Cutaneous Vasculitis and Vasculopathy
World Small Animal Veterinary Association World Congress Proceedings, 2004
Verena K. Affolter
School of Veterinary Medicine, University of California, Davis
Davis, CA, USA

Introduction

Vasculitis is inflammation of the vascular wall and can occur as a primary disease, but is more commonly secondary to another concurrent disease (infections, neoplasia, connective tissue diseases, drug reactions). Vasculitis may involve only one organ system, such as the skin or may involve multiple organ systems. Cutaneous vasculitis typically results from small vessel vasculitis. Vasculitis is more often seen in dogs than in cats.

Etiology and pathogenesis

Vasculitis can be classified based on the histopathologic appearance: lack or presence of inflammatory infiltrates as well as size and type of vessels involved (small vessel vasculitis, arteritis, phlebitis). However, these classifications do not reliably correlate with a specific etiology. Most important is to differentiate between vasculitis induced by infectious pathogens and vasculitis induced by an immune-mediated process due to exogenous or endogenous antigens (Table 1). In over 50% of cases an etiology cannot be determined.

Non-immunopathogenic mechanisms--Vasculopathic effects of endotoxins or hemodynamic factors (example: cold agglutinin disease) can compromise the integrity of the vascular walls. The result is structural damage and inflammation of the vascular wall.

Immunopathogenic mechanisms may be triggered by infectious pathogens (rickettsial infections, babesiosis, leishmaniasis, feline immunodeficiency virus). Perivascular and/or intramural located infectious pathogens initiate the specific immune response and the vascular wall is damaged by the ensuing inflammation. In a similar manner, localized bacterial infections and/or septicemia can result in secondary vasculitis. Immune-mediated vasculitis is typically triggered by an adverse drug reaction (antibiotics, nonsteroidal anti-inflammatory medications, vaccines, therapeutic injections of sera and extracts of allergens for atomic dermatitis therapy) or underlying internal diseases (neoplasia, infections distant from area of vasculitis). Autoimmune diseases (connective tissue diseases such as systemic Lupus erythematosus) may be accompanied by vasculitis.

Table 1. Vasculitis classification

Infectious Vasculitis

Bacterial

bacterial endocarditis, septicemia, mycobacterial disseminated vasotropic

Fungal

fungal

Viral

Herpes virus, FIP, FIV, FeLV

Rickettsial

ehrlichiosis

Parasitic

dirofilariasis, babesiosis, leishmaniasis, trypanosomiasis

Non-Infectious Vasculitis

Exogenous antigen

drugs, food additives

Endogenous antigen

neoplasia, connective tissue diseases

Unknown antigen ("idiopathic")

sub classify according to:
--1st by vessel type, size and location
--2nd by inflammatory infiltrate

a) Deposition and formation of immune complexes (type III hypersensitivity reaction; Arthur phenomenon) is generally associated with a neutrophilic vasculitis. Immune-complexes attract complement factors and the complement cascade is initiated, with formation of the membrane attack complex (MAC). Opsonized pathogens (C3b, C4b, antibodies) are phagocytosis. C5a and leukotrienes are chemo-attractants for neutrophils and C3a, C4a, and C5a act as anaphylatoxins. Perivascular mast cell degranulate and release vasoactive amines, prostaglandins and leukotrienes and cytokines such as TNF-a. Neutrophils are recruited and degranulate, releasing various factors including lysosomal enzymes and oxygen reactive species. This results in fibrinoid necrosis of the vascular wall. In humans antineutrophilic cytoplasmic antibodies (ANCA) can be found in association with neutrophilic vasculitis.

b) Cytotoxic T cells directed against structural components of vascular walls may directly damage the vascular wall. CD8+ cytotoxic T cells can recognize haptens, such as drug metabolites, bound to components of the vascular wall, initiating immunologic reactions resulting in vasculitis.

c) Type I hypersensitivity reactions can cause an eosinophilic vasculitis (arthropod bites, insect-induced eosinophilic dermatitis). Perivascular mast cells release IL-5, which is a potent chemoattractant for eosinophils. Activated eosinophils release preformed major basic protein and eosinophilic cationic protein from cytoplasmic granules, both are toxic to tissue.

d) Vasculitis syndromes of unknown etiopathogenesis: leukocytoclastic vasculitis of the nasal region in Scottish Terriers, familial cutaneous vasculopathy of German Shepherd dogs and idiopathic septal panniculitis, proliferative arteritis of nasal philtrum (Saint Bernard), canine pinnal vasculitis.

Clinical presentation

Vasculitis may develop in any breed; Dachshunds, Rottweilers, Collies, Shetland sheepdogs and Jack Russell terriers may be predisposed. Vaccine-induced vasculitis is mainly seen in small breed dogs (Toy Poodles, Silky terriers, Yorkshire terriers, Pekingese, Maltese and Bichons). Some syndromes have been associated with specific breeds (vasculitis secondary to sulfonamide-trimethoprim therapy in Dobermans, vasculopathy in racing Greyhounds, etc).

Acute vasculitis--Legs and feet, ears, lips, tip of the tail, scrotum, and oral mucosa are mostly affected. These areas are more vulnerable as their blood supply has limited collateral circulation. With cutaneous vasculitis erythema, ecchymoses, areas of necrosis, and well-demarcated, "punched out" ulcers, and occasionally hemorrhagic bullae and/or pustules are seen. Erythema caused by vasculitis does not blanche with diascopy because of extravasation of the red blood cells. Subcutaneous vasculitis presents as nodular lesions. Systemic vasculitis causes variable clinical signs depending on the organ systems involved: phasic pyrexia, lethargy, anorexia, myalgia, arthralgia, lymphadenopathy and nasal discharge are seen. Wide spread systemic vasculitis may progress into shock and disseminated intravascular coagulation.

Chronic vasculitis--Less severe or slowly progressive vasculitis results in low-grade ischemia. Clinically these cases become evident at a chronic stage. Patchy alopecia, scaling, erythema and hyperpigmentation are seen. Lesions typically involve the pinnae, face, feet and tip of the tail often occurring over pressure points.

Diagnosis

Clinicopathologic findings--Anemia, thrombocytopenia, lymphopenia, eosinophilia, neutrophilia with a left shift and toxic changes, hypoalbuminemia, and elevated liver enzymes may be seen with systemic vasculitis. Circulating immune complexes, diminished complement factors and hypergammaglobulinemia may be present with immune-mediated vasculitis.

Evaluation for underlying infectious diseases--serial blood cultures, urine culture, serology, lymph node aspiration, heartworm antigen testing, histopathology and culture of lesional tissue are recommended.

Evaluation for an adverse drug reaction is essential. This includes drugs administered for any concurrent disorder, vaccinations, heartworm preventatives, diet and food additives, herbal supplements or homeopathic remedies.

Evaluation for underlying internal noninfectious disease--Evaluation for internal neoplasia or systemic immune disorder is indicated. This includes complete blood cell count, serum biochemistry panel, urinalysis, anti-nuclear antibody titer, arthrocentesis with evaluation of joint fluid, thoracic radiographs, and abdominal ultrasound.

Histopathology and immunohistochemistry--Inflammatory lesions of vessel walls may be subtle, focal and transient, and it may mimic leukocytic migration through the walls of capillaries and post-capillary venules.

Acute and subacute vasculitis--There are well circumscribed dermal and epidermal areas of coagulation necrosis, micro-hemorrhages, marked protein-rich edema and deposition of fibrin. The vessel walls are thickened and edematous with hyalinization and fibrinoid necrosis; the endothelial cells are swollen and necrotic (cell-poor vasculitis or vasculopathy). Degenerative changes may be associated with intramural inflammation. The presence of degenerative neutrophils, referred to as leukocytoclasia, is pathognomonic for vasculitis. Presence of inflammatory cells within arterial and venous walls indicates vasculitis, as leukocyte migration does not occur through arteries and veins. The nature of the inflammatory infiltrate may change over time. Predominantly neutrophilic vasculitis is the most common form of vasculitis; non-leukocytoclastic and leukocytoclastic (degenerative neutrophils, nuclear dusts) variants are seen. Immunohistology can identify immune complexes along vascular walls (IgG, IgM, complement). With lymphocytic vasculitis, there are tight cuffs of small CD8+ lymphocytes surrounding primarily small arterioles. It is mainly seen with chronic resolving stages of immune-complex vasculitis (vaccine-induced panniculitis, vasculopathy of German Shepherds, drug reactions). Eosinophilic vasculitis may accompany severe eosinophilic dermatitis (arthropod bite hypersensitivity, mast cell tumors). Admixed there may be marked increase of myxoid ground substance. Granulomatous vasculitis is usually a subacute to chronic stage of primary fibrinoid necrosis that may occur with neutrophilic, leukocytoclastic vasculitis. Cel-poor vasculitis or vasculopathy is the most commonly observed type of vascular change. The vascular changes may be subtle, and inflammatory cells are scant.

Affected vessel walls are thickened, hyalinized and have indistinct vessel walls and partial lack of endothelial cells. There may be deposition of PAS-positive material within the vessel walls.

Chronic vasculitis--Predominant changes are atrophy of the hair follicles ("faded follicles") and adnexal glands. The subepidermal collagen is homogenized and pale. Newly formed, arborizing thin collagen is dissecting preexisting dermal collagen. Mucin deposition may be present. The number of small dermal vessels may be decreased. The vascular walls appear thickened and hyalinized and a decrease of factor VIII+ endothelial cells is apparent. The overlying epidermis may be atrophic. Features of cell-poor interface dermatitis are common, characterized by vacuolar changes of the basal cell layer and follicular epithelium, apoptosis of basal cells and pigmentary incontinence. Larger areas of scaring may be present.

Clinical management

The clinical management with cutaneous vasculitis requires identification of the cause. Infectious etiology--appropriate antimicrobial therapy is needed. Drug reactions--all medications should be discontinued. Internal neoplasia--removal of neoplastic process is required. Immuno-suppressive therapy with glucocorticoids and possibly azathioprine or chlorambucil is often required once an infectious etiology has been ruled out. Pentoxifylline, a methylxanthine derivative, has both immunomodulatory and rheologic effects that make it a useful therapy for vasculitis. Pentoxifylline improves peripheral blood flow and decreases inflammation by decreased platelet aggregation, decreased leukocyte response to IL-1 and TNF-a and decreased production of TNF a, IL-1, IL-4, and IL-12. Patients with vasculitis will require supportive fluid therapy or nutritional support if unable to eat or drink. If there are significant areas of ulceration and necrosis, secondary antibiotic therapy may be warranted.

Examples of vasculitis

Ischemic dermatopathy in dogs: small breeds are predisposed. Primary lesion: circular patches of alopecia with perhaps mild crusting at the site of previous vaccination (may have underlying vaccine induced granuloma). Delayed secondary phase in some dogs (1-4 months): alopecia, crusting and ulceration occur on the muzzle, lips, tips and margins of the ears, tip of the tail and extremities. Etiology--A complement-induced microangiopathy is suggested (dermatomyositis in dogs and humans).

Solar induced vasculitis/vasculopathy--Severe erythema, swelling, exudation, erosions and ulcerations are limited to non-pigmented glabrous or poorly haired areas of the skin. Solar vasculopathy may develop secondarily to acquired depigmentation in diseases such as Discoid Lupus Erythematosus or after administration of photosensitizing drugs and herbs. This is mainly seen in dogs. Etiology--UV light induces formation of thymidine dimmers, increase of nitric oxide as well as damage of the DNA repair system.

Familial cutaneous vasculopathy in German Shepherd dogs--Young puppies (4-6 weeks) present with painful areas of focal depigmentation, crusting, exudation and ulceration on the nose and footpads (usually all footpads), occasionally ear and tail tips. Several puppies in a litter can be affected and the lesions often develop 7 to 10 days after first vaccination. Repeating vaccinations may exacerbate the lesions. Some puppies may be lethargic with swollen joints and pyrexia. There is no sex predilection. Biochemical parameters are normal, ANA and Coombs test are negative and peripheral lymphocyte populations within the normal range. There is a mild myeloid hyperplasic in the bone marrow. Etiology--The pattern of occurrence suggests a genodermatosis (autosomal recessive trait) with an environmental trigger (vaccine) resulting in an abnormal immunologic reaction.

Vasculitis with cartilage necrosis of the pinnal fold in dogs--Crusting, exudative, ulcerating linear lesions develop on the medial aspect of the pinna, along the fold of the ear pinna in dogs that traditionally had their ears cropped (example: Boxers). Etiology--Unknown.

Proliferative thrombovascular necrosis of the pinna--wedge-shaped, usually bilateral symmetrical, necrosis of the distal ear pinna in dogs. Progressive syndrome, lesions are painful. Etiology--unknown.

Proliferative arteritis of the nasal planum--Saint Bernards appear predisposed. Well demarcated linear ulcers on the nasal philtrum with hemorrhage are seen. Etiology--unknown.

Septicemic vasculitis--Systemic signs are present (fever, malaise, anorexia) and rapid clinical progression is seen. Necrotizing ulcers, purpura, hemorrhagic bulla and plaques are seen. Etiology: bacterial showering derived from infections (endocarditis, pyoderma, Rocky Mountain spotted fever, ehrlichiosis, Erysipelothrix rhusiopathiae).

Idiopathic cutaneous and renal glomerular vasculopathy in racing Greyhounds--There is no sex predilection. Multiple erythematous, tender cutaneous areas of swelling, predominantly on the tarsus, stifle and inner thigh are noted. Occasionally there are lesions on the forelegs. The lesions rapidly progress to ulceration with serosanguineous discharge. In some dogs the clinical signs are limited to the skin and gradually heal. Other dogs present with skin lesions, lethargy and fever. These dogs may develop acute renal failure with azotemia, polydypsia, polyuria, vomiting, and diarrhea. Less commonly, azotemia may precede the development of cutaneous lesions. Etiology--Unknown. The syndrome has some similarities with thrombocytopenic purpura, hemorrhagic-uremic syndrome and disseminated intravascular coagulation (DIC). A strong genetic predisposition is suggested (affects only racing Greyhounds, restricted to litters or closely related litters). Cultures, special stains of skin and kidney for infectious agents and serology for rickettsial infection are negative.

Cryoglobulinemia or cold agglutinin disease--Erythema, purpura, ulcerations and punched-out necrosis, occurring predominantly on extremities. Acrocyanosis may occur. The lesions are precipitated and exacerbated by cold temperature. Etiology--Formation of auto-antibodies, which are most active at low temperatures (0-4°C). Type one cryoglobulinemia is characterized by cold reacting IgM, auto-antibodies against erythrocytes called cold-agglutinins. A second and rare type is due to non-agglutinating IgG antibodies and has been associated with lead poisoning or upper respiratory tract infections. Most cases are of unknown etiology.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Verena K. Affolter, DVM, DECVP, PhD
School of Veterinary Medicine, University of California-Davis
Davis, CA


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