СОСУДИСТЫЕ ЗАБОЛЕВАНИЯ КОЖИ

There are many reported triggers of vasculitis and it is important to try to identify the etiology for every case (Table 1). It is especially important to identify patients with septic vasculitis (including vasculitis caused by deep pyoderma, endocarditis or cellulitis), because immunosuppressive treatments are contraindicated 3. A thorough history – including details of diet, supplements, topical therapies, vaccination history and any medications given – is critical. Patients should undergo a general physical exam in addition to a dermatological exam. A complete blood count (CBC), serum biochemistry profile, urinalysis and titers for tick-borne diseases should be evaluated in every case.

The diagnosis of vasculitis is made on skin biopsy, which should be collected from acute lesions (erythema and petechiae) rather than completely ulcerated or necrotic skin. Biopsies must be down to the subcutaneous tissue, because the lesions are often very deep. Histopathological lesions essentially show damage to the vascular walls associated with inflammation; there is often microhemorrhage, leukocytoclasia (fragmented granulocyte nuclei) and necrosis. The most common inflammatory cell type is neutrophils, and small vessels are most frequently affected 2.

Treatment options

Given the wide range of severity and clinical signs, treatment protocols should be tailored to the individual patient (Table 2). If a drug reaction is suspected the offending medication should be discontinued. Infectious diseases and neoplasia should be treated where possible. Food hypersensitivity can also be a trigger (especially if a generalized urticarial vasculitis is present) and an elimination diet trial may be considered appropriate 2. 

Very mild idiopathic cases are often managed with pentoxifylline or a combination of doxycycline and niacinamide 2. Pentoxifylline is a methylxanthine derivative that increases red blood cell flexibility, decreases blood viscosity and has anti-inflammatory effects. It is generally well tolerated, but clinical response can take 1-3 months. Doxycycline (a tetracycline antibiotic) and niacinamide (a B-vitamin) used in conjunction have immunomodulatory effects, although the exact mechanisms are not fully understood. Hepatotoxicity with doxycycline has been reported, but is rare. This drug combination also has a very slow onset of action; if a rapid response is necessary, both pentoxifylline and doxycycline/niacinamide can be combined with corticosteroids. Vitamin E has also been used alongside doxycycline/niacinamide.

More severe cases will need more aggressive therapy with a faster onset of action. Glucocorticoids can provide very rapid improvement in clinical signs, but must be used cautiously in patients with extensive ulcerations because they delay wound healing. Anti-inflammatory doses (0.5-1 mg/kg/day) are often sufficient 3.

Secondary immunosuppressive agents (i.e., steroid-sparing drugs, such as ciclosporine or azathioprine) can also be used. Ciclosporin has been used to treat atopic dermatitis and a variety of immune-mediated conditions including vasculitis 2 3 4, although the cost can be prohibitive. Branded microemulsified products have better absorption than generic formulations and are to be preferred 4. Maximal effect is generally seen after 4 weeks, with transient gastrointestinal upset (vomiting and diarrhea) the most common side effect. Freezing the capsules and administering while frozen has been anecdotally reported to decrease the incidence of vomiting 4 and does not appear to impact the bioavailability 5. There are many drugs that interact with ciclosporin, so its use should be evaluated carefully when multiple medications are being administered.

A less expensive option as a secondary immunosuppressive agent would be a purine antagonist such as azathioprine or mycophenolate mofetil 3 4 5 6. Azathioprine can cause hepatotoxicity and bone marrow suppression, as well as an increased risk of pancreatitis, so frequent bloodwork is required 3. A serum biochemistry profile and CBC is generally recommended prior to initiating therapy and should be repeated after 2, 4, 8 and 12 weeks of treatment; if the drug is well tolerated at this point, the tests are then typically repeated every 4 months. A clinical response can take 3-6 weeks. Hepatotoxicity is most likely to occur within the first 2-4 weeks, while bone marrow suppression may occur with chronic usage 7.

Mycophenolate mofetil has not been as extensively employed as azathioprine until recently because of its cost, but generic products are now available and its use is increasing 6. It has fewer side effects when compared to azathioprine, although diarrhea can occur; bone marrow suppression is uncommon. Again baseline CBC and biochemistry are recommended, but intensive monitoring is not generally required. Clinical response can take 3-8 weeks.

Sulfonamides (e.g., sulfasalazine and dapsone) have been recommended for cases of neutrophilic vasculitis that have not responded to other therapies 2 3. They interfere with the neutrophil myeloperoxidase system, but their exact mechanism of action is not fully understood. Sulfasalazine is generally better tolerated but can cause reversible keratoconjunctivitis sicca (KCS). Dapsone has been associated with bone marrow suppression, hemolytic anemia, hepatotoxicity, neurotoxicity and hypersensitivity reactions. Baseline CBC and biochemistry is recommended and testing should be repeated every 2-3 weeks for the first 4 months, then every 3-4 months.

As with other immune-mediated skin diseases, the secondary agents are used at the full dose with or without corticosteroids until remission is achieved. The corticosteroid is then generally tapered, aiming to reduce the dose by 25% every 2-4 weeks. Ideally, the goal is to discontinue the corticosteroid before tapering the secondary agent, again by 25% every 4 weeks until the lowest effective dose is achieved or the drug is discontinued. In some cases low doses of both corticosteroid and the secondary agent may need to be maintained.

Ischemic dermatopathies

These are a group of clinical conditions whereby ischemic tissue damage results in lesions without significant visible vasculitis 8. Often termed “cell-poor vasculitis“, common clinical signs include alopecia, hyper- or hypopigmentation, skin thinning, scale and erosions or ulcers that are slow to heal. These lesions are typically seen at pressure points and the distal extremities. The most common histological lesions are follicular atrophy, pale-staining mucinous collagen and clefting at the basement membrane zone.

Post rabies vaccination panniculitis 

This ischemic dermatopathy presents as a focal area of alopecia with hyperpigmentation and occasionally a swelling or plaque at the site of a rabies vaccination (Figure 4) 9. It is most commonly seen in Miniature Poodles and other small breed dogs 8 9. The signs typically occur 2-6 months after vaccination and the lesions are non-painful. The diagnosis is often made simply on clinical signs, but biopsy shows a cell-poor vasculitis with follicular atrophy and dermal pallor; inflammation in the subcutaneous tissues (panniculitis) may be present 9. Amorphous blue material, thought to be vaccine components, can sometimes be seen, and rabies-specific immunofluorescence has been identified within the walls of blood vessels. These lesions are mainly cosmetic and rarely necessitate therapy, but pentoxifylline may be used if the lesions are expanding. Repeat vaccination should be done with caution as progressive disease is possible.

Pinnal margin vasculopathy

Sometimes referred to as proliferative thrombovascular necrosis of the pinnae, this is a fairly common ischemic dermatopathy that targets the ear margins. Lesions begin as an area of thickening and scale, often wedge-shaped, on the concave surface of the pinnae, and can progress to ulceration and necrosis of the tips (Figure 5a) (Figure 5b) 8. Lesions are generally bilateral and can deform the ear margin. Many cases are idiopathic but there may be an association with recent vaccination or with cutaneous adverse food reactions 8. Since the lesions have a very striking appearance, and because the location is difficult to biopsy, diagnosis is often on clinical signs alone. Biopsy shows ischemic tissue damage with or without a cell-poor vasculitis that can have severe thickening of the arteriole walls. Pentoxifylline, doxycycline/niacinamide and/or vitamin E are the most commonly used treatments. For cases that are ulcerated or bleeding, anti-inflammatory doses of corticosteroids are often required, but must be used cautiously because they can delay healing 8. Tacrolimus 0.1% ointment has a similar mechanism of action to ciclosporin and can be applied topically in these cases, although irritation and pruritus at the site of application has been reported in dogs (and humans). If a cutaneous adverse food reaction is suspected then an elimination diet trial should be performed. For cases that have not responded to medical management surgical removal of the pinnae can be curative, but this should be done cautiously. 

Generalized ischemic dermatopathy 

These cases present with widespread lesions of ischemic tissue damage, especially over bony prominences of the face and extremities (i.e., distal limbs, ears, pinnal folds, and tail) 8 9 10. Lesions often begin as alopecia, scale and crusting, and progress to erosions and ulcers with eventual scarring. The nailbeds can be involved and sloughing of the claws may be seen. There can also be a prominent myopathy causing severe muscle atrophy (Figure 6) 10. Clinically these cases are often indistinguishable from familial canine dermatomyositis (see below). Skin biopsies are consistent with a cell-poor vasculitis and show the typical ischemic epidermal and dermal changes. This condition can occur in juvenile or adult animals and has been associated with vaccination, although it is often idiopathic 8 9 10. Secondary bacterial infections can cause pruritus which can result in these cases being mistaken for allergic animals. Treatment options include pentoxifylline, vitamin E, doxycycline/niacinamide or ciclosporin, depending on the severity, but corticosteroids are often avoided because they can exacerbate the epidermal and muscle atrophy. If triggered by a vaccine, repeat vaccinations should be avoided as they can cause a relapse.

Familial vasculitis and vasculopathy

Several unique familial vasculitis and vasculopathy syndromes have been reported, and they are briefly discussed below.

Familial canine dermatomyositis

This is a familial generalized ischemic dermatopathy that has been reported in the Border Collie, Shetland Sheepdog, Beauceron Shepherd, Australian Kelpie, Portuguese Water Dog and Belgian Tervueren Shepherd 11 12 13 14 15 16. Signs typically occur in dogs under 6 months of age, although adult onset has been reported, and signs can vary in severity from mild to severe 8 11 12 13 14 15 16. These cases are clinically and histologically indistinguishable from generalized ischemic dermatopathy, and the treatment is the same for both conditions.

Cutaneous vasculopathy of German Shepherd Dogs

Affected dogs usually develop signs between 4-7 weeks of age and often within 7-10 days of their initial vaccination 17. The signs typically include swelling, depigmentation and ulceration of the footpads, ulcers on the pinnae, tail tip and nasal planum, swelling on the bridge of the nose, and nasal depigmentation. Repeat vaccination causes a recurrence or worsening of signs. Affected dogs are usually lethargic, febrile and can be lame with swollen joints. There are no consistent laboratory abnormalities in these cases, and patients generally recover by 5-6 months of age; no treatment has been shown to be effective. Biopsies show subtle vasculopathy and panniculitis with inflammation centered around degenerate collagen bundles 17.

Leukocytoclastic vasculitis of the nasal planum in Scottish Terriers

Clinical signs start at 3-4 weeks of age with a clear nasal discharge and ulceration of the nasal planum, and progressively worsen with destruction of the planum and nasal mucosa 18. Biopsies show pyogranulomatous inflammation, neutrophilic leukocytoclastic vasculitis and epidermal necrosis. No effective treatment has been reported and all affected dogs have been euthanized.

Cutaneous vasculitis of the Parson Jack Russell Terrier

The most common clinical signs are alopecia, crusting and ulcerations over bony prominences, wedge-shaped necrosis of the pinnae tips, and ulceration of the footpads 19. Reports note that vaccinations were given 2-3 weeks prior to the onset of lesions in 60% of cases. Histopathology shows leukocytoclastic vasculitis, apoptotic keratinocytes and ischemic degeneration of hair follicles. The clinical and histological appearance is similar to dermatomyositis. Cases have been managed successfully with prednisone, dapsone and/or vitamin E 19.

Dermal arteritis of the nasal philtrum

A proliferative vasculitis affecting the dermal arteries and arterioles underlying the nasal philtrum has been described primarily in Saint Bernards, but also in Giant Schnauzers and Basset Hounds 20 21. The primary lesions consist of an ulceration affecting only the nasal philtrum that hemorrhages (Figure 7). The bleeding can be severe enough to cause anemia and require hospitalization. This condition has been successfully medically managed with prednisone acutely and doxycycline/niacinamide, fish oils and/or topical fluocinolone in dimethyl sulfoxide 20. Surgery to resect the affected tissue, ligate the vessels and reconstruct a new “philtrum” has also been successful 21.

Cutaneous and renal vasculopathy of Greyhounds

This condition most commonly affects Greyhounds between the ages of 1 and 4 years 22. Lesions occur most commonly on the tarsus, stifle or thigh and begin as bruising that progresses into sharply demarcated ulcers; these extend into the subcutaneous tissue and heal slowly. Azotemia, polyuria, polydipsia, vomiting, dark or tarry stools, salivation, pyrexia and distal limb edema develops in some cases. Skin biopsies show thrombosis and necrosis of arteries, arterioles, venules and capillaries which cause large areas of tissue necrosis. Renal biopsies show peracute glomerular necrosis involving afferent arterioles, with thrombi in glomerular capillaries. When signs of renal failure are present, aggressive fluid therapy and supportive care is required, but these cases often die. There is some suggestion that this may be similar to hemolytic uremic syndrome in humans, which is caused by a Shiga-like toxin produced by Escherichia coli 22.

Environmental vascular diseases

Solar vasculopathy

Chronic sun exposure can cause damage to the vessels in the superficial dermis. This most commonly affects non-pigmented and lightly haired skin on the dorsal muzzle and nasal planum. Acute clinical signs are erythema, swelling, erosions or ulceration, and with chronic sun exposure this can lead to scarring and further depigmentation. Treatment is mainly through sun avoidance.

Cryofibrinogenemia and cryoglobulinemia

This is a very rare disease whereby cold temperatures cause either fibrinogen or globulins in the blood to form thrombi or immune complexes which precipitate and induce vasculitis. The end result is disruption of blood flow to the extremities, resulting in pain, erythema, purpura, acrocyanosis and necrosis. The cryoglobulins can also target erythrocytes and cause a hemolytic anemia, renal disease or peripheral polyneuropathy. These conditions may be primary in nature or can be secondary to infection or lead poisoning. Diagnosis is by demonstrating agglutination of blood at cold temperatures, a Coombs test, or measuring cryoprecipitate levels. Management involves avoiding a cold environment, correcting the underlying cause, and occasionally medical management with corticosteroids or pentoxifylline.

Vascular diseases of the skin most commonly affect the skin over pressure points and distal extremities, such as the footpads, tail, pinnae and scrotum. Vasculitis often causes a severe clinical syndrome with systemic signs, with ulcerations and necrosis of the skin, while ischemic dermatopathy is typically much milder with lesions resulting from epidermal hypoxia. In all instances the underlying triggers should be identified whenever possible, and whilst treatment for both vasculitis and ischemic dermatopathies employ similar medications, the therapy should always be tailored to the severity of disease.