granulomatosis Wegener s granulomatosis is a rare, multisystem disease characterized by a necrotizing granulomatous vasculitis. The upper respiratory tract and kidneys are primary sites of involvement [37]. The classic cutaneous lesions are pyoderma gangrenosum-like lesions that may occur anywhere

4 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 common, as they are in polyarteritis nodosa. These lesions result from post-capillary venular vasculitis. Systemic involvement is often heralded by necrotizing granulomatous lesions of the upper respiratory tract. The nose, nasopharynx, tongue, trachea, and bronchi may be affected. Focal necrotizing glomerulonephritis with extra glomerular granulomas is another classic feature. Antineutrophil cytoplasmic antibody may have a special role in diagnosis [40]. Survival prior to recent therapeutic advances was as low as 10% at 2 years. Newer regimens using cyclophosphamide and prednisone have resulted in up to 90% 5-year survival rates and to apparent cures [37]. Not all centers support quite such high success rates [41]. Granulomatous Vasculitis Allergic Granulomatosis of Churg and Strauss Churg and Strauss separated allergic granulomatosis from polyarteritis nodosa in the early 1950s. Patients usually have a history of chronic asthma. They develop pulmonary infiltrates and a peripheral blood eosinophilia that may be in the 10 20% range. Small arteries and 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 required for diagnosis. Cutaneous findings usually include lesions associated with larger-vessel vasculitis such as cutaneous ulcers and subcutaneous nodules but, as with the other larger-vessel vasculitides, palpable purpura due to post-capillary venular involvement can also be seen. Up to 70% of patients have cutaneous lesions [42,43]. Systemic corticosteroids are a mainstay of therapy. A second immunosuppressive agent may be required [42,43]. The prognosis for untreated patients is generally better than that for polyarteritis nodosa or Wegener s granulomatosis. Granulomatous Vasculitis Lymphomatoid Granulomatosis Lymphomatoid granulomatosis is a systemic disorder that represents an 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 develop widespread lymphoma. Giant Cell Arteritis Temporal Arteritis Large or medium-sized arteritis in the temporal region are the most common site for giant cell arteritis, which can be unilateral or bilateral. Elderly Caucasian women are primarily affected. Fever, headache, polymyalgia rheumatica, anemia, and elevated erythrocyte sedimentation rate are common features [47]. The classic cutaneous lesion is scalp ulcer-ation [48]. Retinal arteritis can lead to blindness. The histopatho-logic features include a panarteritis with multinucleated giant cells. Systemic corticosteroid therapy is often required. Giant Cell Arteritis Takayasu s Disease Takayasu s arteritis is a chronic arteritis that affects the aorta and its main branches. Systemic features may be widespread and depend on the location and severity of involvement of the vascular bed that is affected [49]. Cutaneous lesions include palpable purpura, ulcers, or pyoderma gangrenosum-like lesions [50]. Granulomatous 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. Vasculitis in Patients with Collagen Vascular Diseases A thorough discussion of vasculitis in collagen vascular diseases is beyond the scope of this review. These diseases are possible underlying causes of smallvessel necrotizing vasculitis as discussed above. Larger vessel involvement may be suggested clinically by large cutaneous ulcers, digital gangrene, necrosing livedo reticularis, or pyoderma gangrenosum like lesions. Other causes of peripheral gangrene and the other cutaneous 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 accepted. Histologic confirmation of the diagnosis of vasculitis should always be sought. Larger vessel vasculitis is a particularly relevant feature Table IV. Selected Other Vessel-Based Inflammatory Dermatoses I. Neutrophilic vascular reactions A. Sweet s syndrome B. Pustular vasculitis 1. Behcet s disease 2. Bowel-associated dermatosis arthritis syndrome 3. Idiopathic type C. Erythema nodosum D. Other 1. Familial Mediterranean fever 2. Selected disseminated infections E. Pyoderma gangrenosum II. Lymphocytic vascular reactions A. Erythema multiforme B. Chilblains (pernio) C. Pityriasis lichenoides acuta (PLEVA) D. Some infections E. Some insect bite reactions F. Annular erythemas G. Pigmented purpuric eruptions H. Other of rheumatoid arthritis [51], systemic lupus erythematosus [52], and juvenile dermatomyositis [53]. Nodular Vasculitis Nodular vasculitis was originally called erythema induratum. Patients develop red, indurated plaques on the lower legs. Older lesions may suppurate. Vasculitis of a subcutaneous artery or vein is found in the center of an area of lobular panniculitis. Although initially described in patients with tuberculosis, a host of underlying causes including drugs, infections, or diseases associated with immune complexes are now considered as possible underlying causes of nodular vasculitis [54]. VASCULITIS-RELATED SYNDROMES Selected other vessel-based inflammatory dermatoses sometimes confused with vasculitis are listed in Table IV. The designation vasculitis should not be applied to these conditions despite inflammation of vessels, which characterizes these conditions histologically. SUMMARY The classification of vasculitis remains controversial in 1991, with various authors struggling with how to incorporate histopathologic features, size of affected blood vessels, etiology, and other factors in their classification schemas. Dr. James Gilliam was a significant player in the attempt to classify vasculitis. 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