Diagnosing and managing canine cutaneous vasculitis (Proceedings)

Background/Etiology/Pathophysiology

Vasculitis is characterized by an aberrant immune response directed toward blood vessels. Histologically there is an inflammatory response involving and destroying blood vessels leading to ischemic changes (see histopathology). A vasculopathy is a disease process in which tissue changes are consistent with ischemia but histologically vasculitis can't be identified. Clinically, vasculitis can involve just the skin or there can be systemic involvement (eg uveitis, glomerulonephritis) or both. Vasculitis may be caused by drugs (including vaccinations); bacterial, viral, fungal or rickettsial infections (either induced by direct invasion of the vessel walls by the pathogen or as a result of immune complex formation (type III hypersensitivity); idiopathic/genetic (Jack Russell dogs); neoplasia; cutaneous adverse food reactions or an autoimmune disease (systemic lupus erythematosus)

The pathophysiology of vasculitis remains poorly understood, however, immunologic mechanisms appear to play an active role. It has been hypothesized that cytokine-mediated changes in the expression and function of adhesion molecules together with inappropriate activation of leukocytes and endothelial cells are key factors influencing vessel inflammation and damage. Although the primary events that initiate this process remain largely unknown, recent advances in human medicine have allowed investigators to examine the pathogenesis involved in disease. Three of the more popular theories are:

     1. Circulating immune complex formation and deposition in the vessel wall (type III hypersensitivity);

     2. Direct binding of antibody to vessel wall antigen (type II hypersensitivity)

Cutaneous small vessel vasculitis (CSVV) affects small dermal vessels especially the post capillary venules. CSVV is the most common form of canine cutaneous vasculitis. In dogs, the cellular infiltrate is the most common method used for categorizing the vasculitis. These forms include neutrophilic leukocytoclastic, neutrophilic non-leukocytoclastic, lymphocytic, eosinophilic or granulomatous. It is important to realize that the findings on biopsy are time dependent. The predominant cell type found on biopsy may only be a reflection of the stage of the disease process rather than a reflection of different diseases. In cutaneous small vessel leukocytoclastic vasculitis, if the lesions are biopsied early (< 24 hours) in the disease process, a granulocytic infiltrate may be seen, while if biopsied 48 hours or later it will be mostly a lymphocytic infiltrate. There are some forms of cutaneous small vessel vasculitis (CSVV) that are lymphocytic from the onset (eg vaccine associated)

Diagnosis

Clinical findings that are seen with CSVV include: scaling, alopecia, purpura (bleeding into the skin manifested as petechiation and/or ecchymoses), ulcers, wheals, nodules, dependent edema, acrocyanosis, and panniculitis (if deeper vessels are involved). Distribution of the lesions includes the distal extremities (including the tip of the ears and tail) and pressure points. Systemic disease may be present as a consequence of the vasculitis (hepatopathies, glomerulonephritis, synovitis-arthritis, gastroenteritis, pleuritis/pericarditis) and/or due to the underlying disease (eg anemia and/or thrombocytopenia with SLE).

There are a number of subtypes of vasculitis/vasculopathy including

     1. Urticarial vasculitis that represents a peculiar subset of small vessel vasculitis. The clinical presentation is that of wheals or serpentine papules, sometimes with surrounding or geographically separate angioedema. In contrast to other forms of urticaria, urticarial vasculitis lesions are slow to resolve, often lasting for several days and purpura may be present. This form has been reported to be frequently associated with cutaneous adverse food reaction.

     2. Proliferative thrombovascular necrosis of the pinna has an unknown etiology. There is no predilection based on signalment. The lesions begin on the pinnal tip and spread proximally on the concave surface. There is a wedged shaped appearance to the lesion – w/the tip of the wedge most proximally. There are ulcers, crusting and scaling present.

     3. Familial (autosomal recessive) cutaneous vasculopathy in German Shepherd dogs has been reported in Canada. This genodermatosis is frequently triggered by vaccinations, w/the lesions appearing 7-10 days post vaccination. The pup is systemically affected (lethargy, lameness, joint swelling, fever +/- lymphadenopathy). Cutaneous lesions include firm swelling of the bridge of the nose, ulcers and crusting on the pinnae, nasal planum and the tip of the tail. Footpads are swollen, depigmented and may ulcerate. CBC, serum chemistry profiles, ANA titers, RF titers, Coombs tests and immunoglobulin levels have all been normal

     4. Proliferative arteritis of the nasal planum has been reported in Saint Bernards and Giant Schnauzer. The author has also identified it in a Great Dane. The etiology is unknown. There are linear ulcers on the nasal planum (nasal philtrum) that are non-pruritic. There may be significant hemorrhage from the lesions. Therapy w/prednisone, topical steroids, tetracycline, niacinamide and fatty acids (omega 3/6 combination) have all been reported to be helpful in managing this disease.

     5. Idiopathic cutaneous and renal glomerular vasculopathy in racing Greyhounds ("Alabama rot"). There is no age or sex predilection. There may be a genetic predisposition to this disease. Clinically it begins as multifocal erythematous cutaneous swellings that then ulcerate. The lesions involve the limbs +/- abdomen and trunk. The swellings may drain a serosanguineous fluid. Pitting edema may be present. Systemic signs (fever, lethargy, GI signs) including signs associated w/ acute renal failure have been reported. Etiology is thought to be associated w/verotoxin produced by E. coli that is present in undercooked beef products.

     6. Vasculitis of Scottish terrier has been reported as a probable genodermatosis. At 3-4 weeks of age the dogs developed a nasal discharge w/subsequent ulceration and destruction of the nasal planum and nostrils. There is no effective treatment.

     7. Vasculitis of Jack Russell Terriers has been reported. In one case report the age of affected dogs (5) ranged from 3 months old to 11 years of age. The cause of the disease is not known but in 3 of 5 dogs the symptoms occurred 2-3 weeks post vaccination. The author suggests that perhaps these dogs had adult onset dermatomyositis. There is a good possibility that these dogs had vasculitis.

     8. Dermatomyositis may occur as a genodermatosis in collies and shelties or spontaneously in adults of other breeds. The age of onset is between 6 weeks and 1 year of age- usually before 6 months of age. The lesions may be fairly limited and heal as the puppy matures or they may progress. Usually the lesions cease by the time the dog is a year old. The cutaneous lesions, which are usually the more prominent clinical sign, include alopecia, scaling, crusts, erosions, ulcers, depigmentation, hyperpigmentation and scarring. These lesions occur on the face, mucocutaneous junctions, carpal and tarsal regions and the tip of the tail and ears. Onychodystrophy may also be present. Secondary bacterial pyodermas may occur. Muscle involvement tends to be proportional to the severity of the skin lesions and is usually identified subsequent to the cutaneous lesions developing. These dogs may develop megaesophagus or muscle atrophy involving the muscles of mastication and ambulation. Differential diagnoses include demodicosis, dermatophytosis, superficial bacterial folliculitis, discoid lupus erythematosus and epidermolysis bullosa simplex. In the author's experience, puppies are mostly commonly presented with limited facial lesions that the breeder claims are wounds/scars from the other puppies or a cat in the house. Diagnosis is based on signalment, physical examination and histopath changes consistent w/a vasculopathy.

     9. Post rabies vaccination alopecia is a syndrome that occurs 2-12 months after administering a rabies vaccine. Small white breeds of dogs seem to be at risk for developing these lesions. SQ or IM injections have no impact on the occurrence of this reaction. Lesions consist of scaling, alopecia, plaques, hyperpigmentation, nodules, erosions, crusts and cutaneous atrophy (scarring). The lesions may also develop at sites distant from the vaccination site. Histologically, in addition to the vasculitis changes, septal panniculitis and focal lymphoid nodules will be seen.

The diagnosis of any skin disease is based on detailed history taking, clinical findings (identification of primary lesions, distribution of lesions), laboratory testing and therapeutic trials. For vasculitis the most beneficial laboratory procedure is histopathologic evaluation. Evaluation of a patient w/confirmed vasculitis should include a detailed history of drug exposures (including vaccinations), a thorough examination (including a retinal exam) and as a minimum database – a CBC, serum chemistry profile and urinalysis. A urine total protein/creatinine ratio or a test for microalbuminuria should also be performed. Other diagnostics that may be performed depend on the signalment and presentation. These tests could include; tick titers; blood, tissue or urine cultures; Coomb's test, ANA, thoracic or abdominal radiographs; or abdominal ultrasound.

Histopathology

Because there are only a limited number of histopathologic manifestations of vasculitis, regardless of the cause, it is best to think of vasculitis as a reaction pattern with a variety of different etiologies. Regardless of the cause, vasculitis is a disease process characterized histologically by inflammation and destruction of blood vessels and ischemic changes characterized by smudging and paleness of the dermal collagen, a cell poor interface dermatitis, dyskeratotic keratinocytes, full thickness necrosis of the epidermis, follicular and adnexal atrophy and a mural folliculitis.

Differential diagnosis

Coagulopathies, cold agglutinin disease, frostbite, DIC, demodicosis, dermatophytosis, superficial bacterial folliculitis and discoid lupus erythematosus are possible differential diagnoses depending on the distribution and appearance of the lesions.

Treatment

The first step is to identify and treat the underlying cause (if possible) and/or avoid it (eg drug induced). When planning treatment be sure to consider the severity of the disease so that the treatment is not worse than the disease. Depending on the severity of the symptoms therapy may include: pentoxifylline, glucocorticoids (GC), other immunosuppressive agents, sulfones and immunomodulating agents. All cases of vasculitis that the author treats systemically will have pentoxifylline included as part (or all) of the initial therapy. Pentoxifylline is a methyl-xanthine derivative that increases RBC deformability and lowers blood viscosity thereby allowing for better blood flow through narrowed/edematous vessels. It also suppresses synthesis of proinflammatory cytokines such as IL-1, IL-4, IL-12 and TNF-α. Pentoxifylline is administered at 15 mg/kg tid. There may be a 30-90 day lag before full clinical response is seen. Vitamin E (400-800 IU bid) and Essential Fatty Acids may also be useful as part of the treatment since these nutrients have anti-inflammatory properties and anti-oxidant activities. D-alpha-tocopherol (natural form) is recommended.(dl form is synthetic is not absorbed as well)

Tetracycline/Niacinamide may be used in milder forms of the disease. Tetracycline and niacinamide have various anti-inflammatory & immunomodulating properties. The dosage for tetracycline and niacinamide in dogs or cats <10 kg is 250 mg of each, q 8 hours. For dogs >10kg - 500 mg of tetracycline and 500 mg of niacinamide q 8 hours are administered. If there is clinical response (usually waiting for a few months) it is slowly decreased from tid, to bid to sid. Side effects are rare but when they occur as usually due to niacinamide. These side effects include vomiting, anorexia, lethargy, diarrhea and elevated liver enzymes.

Glucocorticoids (GC) are the main stay of therapy for many forms of vasculitis. The most potent topical GC (veterinary product) is a product containing fluocinolone acetonide (Synotic). If the disease is localized (eg tip of the pinna) but is not adequately controlled with synotic, the author uses an even more potent product containing desoximetasone – at a concentration of 0.25%. These topicals are applied bid until clinical remission (not to exceed 21 days) and then tapered slowly over the next few months. Be sure to have the owners wear gloves when applying these products. Please note that topical steroids may cause pu/pd/polyphagia. This sensitivity to steroids is quite variable and may occur in unexpected situations. If side effects occur or if the lesions fail to respond to topical steroids, topical tacrolimus (0.1%) may be helpful.

Prednisone is administered at 1 mg/# bid for 4 days then ½ mg/# bid for another 10 days. The dog is rechecked every 14 days. If the disease is in remission, the dose is decreased 25% every 14 days. The author defines "remission" as the absence of any active lesions. Don't taper the dose too quickly. The goal is to maintain the dog on 0.25 mg/# or less every other day. If this is not achievable, then azathioprine is added to the therapy (see below).

If an animal fails to respond to prednisone, not only will other immunosuppressive agents (see below) be added to the therapy but also changing to either dexamethasone or triamcinolone may be necessary. For either of these drugs, use 0.05-0.1 mg/# bid as the starting dose and then taper as previously discussed.

Animals on chronic GC, regardless of dose should have a CBC, serum chemistry profile, urinalysis and urine CULTURE (looking for asymptomatic bacteriuria) every 6 months.

Azathioprine (AZA) is an antimetabolite that is a competitive inhibitor of purine. Purine is necessary for DNA formation, so in the presence of AZA, defective DNA is formed preventing cell replication. It is absorbed as a pre-drug that is transformed to its active form, 6 mercaptopurine, in the liver. 6-MP disrupts the normal DNA and RNA synthesis, preventing cell division leading to cell death. It is metabolized in the liver by 3 distinct enzyme systems- one being xanthine oxidase (XO). XO metabolizes AZA to an inactive metabolite. Remember that allopurinol is a xanthine oxidase inhibitor used for treating urate stones in dogs. So don't use azathioprine in a dog that is on allopurinol. AZA has a lag phase of four to six weeks before it reaches its full potential. The drug is administered concurrently with GC. The initial dose of azathioprine is 1.0 mg/# sid. Once remission is achieved, and the dog is either off of GC or the lowest dose of GC has been obtained, AZA is then tapered, also every 14-30 days. Usually the author will decrease the frequency, not the dose of azathioprine, first decreasing it to every other day and then if the disease is still in remission, to every 72 hours. A CBC, platelet count, serum chemistry profile are performed every 14 days for 2 months, then q 30 days for 2 months then q 3 months for as long as the dog is on azathioprine. Potential adverse effects include anemia, leukopenia, thrombocytopenia, hypersensitivity reactions (especially of the liver) and/or pancreatitis. AZA should not be used in cats- it may cause irreversible bone marrow suppression.

Chlorambucil (CAL) in dogs who failure to respond to azathioprine or can't tolerate it. The protocol/precautions/monitoring for CAL is the same as w/AZA. The induction dose is 0.1-0.2 mg/KG/day.

Cyclosporine (CSA) could be added to cases that fail to respond to the previous treatments. Be sure to use modified cyclosporine (Atopica®) since unmodified CSA is not absorbed as well. The dosage is 5 mg/kg sid.

In cases of neutrophilic vasculitis that fail to respond to the above treatment, sulfasalazine (SZA) at a dose of 25 mg/kg tid (maximum 3 grams/day) may be useful. Side effects associated with this drug include anemia, KCS and hepatotoxicity so a CBC, serum chemistry profile and Schrimer tear test are performed every 14 days for 2 months, then q 30 days for 2 months then q 3 months for as long as the dog is on SZA. In cases of neutrophilic vasculitis that fail SZA can sometimes be successfully treated w/dapsone, however, dapsone appears to be more toxic than SZA.

Dapsone acts against bacteria and protozoa in the same way as other sulfas, it inhibits folic acid production via a competitive inhibition of PABA. The mechanism of action for its anti-inflammatory actions is not thoroughly understood. It appears that neutrophilic inflammatory diseases respond best to dapsone. This may be due to dapsone's ability to interfere w/one of the neutrophils killing mechanism, the respiratory burst that releases cytotoxic substances. Dapsone also inhibits neutrophil chemotaxis and lysosomal enzymes production along w/decreasing complement activation and antibody production. It is also an antioxidant (scavenges ROS). The dose is 1 mg/kg tid. A CBC, platelet count, serum chemistry profile are performed every 14 days for 2 months, then q 30 days for 2 months then q 3 months for as long as the dog is on dapsone. Side effects include hepatotoxicity, anemia, thrombocytopenia, neutropenia and GI disturbances.

In cases of eosinophilic vasculitis, urticarial vasculitis or poorly responsive vasculitis, a home cooked elimination diet trial should be performed.