Vasculitis

Vasculitis is defined as inflammation of blood vessels. Vasculitis may be confined to the skin; however, the majority of cases of cutaneous vasculitis are part of multisystemic disorders that in addition to involving skin also involve other organ systems. Classification is problematic due to the lack of standardization and definition. The most accepted classification scheme for systemic vasculitis syndromes is based on the size of the involved blood vessels, as shown in Table 15-1. Subclassification of these syndromes is based on clinical and histologic criteria that have been determined to be suggestive of a specific disorder. The American College of Rheumatology Subcommittee on Classification of Vasculitis has determined classification criteria for many of these disorders (see Table 15-1). This classification system is excellent for systemic vasculitis but it omits some forms of vasculitis that are confined to the skin.

Yes. Antimyeloperoxidase antibodies directed against cytoplasmic components of neutrophils have been used to help identify patients with segmental necrotizing glomerulonephritis and some types of systemic vasculitis. Antibodies directed against serine proteinase 3 that is found in the cytoplasm of neutrophils (c-ANCA) have been detected in 66% to 90% of patients with active Wegener’s granulomatosis. Patients with pulmonary-renal syndrome who have antibodies directed against cytoplasmic myeloperoxidase, in neutrophils that produce a peripheral antineutrophil cytoplasmic pattern (p-ANCA), are most likely to have microscopic polyangiitis.

Table 15-1. Classification of Systemic Vasculitides

VESSEL SIZE	VASCULITIC SYNDROME
Large vessel vasculitis	Giant cell (temporal) arteritis Takayasu arteritis
Medium vessel vasculitis	Polyarteritis nodosa (classic PAN) Kawasaki disease
Small vessel vasculitis	Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis (polyarteritis) Henoch-Schönlein purpura Essential cryoglobulinemic vasculitis Cutaneous leukocytoclastic vasculitis

Adapted from Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides: proposal of an International Consensus Conference, Arthritis Rheum 37:187–192, 1994. Adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis, 1994.

Harper L, Savage CO: Pathogenesis of ANCA-associated systemic vasculitis, J Pathol 190:349–359, 2000.

Patients with leukocytoclastic vasculitis, also referred to as leukocytoclastic angiitis and allergic or necrotizing vasculitis, present with characteristic purpuric papules, most frequently involving the extremities, known as palpable purpura (Fig. 15-1). Biopsies of cutaneous leukocytoclastic vasculitis demonstrate an intense perivascular infiltrate composed of intact and fragmented neutrophils (nuclear dust) that focally infiltrate the vessel wall producing fibrinoid changes and/or necrosis. These damaged vessels frequently demonstrate extravasation of erythrocytes and may also demonstrate thrombosis.

Kluger N, Francès C: Cutaneous vasculitis and their differential diagnoses, Clin Exp Rheumatol 27(1 Suppl 52):S124–S138, 2009.

• Malignancies: Lymphomas, colonic carcinoma, hairy cell leukemia, multiple myeloma, lung cancer, renal cell carcinoma, prostate cancer, breast cancer, head and neck cancer

In the majority of cases of leukocytoclastic vasculitis, the precipitating antigen cannot be identified.

Veraldi S, Mancuso R, Rizzitelli G, et al: Henoch-Schönlein syndrome associated with human parvovirus B19 primary infection, Eur J Dermatol 9:232–233, 1999.

Henoch-Schönlein purpura is a variant of leukocytoclastic vasculitis characterized by the deposition of immune complexes containing IgA in small vessels with the most commonly affected vessels being in the skin, kidney, and gastrointestinal tract. The precipitating antigen is not identifiable in all cases but many cases are associated with streptococcal or viral infections. It is usually seen in young children although any age can be affected. The classic four components of the syndrome include cutaneous palpable purpura, colicky abdominal pain, arthralgias and/or arthritis and kidney involvement.

González LM, Janniger CK, Schwartz RA: Pediatric Henoch-Schönlein purpura, Int J Dermatol 48:1157–1165, 2009.

Acute hemorrhagic edema of infancy, which also called “cockade purpura,” is also an IgA-mediated immune complex leukocytoclastic vasculitis that affects small cutaneous vessels. This variant almost always affects young children (median age is 11 months), and like Henoch-Schönlein purpura, it is usually associated with a preexisting upper respiratory infection. It differs in that the primary cutaneous clinical lesions are typically indurated, edematous plaques with variable hemorrhage that are less likely to ulcerate. The lesions frequently affect the head and neck region and extremities (Fig. 15-2). The children typically do not demonstrate significant involvement of the gastrointestinal tract, joints or kidneys and do not develop permanent sequelae.

Fiore E, Rizzi M, Ragazzi M, et al: Acute hemorrhagic edema of young children (cockade purpura and edema): a case series and systematic review, J Am Acad Dermatol 59:684–695, 2008.

Cryoglobulins are abnormal circulating IgG and IgM immunoglobulins that precipitate at low temperatures and redissolve at 37° C. Cryoglobulins are frequently found in patients with paraproteinemias, such as multiple myeloma and macroglobulinemia. Mixed cryoglobulinemia, with more than one antibody class involved, has been reported in systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and hepatitis B and C infection.

Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al: Cryglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center, Medicine (Baltimore) 80:252–262, 2001.

Churg-Strauss syndrome (allergic granulomatosis) is an uncommon multisystemic vasculitis that is characterized with asthma, eosinophilia, extravascular granulomas, and positive ANCA titers. The main systemic features of Churg-Strauss syndrome are summarized in Table 15-2. Pulmonary involvement and eosinophilia helps discriminate Churg-Strauss syndrome from polyarteritis nodosa. The primary cutaneous lesions most commonly consist of palpable purpura involving the extremities, although some patients may also demonstrate fixed papules or plaques or even subcutaneous nodules. Cutaneous lesions have been reported in 45% to 70% of patients. Cutaneous involvement should be considered an important feature when present; biopsies in addition to demonstrating vasculitis of small blood vessels, frequently demonstrate large numbers of eosinophils and, less commonly, may demonstrate extravascular granulomatous inflammation.

There are four criteria for establishing the diagnosis of Wegener’s granulomatosis:

Table 15-2. Clinical Features of Churg-Strauss Syndrome

FINDING	SENSITIVITY
Asthma	100%
Blood eosinophilia >10%	95%
Paranasal sinus abnormalities	86%
Mononeuropathy or polyneuropathy	75%
Pulmonary infiltrates	40%
Extravascular (perivascular) eosinophils	14%
History of seasonal allergies	−

The presence of two or more of the four criteria gives a diagnostic sensitivity of 88% and a specificity of 92%. The majority of patients with active disease also demonstrate a positive c-ANCA; however, although supportive of this diagnosis, it is not specific because patients with Churg-Strauss syndrome, microscopic polyarteritis, and polyarteritis nodosa may also demonstrate elevated c-ANCA titers.

de Groot K, Gross WL: Wegener’s granulomatosis, Lupus 7:285–291, 1998.

Simply remember the mnemonic ROUGH:

Hemoptysis during illness has been added as a fifth criterion.

• Leukocytoclastic vasculitis (Fig. 15-3A)

• Papules (Fig. 15-3B)

• Ulcerative lesions (Fig. 15-3C)

• Pyoderma gangrenosum

None of these cutaneous findings is specific for Wegener’s granulomatosis.

It is often difficult to distinguish between Wegener’s granulomatosis and Churg-Strauss syndrome due to the presence of nasal, sinus, and pulmonary involvement in both diseases and the fact that all the classic features are rarely found in a single patient. There are many situations in which the features of systemic vasculitides overlap, and these are referred to as overlap vasculitis syndromes, similar to the overlap syndromes reported for other rheumatologic conditions.

The use of cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) for differentiating between these two disorders is helpful (c-ANCA is usually present in high titers in Wegener’s but not in Churg-Strauss), but is not included in the current diagnostic criteria for either syndrome. The presence or absence of other features should confirm the diagnosis in most cases (Table 15-3).

Systemic corticosteroids are the mainstay for treatment of most forms of systemic vasculitis, and it is the most common treatment used in Churg-Strauss syndrome. Corticosteroids alone are often not effective in Wegener’s granulomatosis, and most patients require cyclophosphamide in combination with corticosteroids for effective control. This is one of the most important reasons for distinguishing between these two disorders.

Koldingsnes W, Gran JT, Omdal R, Husby G: Wegener’s granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide, Br J Rheumatol 37:659–664, 1998.

Stein SL, Miller LC, Konnikov N: Wegener’s granulomatosis, Pediatr Dermatol 15:352–356, 1998.

Kidneys, heart, liver, gastrointestinal (GI) tract, and peripheral nerves. PAN, in its classic form, is a multisystem, segmented necrotizing inflammation of small- and medium-sized muscular arteries. Signs and symptoms are nonspecific and constitutional, reflecting the organ involvement. Pulmonary arteries are typically not involved. The mean age of onset is 48 years, with a male:female ratio of about 4:1. Diagnosis is established by demonstrating vasculitic changes on biopsy of involved organs or by demonstrating typical aneurysms of medium-sized vessels on angiography.

Ishiguro N, Kawashima M: Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a review of the published work, J Dermatol 37:85–93, 2010.

As the name implies, this is polyarteritis nodosa that is essentially confined to the skin, although it is not uncommon for patients to experience fever, arthralgias, and mysositis. The cutaneous lesions are most commonly located on the lower extremity and manifest as painful subcutaneous nodules that may resemble erythema nodosum, or demonstrate a characteristic “star-burst” appearance (Fig. 15-4). This diagnostic appearance is due the arteritis following the bifurcations of the small- and medium-sized arteries. Secondary changes that may be present include associated livedo reticularis and ulceration. In contrast to systemic polyarteritis nodosa, peripheral gangrene is not seen. Laboratory studies are generally normal except for variable mild leukocytosis and an elevated erythrocyte sedimentation rates (ESR).

The distinguishing feature for these two systemic disorders is primarily based on the size of the vessel that is affected. Patients with microscopic polyangiitis have involvement of small arterioles, whereas individuals with classic PAN have involvement of medium-sized arteries. Some authors consider microscopic polyarteritis a subset of PAN, although others consider it a distinct form of vasculitis.

Homas PB, David-Bajar KM, Fitzpatrick JE, et al: Microscopic polyarteritis: report of a case with cutaneous involvement and antimyeloperoxidase antibodies, Arch Dermatol 128:1223–1228, 1992.

Both disorders affect large vessels. Takayasu’s arteritis manifests with a progressive granulomatous inflammation of the aorta and its major branches and most frequently afflicts patients aged <50 years. Giant cell arteritis usually affects patients >50 years old with a granulomatous vasculitis that can also involve the aorta and its major branches. However, giant cell arteritis shows a predilection for the extracranial branches of the carotid artery, particularly the temporal artery, which can progress to visual loss and blindness if not treated with systemic steroids. Patients with giant cell arteritis may occasionally demonstrate unilateral alopecia, cutaneous ulceration or atrophy of the scalp due to loss of the blood supply to the skin.

Nordborg C, Nordborg E, Petursdottir V: Giant cell arteritis. Epidemiology, etiology, and pathogenesis, APMIS 108:713–724, 2000.

Erythema elevatum diutinum is a rare form of small vessel vasculitis that is confined to the skin. This chronic disorder is characterized by persistent, elevated, erythematous plaques and/or nodules, with a predilection for overlying joint spaces, such as the fingers, wrists, elbows, knees, ankles, and toes (Fig. 15-5). The lesions are usually painful. Biopsies of developed lesions demonstrate a chronic leukocytoclastic vasculitis with extensive tissue fibrosis. There may be an associated IgA or, less commonly, an IgG monoclonal gammopathy (immune complex disease) and an association with inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, streptococcal infection, IgA monoclonal gammopathy, multiple myeloma, myelodysplasia, celiac disease, relapsing polychondritis, and human immunodeficiency virus (HIV) infection. Some patients have shown a dramatic response to dapsone.

Farley-Loftus R, Dadlani C, Wang N, et al: Erythema elevatum diutinum, Dermatol Online J 14(10):13, 2008.

Yes—granuloma faciale, which is an uncommon, chronic, benign, small vessel vasculitis that most commonly affects middle-aged adults. While sun-exposed skin on the face is the area most commonly affected, it has also been reported to appear on extrafacial sites including the trunk and upper and lower extremities. The lesions are characteristically solitary but can be multiple. The primary lesion is a papule, nodule, or plaque that varies in size from millimeters to several centimeters (Fig. 15-6). The overlying epidermis is characteristically smooth with the follicular orifices being accentuated producing a characteristic “peau de orange” appearance. The color is highly variable and varies from yellowish to amber to brown to red to violaceous. Most lesions are asymptomatic, although occasional patients may complain of mild pruritus or burning. Once present, the lesions typically persist for years or decades, and progressive enlargement of lesions is not uncommon. The pathogenesis of this peculiar form of cutaneous vasculitis is unknown.

Thiyanaratnam J, Doherty SD, Krishnan B, Hsu S: Granuloma faciale: case report and review, Dermatol Online J 15(12):3, 2009.