Introduction

Vascular inflammation and/or insufficiency (vasculitis, vasculopathy) is a common cause of dermatologic disease in humans and animals. Disruption of the cutaneous vasculature may be associated with a number of local or systemic disorders, including drug or vaccine administration, infection, inflammation, neoplasia, hypersensitivity, photodermatitis and immune mediated phenomena, or may be idiopathic (Table 1). Regardless of the underlying cause, the resulting vascular compromise impedes tissue oxygenation, causing cutaneous atrophy and potentially overt necrosis. Proper management of these phenomena requires a thorough understanding of potential etiologies and appropriate diagnostic measures.

Table 1. Conditions known or suspected to cause vasculitis/vasculopathies in small animals

Immunopathogenesis

Numerous immunologic phenomena may result in the development of vasculitis. IgE-mediated mast cell degranulation may be seen in early urticarial vasculitis. The development of anti­neutrophil cytoplasmic antibodies can trigger mediator release and secondary endothelial damage. These antibodies have been reported to play a role in some forms of vasculitis in humans, although this association with vasculitis has not yet been reported in animals.

Perhaps the most relevant pathophysiologic mechanism in the development of vasculitis is immune complex formation/deposition (Type Ill hypersensitivity). Large antigen-antibody complexes deposit in blood vessels, resulting in the activation of complement and endothelial damage. This in turn results in the recruitment of neutrophils and further cell damage.

Clinical Appearance, General

Mildly affected animals may present with only alopecia (secondary to ischemic follicular atrophy), recurrent urticaria or edema. More severe cases may be associated with crusting, erosion, ulceration or frank necrosis, especially on areas with poor collateral circulation (such as the pinnae and tail tip) or which are prone to trauma (face and over bony prominences). Lesions often heal with scarring. Footpads (especially digital pads) may develop circular “punched­ out” areas of erosion or ulceration. Another common syndrome is palpable purpura, in which raised indurated areas of erythema or violaceous change are seen.

Patients with vasculitis may or may not demonstrate systemic signs at the time of presentation. Concurrent organ involvement may include kidneys (glomerulonephritis), mesothelium (pleuritis, pericarditis, peritonitis), the gastrointestinal tract, muscle (myositis), joints (polyarthropathy), heart, lungs and CNS. Depending upon the degree of associated endothelial damage, patients may be in a hypercoagulable state secondary to widespread platelet and clotting factor activation.

Specific Clinical Vasculitis Syndromes

Vaccine-Induced Vasculitis

Any vaccine may be associated with this phenomenon, especially rabies vaccines. Lesions may occur at the site of vaccination and/or at locations distant from it. Injection site lesions often appear initially as dermal induration, which may be followed by focal alopecia and cutaneous atrophy. Atrophic lesions often feel somewhat “adhered” to underlying tissue. Myositis or muscle atrophy may also be seen. Distant lesions typically affect areas with poor collateral circulation and/or areas prone to trauma. Mild lesions may present with focal or multifocal alopecia, while more severe lesions may demonstrate crusting, erosion and ulceration. “Punched out” lesions on the digital pads are particularly suggestive. Sloughing of one or multiple nails and/or erosion of mucous membranes may be seen. Most patients are systemically well, but severe systemic involvement has been reported.

Fulminant Multisystemic Vasculitis Associated with Human Serum Albumin (HSA) Administration

Several cases have been reported of vasculitis following a single administration of HSA. In one report, several healthy dogs administered HSA developed reactions between 5 and 13 days following administration. These included lameness, edema, “cutaneous lesions indicative of vasculitis,” ecchymoses, vomiting, bloody diarrhea and facial muscle atrophy. One of these dogs had also experienced an immediate hypersensitivity event. Four of the dogs required hospitalization. In two dogs, symptoms progressed to include oliguric renal failure and pulmonary edema, resulting in death.

Cutaneous and Renal Vasculopathy

This condition has been reported most commonly in racing greyhounds fed raw or undercooked beef, but can be seen in non-racing greyhounds or other breeds. A verotoxin produced by E. coli has been proposed as an inciting cause, although this has not been proven. The condition presents initially as multifocal areas of erythematous swelling, which can evolve into ulcers. Lesions may or may not drain a serosanguineous fluid. The ventral abdomen and extremities are most commonly affected. Affected animals are often febrile and lethargic and may or may not have gastrointestinal involvement or renal failure.

Vasculitis Associated with Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is frequently associated with multisystemic vascular disease secondary to immune complex deposition. Although animals are frequently systemically ill by the time of appearance of cutaneous lesions, the author has recently seen a case in which cutaneous lesions preceded overt systemic illness by several months.

Other Ischemic Dermatopathies

Familial Canine Dermatomyositis

This condition is most common in Collies and Shetland Sheepdogs but may appear in other breeds as well. The condition usually appears prior to 6 months of age, but occasionally appears in adulthood. Affected animals develop erythema, alopecia and crusting on areas prone to trauma and on pressure points. Later lesions may demonstrate erosions and ulcerations, which heal by scarring. Lesion severity varies greatly between individuals. Affected animals may have significant clinical myopathy (often presenting as muscle weakness or atrophy of the muscles of mastication) or may demonstrate electromyographic abnormalities in the absence of clinical myositis.

Proliferative Thrombovascular Necrosis of the Pinnae

Dachshunds and Rhodesian ridgebacks appear to be predisposed to this condition, although other breeds may also be affected. Affected pinnae demonstrate varying degrees of swelling, crusting, scaling, fissuring and bleeding. In extreme cases, overt progressive necrosis of the pinnae may be seen. Individual cases have been reported in association with drug or vaccine administration, or food hypersensitivity.

Diagnosis

The presence of crusting, ulcerative to erosive lesions on the extremities and pinnae is strongly suggestive (but not diagnostic for) of the presence of a vasculopathy, especially when combined with punched-out lesions of the footpads. Erythematous lesions may be examined by diascopy. Failure to blanch with pressure suggests extravascular hemorrhage. It is important to note that this result may also be seen in other conditions (e.g., coagulopathies).

Skin biopsy is the definitive diagnostic tool to demonstrate the presence of a vasculitis. Samples should ideally be taken from active edges of lesions, as these are the most likely to contain active vascular inflammation. Biopsies taken from more chronic lesions may be suggestive of prior ischemia. Biopsies obtained of vaccine associated lesions may occasionally demonstrate deep dermal to subcutaneous inflammation associated with amorphous debris (presumed vaccine adjuvant).

Since vasculitis is considered to be a cutaneous reaction pattern rather than a specific diagnosis, any diagnostic approach must include an attempt to identify an underlying cause, although in many patients no obvious cause can be found. A thorough questioning of the owner to identify any drug administration (including vaccinations, flea and heartworm prevention) should be performed and any suspect drugs discontinued immediately. A minimum data base (CBC, chemistry profile, urinalysis) may be useful to help detect systemic involvement and possibly demonstrate infectious diseases (e.g., Babesia, Histoplasma). Serum titers for tick-borne diseases are indicated in endemic areas. Tissue or blood cultures may be appropriate. If systemic involvement is demonstrated, an anti-nuclear antibody test may help to identify SLE. In severe cases, coagulation panels may detect the presence of hypercoagulability and provide prognostic value.

Therapy

Effective therapy involves the identification and elimination of underlying disease, whenever possible. If the condition is thought to be vaccine-associated, it may be prudent to avoid further vaccination in that animal, where laws permit this option. If re-vaccination is unavoidable, eliminating optional vaccines and minimizing the number of vaccines given at any one time may be advisable.

Symptomatic management of vasculopathy generally involves a combination of anti-inflammatory medications (reviewed in Innera 2013 and Morris 2013). Pentoxifylline is often useful as a sole or adjunct therapy because of its several anti-inflammatory effects. A wide range of doses have been suggested for this drug, with 20 mg/kg TID being the author’s preference. Other therapies used for less severe cases of vasculitis include Vitamin E and the combination of tetracycline (or doxycycline) and niacinamide.

More severe cases may benefit from systemic glucocorticoids at high anti-inflammatory to immunosuppressive dosages. Prolonged administration of high doses may be counterproductive, but intermittent “pulse” administration may be useful for treatment of flares. Potent topical glucocorticoids may be used as adjunctive treatment for individual refractory lesions, although over usage may result in significant atrophy. Alternately, focal lesions may respond to topical tacrolimus applied once daily to every other day. In persistent, chronic or refractory cases, adjunctive immunosuppressive therapy may be required. These drugs may include cyclosporine, azathioprine, chlorambucil, dapsone, and sulfasalazine.

References

1.  Innera M. Cutaneous vasculitis in small animals. Vet Clin North Am Small Anim Pract. 2013;43(1):113–134.

2.  Nichols PR, Morris DO, Beale KM. A retrospective study of canine and feline cutaneous vasculitis. Vet Dermatol. 2001;12(5):255–264.

3.  Francis AH, Martin LG, Haldorson GJ, et al. Adverse reactions suggestive of type III hypersensitivity in six healthy dogs given human albumin. J Am Vet Med Assoc. 2007;230(6):873–879.

4.  Morris DO. Ischemic dermatopathies. Vet Clin North Am Small Anim Pract. 2013;43(1):99–111.

5.  Vitale CB, Gross TL, Magro CM. Vaccine-induced ischemic dermatopathy in the dog. Vet Dermatol. 1999;10:131–42.

6.  Langford CA. Vasculitis. J Allergy Clin Immunol. 2010;125(2 Suppl2):S216–25.