Vasculitis and Angiitis

By | 2013-07-19

The terms vasculitis and angiitis refer to the pathologic syndrome that is characterized by vascular inflammation and necrosis. Although there have been many reported causes of vasculitis, only a few histologic manifestations of the disease have been diagnosed. Vasculitis can occur in toxic, immune-mediated, infectious, inflammatory, and neoplastic disorders. Blood vessels of any type in any organ can be affected, resulting in a wide variety of clinical signs. The nonspecific nature of histologic lesions, coupled with variable clinical presentations, makes the diagnosis of primary vasculitis quite challenging. The clinical consequences of vasculitis depend on the size, number, type, and extent of blood vessels that are affected.

Histologically, vasculitis is characterized by the presence of inflammatory cells within and around blood vessel walls. Vascular injury is associated with necrosis and degeneration of endothelial and smooth muscle cells and fibrin deposition. A collection of fibrin, immunoglobulins figs), complement, and platelets appears by light microscopy as eosinophilic material within the vessel wall and lumen and is referred to as fibrinoid. Eosinophilia secondary to degeneration of collagen and smooth muscle can also be present within the vessel wall. These histopathologic lesions distinguish vasculitis from perivascular inflammation. Vasculitides have been classified based on specific inflammatory cell infiltrates that may include neutrophils, lymphocytes, or macrophages. As the disease becomes chronic or begins to resolve, predominant cell populations may change. Vasculitis may develop from within a vessel as a result of infectious, immune-mediated or toxic injury or by extension from adjacent areas of inflammation. Infectious agents can injure endothelial cells direcdy or through the production of endotoxins and exotoxins. The exact mechanism of endothe-lial injury is not known but involves the formation of oxygen free radicals, local inflammatory mediators, and the recruitment of inflammatory cells. Exposure of subendothelial collagen during endothelial injury results in the activation of Hageman’s factor and the subsequent activation of the complement, kinin, and plasmin systems. These lead to increased vascular permeability and inflammation.

Type III hypersensitivity reactions can cause necrotizing vasculitis from the deposition of immune complexes within the vessel walls. Activation of the complement cascade may attract neutrophils, cause immune complex phagocytosis, and result in the release of lysosomal enzymes and oxygen free radicals, thereby leading to further inflammation and necrosis. In the chronic state this reaction becomes diminished, and mononuclear cells replace the neutrophilic inflammation. Immune complex reactions of this type can occur in many disease conditions such as primary immune-mediated disease or be secondary to infectious disease. Emphasis on immune complex activity can only be misleading because immune complexes are rapidly cleared from the circulation. In humans the discovery of antineutrophil cytoplasmic autoantibodies (specific for antigens in neutrophil granules and monocyte lysosomes) has allowed further identification of immune-mediated processes in which immune complexes were suspected but not identified. Cell-mediated immunopathogenic mechanisms are initiated in the blood vessel wall. This type of vasculitis is characterized by accumulations of lymphocytes and macrophages within vascular walls. Myocyte necrosis results in fibrinoid degeneration, endothelial hyperplasia, and occasionally thrombosis. A granulomatous type of reaction of the vessel wall can result, particularly in chronic cases. These changes may be accompanied by hemorrhage and ischemic changes in surrounding tissues.

The cause of secondary vasculitides is, by definition, known, and classifications are based accordingly. These conditions usually result from infectious diseases such as feline infectious peritonitis (FIP), canine coronavirus infection, parvovirus infection (rare), Rocky Mountain spotted fever (RMSF), leish-maniasis, and dirofilariasis. They may also occur in drug reactions and in immunopathogenic connective tissue and collagen diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.

Microscopic Necrotizing Vasculitis

Microscopic necrotizing vasculitis (MNV) refers to a large heterogeneous group of clinical syndromes that share similar histologic properties. Hypersensitivity vasculitis is often referred to in dermatologic manifestations and is often clinically distinct from the multi-systemic form of necrotizing vasculitis. Termed juvenile pol-yarteritis syndrome (JPS), it has been reported in young beagle dogs. Less distinction exists between JPS and those syndromes described as idiopathic steroid-responsive vasculitides that can manifest as multisystemic or localized disease. Lesions can affect mainly arterioles, capillaries, and venules.

Clinical abnormalities of microscopic necrotizing vasculitis are often associated with phasic pyrexia, listlessness, and anorexia. In some cases, lymphadenopathy, myalgia, epistaxis, drooling, sneezing, and arthralgia may occur. In addition to the generalized signs, manifestations of specific organ lesions may occur. The most common presenting clinical signs in small animals are dermatologic lesions. Hemorrhagic maculae resembling circular petechiae and ecchymoses are common. Other lesions seen include wheals, urticaria, purpura, nodules, bullae, necrosis, and ulcers. In many cases the skin lesions are associated with pain, pruritus, or both. Less frequently encountered lesions include ulcers at the mucocutaneous junctions or of the mucous membranes, especially located on the head (external ear canal and pinnae, face), bony prominences of the limbs, and the foot pads, as well as pitting edema involving dependent areas such as limbs, ventral trunk, head, and scrotum.

Internal organ involvement with microscopic necrotizing vasculitis frequently goes undiagnosed. This is because clinical signs are vague, simultaneous multiorgan involvement often occurs, or organ manifestations are confused with those of infectious, degenerative, or traumatic conditions (e.g. pneumonia, glomerulonephritis, arthritis, spinal or neuromuscular conditions). The clinicopathologic findings of primary microscopic necrotizing vasculitis vary according to severity, duration, and specific organ. Lymphopenia, eosinopenia, hypoalbuminemia, hyper-globulinemia, and hyperfibrinogenemia occur commonly. Less consistent findings include leukocytosis with a left shift and toxic neutrophils; leukopenia; neutropenia; monocytosis; a mild normocytic, normochromic anemia; and thrombocytopenia. Serum liver enzymes and triglycerides are often elevated.

An idiopathic cutaneous and renal glomerular vasculopathy has been described in kenneled and racing greyhounds, with many characteristics similar to microscopic necrotizing vasculitis. It is characterized by fibrinoid arteritis, thrombosis, and infarction with deep, slowly healing skin ulcers and peracute renal glomerular necrosis with a predilection for afferent arterioles.

Diagnostic confirmation requires histologic examination of skin, organ, or lymph node biopsies specimen and exclusion of other immune-mediated disease. Special immunologic tests have been recommended to demonstrate a low or high concentration of complement, C3, and elevated levels of circulating immune complexes. The history may be helpful if drug hypersensitivity is suspected.

Primary periarteritis, or polyarteritis, a necrotizing vasculitis affecting small- and medium-sized muscular arteries has been identified in colonies of beagles. This polyarteritis occurs in two forms. One form occurs mainly in young beagles, in which arteritis affects major branches of coronary arteries almost exclusively. Clinical signs are usually absent. A second form of polyarteritis is associated with vague multisystemic signs (fever, depression, anorexia, neutrophilia, decreased albumin-to-globulin ratio), a stiff gait, pain on abdominal palpation (beagle pain syndrome), or a combination of these symptoms. The signs are associated with vascular lesions including disseminated, focal, or diffuse intimal thickening and acute fibrinoid necrosis of the media resulting in occlusion and thrombosis.

The differential diagnosis includes pemphigus vulgaris and foliaceus, bullous pemphigoid, SLE; dirofilariasis, specific infectious diseases, chronic neoplasia, and cold hemagglutination disease. The prognosis is usually favorable.

Many therapies have been advocated. Administration of all unnecessary drugs should be discontinued. In many cases immunosuppressive doses of glucocorticoids with or without an antibiotic have been used successfully. Cyclophosphamide may be administered if that fails. Dogs with lesions involving only the skin can be given sulfasalazine (Azulfidine) at an initial dose of 22 mg/lb (49 mg/kg) every 8 hours. Dose frequency can be decreased after lesions improve from three times to twice a day and, later, to once a day. Dogs receiving sulfasalazine should be observed for side effects such as fever, keratocon-junctivitis, and hematologic abnormalities.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a rare polysystemic disease associated with a necrotizing vasculitis of unknown cause. The disease affects predominandy segments and bifurcations of small and medium-sized muscular arteries. In humans, PAN is classified among immune-mediated collagen disorders and derives its name from purpural lesions that are palpable in the subcutaneous tissue. In contrast, palpable nodules are not a regular feature of PAN in animals. The vascular lesions consist of intimal proliferation, vessel wall degeneration, necrosis, and thrombosis in all stages of development. Polyarteritis nodosa leads to a loss of vessel wall integrity, petechial and ecchymotic hemorrhages, focal areas of tissue infarction and necrosis, aneurysm formation, nodular swelling, and thickening of the major arteries. Target tissues of canine polyarteritis nodosa include the kidneys, skin, mucous membranes, adrenals, meninges, GI tract, connective tissue, and myocardium. The lungs are usually spared.

The clinical presentation includes systemic signs (pyrexia, lethargy, reluctance to walk, vague pain, or weight loss) and a wide spectrum of organ system abnormalities (linear skin ulceration, ulceration of mucous membranes, nasal discharge, spinal pain, and signs of cardiac or renal failure (or both]). Clinicopathologic findings may include leukocytosis with a left shift and proteinuria.

The main differential diagnoses are hypersensitivity angiitis and idiopathic polyarteritis. The diagnosis is confirmed by histologic examination of a skin biopsy specimen, and the prognosis is guarded to poor. Treatment includes glucocorticoids, cyclophosphamide, or both.

Lymphomatoid Granulomatosis and Miscellaneous Vasculitides

Lymphomatoid granulomatoses and other unclassified vasculitides are characterized by a polymorpholymphocytoid, plasmacytoid, and histiocytoid granulomatous infiltration around blood vessels. Pulmonary nodular lesions of variable size due to lymphomatosis were first described in dogs. Infarction, necrosis, and cavitation occur in some of the masses. The bronchial lymph nodes can be slightly to greatly enlarged, and pulmonary thrombosis is common. The cause of this rare condition is unknown. Occasionally, similar lesions are associated with eosinophilic pneumonitis in occult dirofilariasis, although they can also occur outside of endemic areas of dirofilariasis. An immune-mediated cause is likely because, in some cases, large amounts of IgG and IgM can be demonstrated in plasma cells and macrophages. The differential diagnosis is primary or secondary ncoplasia, with which this condition is often confused. Diagnosis is rarely made clinically and requires histologic examination of biopsy material. The prognosis is usually poor. In some patients, multicentric lymphosarcoma has developed at a later date. Surgery or treatment with glucocorticoids and cytotoxic immunosuppressive drugs is only temporarily effective.