Vasculitis

General Features

Vasculitis is a feature of many immunologic diseases, but vasculitis can occur in a variety of idiopathic forms. Patients may report flu-like symptomatology early in the course of their disease. Common patient presentations are protean and include:

• Fever
• Weight loss
• Malaise
• Arthralgia (small or large joints)
• Myalgia

One or more of the immunologic hypersensitivity reactions (type I - anaphylaxis, type II - antibody dependent, complement mediated, type III - immune complex mediated, and type IV - cell mediated) may contribute to the inflammation. The pattern of vascular involvement and the nature of the inflammatory response help to characterize the different patterns of vasculitis. Many disease states can be accompanied by vasculitis, including:

• Autoimmune diseases
• Infections
• Drug reactions

Clinical Laboratory Testing

Clinical laboratory testing for antineutrophil cytoplasmic autoantibodies (ANCA) is helpful for diagnosis. By immunofluorescence microscopy, ANCA's can be divided into two major categories:

• cANCA - A cytoplasmic staining pattern which correlates with anti-proteinase 3 (anti-PR3) antibody

• pANCA - A perinuclear pattern of staining, which correlates with anti-myeloperoxidase antibody (anti-MPO)

The presence of cANCA (anti-PR3) is more indicative of Wegener's granulomatosis, whereas presence of pANCA (anti-MPO) more strongly suggests a vasculitis typical for polyarteritis, though pANCA can appear with other vasculitides as well as idiopathic crescentic glomerulonephritis.

Of course, a positive antinuclear antibody test (ANA) is helpful to determine if the underlying disease is autoimmune, such as systemic lupus erythematosus (SLE).

A simple sedimentation rate (sed rate) is non-specific for many types of inflammation, but a very high sed rate in conjunction with specific findings such as a tender temporal artery can be highly suggestive of giant cell arteritis.

Types of Vasculitis

Hypersensitivity vasculitis

Many autoimmune diseases that lead to formation of immune complexes, such as systemic lupus erythematosus (SLE) or its less severe variant with mainly skin involvment called discoid lupus erythematosus (DLE), can be associated with an acute vasculitis. The skin is often affected with other organs less commonly involved. Small arteries, capillaries, and venules are mainly affected. This pattern of vasculitis may also be seen with drug reactions and infections.

Histologically, there can be predominantaly a neutrophilic inflammatory reaction with leukocytoclasis (hence the term "leukocytoclastic vasculitis"). This leukocytoclasis results in leakage of red blood cells from vessels into surrounding tissues, called purpura. The neutrophils undergo karyorrhexis with formation of fragements called "nuclear dust". In some cases there may be mainly lymphocytes.

Henoch-Schoenlein Purpura

A variant of hypersensitivity vasculitis seen in children (rarely in adults) is Henoch-Schoenlein purpura. Arterioles, capillaries, and venules are involved. The vasculitis leads to a skin rash (purpura) seen on extensor surfaces of arms and legs. Vasculitis may also involve the gastrointestinal tract, leading to colicky abdominal pain. Musculoskeletal involvement with arthralgias and myalgias are often present, but pulmonary involvement is rare. There is typically an associated renal disease with nephritic or nephrotic features. Most patients do well, but a few go on to end stage renal disease. In adults, a rapidly progressive (crescentic) glomerulonephritis can occur. Deposition of IgA in skin and renal lesions can often be demonstrated.

Polyarteritis Nodosa

The "classic" form of polyarteritis nodosa (PAN) mainly affects medium to small arteries in skin as well as visceral organ sites. This vasculitis is mainly mediated via type III hypersensitivity, through antigen-antibody complexes. Serologic testing will often reveal pANCA to be present.

The disease can occur at any age, but young adults are most frequently affected, particularly women. The course of PAN waxes and wanes over time, leading to varied signs and symptoms that can be confusing to diagnose. Organ involvement is most frequent in kidney, heart, liver, and gastrointestinal tract. Other organ involvement can include pancreas, skin, muscle, and brain. Pulmonary involvement is infrequent. Unusual findings, such as infarcts in odd places such as liver or testes, should heighten suspicion for PAN. Renal involvement often leads to hypertension. Untreated, the disease is progressive, but most patients improve with corticosteroid and/or cytotoxic drug therapy.

There is focal and segmental vascular involvement with mixed inflammatory cell infiltrates that can be acutely necrotizing with fibrinoid necrosis, though healed chronic lesions may show mainly fibrosis with loss or disruption of arterial elastic lamina. Microaneurysms, demonstratable by angiography, can be present in up to half of cases.

A "microscopic" variant of PAN occurs in the kidney. It is manifested by a segmental necrotizing glomerulonephritis.

Wegener's Granulomatosis

Wegener's granulomatosis (WG) involves small arteries and veins of the upper and lower respiratory tract, but renal involvement is also common. Other organs are less commonly involved. Type II, III, and IV hypersensitivity reactions all contribute to the development of WG. Serologic testing often reveals cANCA to be present.

Persons most commonly affected by WG are middle aged. Males are affected more often than females. Many organ systems are involved. Findings can include: sinusitis, nasopharyngeal ulcerations, or pneumonitis. Fever, myalgias, arthralgias, and skin rashes may also occur with WG. Chest radiograph may demonstrate bilateral nodular infiltrates or cavitary lesions. Renal failure can occur with renal involvement. Untreated, death often occurs within a year in WG, but many patients improve with corticosteroid and/or cytotoxic drug therapy.

Histologically, fixed inflammatory cell infiltrates, but few eosinophils, with necrotizing and/or granulomatous inflammation are present. Capillaritis is common, but not fibrinoid vascular necrosis. Aside from renal arterial lesions with WG, there can be a focal necrotizing glomerulonephritis. Affected organs may show areas of geographic necrosis surrounded by palisading epithelioid macrophages and giant cells. Fibrosis occurs with chronic lesions.

Churg-Strauss Vasculitis

Also known as allergic granulomatous angiitis, this form of vasculitis has a broad pattern of involvement including both small arteries and arterioles and veins and venules. Type I , III, and IV hypersensitivity reactions contribute to the formation of this form of vasculitis. Serologic testing may reveal ANCA to be present, usually pANCA.

Though features of the Churg-Strauss syndrome are quite similar to polyarteritis nodosa, affected persons often have a history of atopy and bronchial asthma. Upper and lower respiratory tract, viscera (particularly heart), and skin can all be involved. A peripheral blood eosinophilia is often present.

There is mainly extravascular mixed inflammatory cell infiltrates, often with a prominent component of eosinophils, with necrotizing granulomas, appearing in either arteries or veins. Necrosis with a granulomatous reaction including giant cells can also be seen.

Microscopic Polyangiitis

There is a broad pattern of vascular involvement, similar to Churg-Strauss vasculitis and Wegener's granulomatosis. Unlike Wegener's, there is no granulomatous inflammation, and unlike Churg-Strauss, there is no asthma. The pANCA is often positive. Immune deposits in the involved vessels are not common.

Histologically, there is a necrotizing vasculitis. The features can appear similar to polyarteritis nodosa, but microscopic polyangiitis involves smaller vessels.

Giant Cell Arteritis

The typical pattern of involvement includes temporal artery and branches of external carotid arteries. Therefore, it is more often diagnosed as "temporal arteritis". Type IV hypersensitivity mediates this form of vasculitis. A sixth of cases may have involvement of aorta and its major branches. Involvement of the ophthalmic branch of the external carotid can lead to blindness.

The prevalence of giant cell arteritis increases with age. Signs and symptoms can include headache and a painful, palpably enlarged and tender temporal artery. Some persons will also have polymyalgia rheumatica. There are no specific laboratory findings, though the sedimentation rate is often quite elevated (as high as 100 mm/hr or more).

A trial of corticosteroid therapy, if succesful, may provide a presumptive diagnosis in lieu of biopsy. The inflammation is mixed with scattered giant cells. It can be quite focal, requring serial sections even of a small biopsy. If chronic, only fibrosis may be seen.

Takayasu's Arteritis

Takayasu's arteritis is rare, but seen more in Asia and Africa than elsewhere. This is an idiopathic, chronic, progressive vasculitis that leads to stenosis and/or aneurysmal dilation of affected arteries. The aorta, particularly the arch and its branches (carotids, subclavians) are most commonly affected. However, other large to medium-sized arteries can also be affected, including pulmonary, coronary, and renal arteries. A type IV hypersensitivity reaction is mainly responsible for the formation of this form of vasculitis.

The signs can include visual disturbances and decreased or absent peripheral pulses in upper extremities ("pulseless" disease). Younger persons are usually affected, with females suffering this disease more often than males. Coronary artery involvement may predispose to myocardial ischemia. Renal artery orifices may be occluded to produce hypertension.

The inflammation, which early on appears granulomatous, can weaken the arterial wall to produce aneurysms which predispose to dissection. In more chronic cases fibrosis is present that results in stenosis.

Kawasaki's Disease

Also known as mucocutaneous lymph node syndrome, Kawasaki's disease features an arteritis as one of its manifestations. This rare disease has most often been seen in Japan, mainly in children under the age of 10. Affected persons have skin rash, oral mucositis, and lymphadenopathy. The arteritis mainly affects medium-sized to larger arteries. Aneurysmal dilation can occur.

Histologically, Takayasu's arteritis has features similar to polyarteritis nodosa. The disease is most often self-limited. However, coronary artery involvement is frequent, and in a small number of cases death can occur because of coronary thrombosis or aneurysmal rupture.

Buerger's Disease

Also known as thromboangiitis obliterans, Buerger's disease involves the medium-sized and small arteries, and veins, of extremities, particularly the legs. This distinguishes thromboangiitis obliterans from the more common peripheral vascular disease of larger arteries seen with atherosclerosis. It is seen more commonly in young to middle aged adults. There is a close association with a history of smoking. Clinical features include claudication, superficial phlebitis, and Raynaud's phenomenon. A late complication is gangrene.

Histologically, there is segmental involvement of affected arteries. Neutrophils infiltrate throughout the artery. Complications include thrombosis and microabscess formation. The microabscesses may have a granulomatous appearance.

Drug-induced Leukocytoclastic Angiitis

When the skin is primarily involved with vasculitis, a drug should be suspected as the cause, though systemic disease must be ruled out. Onset of vasculitis generally occurs 1 to 3 weeks after initiation of drug therapy. Most patients will have a single episode of "drug rash" that resolves spontaneously in a few weeks to months. A few will have recurrent vasculitis.

Histologically, the dermis demonstrates leukocytoclastic lesions, mainly of post-capillary venules, with neutrophilic infiltrates, nuclear "dust", and resultant purpura.

Cryoglobulinemic Vasculitis

Most patients with this disorder are infected with hepatitis C. The acute vasculitis involves arterioles, capillaries, and venules. Laboratory findings include the presence in serum of mixed cryoglobulins and rheumatoid factor. Complement C4 is decreased, while C3 is normal. The most common problems are purpura of skin, arthralgia, and glomerulonephritis. The latter problem can be life-threatening.

Images

1. Medium sized muscular artery with vasculitis, medium power microscopic.
2. Vasculitis of dermal vessels with SLE, low power microscopic.
3. Vasculitis of dermal vessels with SLE, high power microscopic.
4. Vasculitis in renal artery branch with Wegener's granulomatosis, medium power microscopic.
5. Vasculitis in skin with polyarteritis nodosa, low power microscopic.
6. Vasculitis in skin with polyarteritis nodosa, high power microscopic.
7. Temporal artery with giant cell arteritis, low power microscopic.
8. Temporal artery with giant cell arteritis, medium power microscopic.
9. Temporal artery with giant cell arteritis, gross.

References

1. Jeannette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med. 1997;337:1512-1523.

2. Li PK, Leung JC, Lai FM, et al. Use of antineutrophil cytoplasmic autoantibodies in diagnosing vasculitis in a Chinese population. Am J Nephrol. 1994;14:99-105.

3. Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am. 1995;21:883-909.

4. Mandell BF, Hoffman GS. Differentiating the vasculitides. Rheum Dis Clin North Am. 1994;20:409-442.

5. Parums DV. The arteritides. Histopathology. 1994;25:1-20.

6. Smith JG Jr. Vasculitis. J Dermatol. 1995;22:812-822.