Pemphigus foliaceus: Chronic cases typical, challenging to treat

As the years go by, I am amazed by the number of difficult cases that I continue to see in my practice.

The following case is a patient that made me work hard to come to a definite diagnosis, but who responded modestly to appropriate medical therapy.

A 4-year-old spayed female Cattle Dog presented with a three- to four-month history of alopecia, crusts and some loss of pigment on the nose. The owner reported that the dog rubbed the muzzle a fair amount, and that blood was seen on the rug where the dog rubbed its nose. In addition, the owner was told by her primary veterinarian to keep the dog away from sunlight between 10 a.m. and 4 p.m., since this was most likely exacerbating the lesions. The referring veterinarian recommended sunblock applied to the affected area every 12 hours and prescribed topical triamcinolone cream and 500 mg niacinamide every eight hours as well as 500 mg tetracycline every eight hours.

The owner felt the lesions did not respond to treatment (the dog licked off most of the topical products after application), and seemed to get worse over time.

Photo 1: Note the patches of depigmentation on the planum near the nares opening.

Photo 2: Note alopecia was noted on the dorsal muzzle, accompanied by focal crusts and erosions, and one large pustule.

The physical examination revealed patches of depigmentation on the planum near the nares opening as well as the alar folds in a symmetrical pattern (Photo 1). Alopecia was noted on the dorsal muzzle (haired area near the planum) and was accompanied by focal crusts and erosions, and one large pustule (Photo 2). A higher magnification of the pustule is seen in Photo 3.

The problem list for this patient included alopecia, crusts, erosions, depigmentation and pustules. In my opinion, the crusts have evolved from dried, older pustules. The erosions have resulted from rubbing and the subsequent removal of the crusts. This type of erosion suggests a fairly superficial process, perhaps upper or mid-epidermis.

Photo 3: A higher magnification photograph of the pustule in Photo 2.

Differential diagnoses for these lesions included pemphigus foliaceus, pemphigus erythematosus, superficial bacterial folliculitis, discoid lupus erythematosus, drug eruption, pustular dermatophytosis, T-cell lymphoma and Vogt-Koyanagi-Harada-like syndrome.

My initial diagnostic plan included cytology of the pustule. A skin biopsy of the crusts and pustule was performed with local analgesia in combination with intravenous medetomidine/butorphanol. The results revealed numerous intact, non-degenerate neutrophils; few eosinophils; and numerous acantholytic cells (rounded keratinocytes). These findings were compatible with pemphigus foliaceus as described in the dog.

The results of skin histopathology revealed broad, superficial, subcorneal pustules containing varying degrees of acantholytic cells (normal epidermal kertinocytes that have lost their cohesion). Some of the pustules extended into the follicular epithelium. All the pustules contained numerous neutrophils and few eosinophils. Some dermal inflammation was noted just below the basement zone.

The combination of the clinical presentation, results of cytology, and the results of skin histopathology proved diagnostic for facial pemphigus foliaceus.

Clinical remission was not achieved with the combination of prednisone and azathioprine. Cyclosporine alone and oral triamcinolone also failed to reduce the pustule formation. The case was lost to follow-up.

Immunosuppression is the main foundation therapy for dogs diagnosed with pemphigus foliaceus. Corticosteroids serve as the foundation treatment, tend to provide clinical remission, but may produce undesirable side effects. Initially, the dosage of prednisone for the treatment of pemphigus foliaceus ranges from 2-6 mg/kg daily. My experience with prednisone in dogs, is the occurrence of unacceptable polydypsia and polyuria as well as incontinence occurs more frequently than with methylprednisolone. Methylprednisolone is 20 percent more potent than prednisone or prednisolone, so the dosage is a bit lower. Triamcinolone (available in 0.5 mg and 1.5 mg tablets) can be most useful in cats and should be reserved for severe, refractory cases in the dog. Triamcinolone is about 10 times more potent than prednisone per milligram. Dexamethasone is safe only for cats and has a similar potency as triamcinolone.

In most cases of pemphigus foliaceus, the disease tends to be chronic. As a result, I recommend the addition of azathioprine (chlorambucil in the cat) as an adjunct to corticosteroid therapy. The goal would be to taper off corticosteroid therapy and use azathioprine long-term. The dosage of azathioprine is 1-2 mg/kg/day daily for one to two weeks, then reduced to every other day or every third day. Monitoring the results of complete blood counts (CBC) as well as liver enzymes is important, since bone suppression and hepatotoxicity are rare but potentially serious side effects. A CBC is recommended two weeks after initiation of therapy, then every two to three months. Blood chemistries, including measurement of liver enzymes, should be performed every three to six months.

Photo 4: Results of the skin histopathology show broad, superficial subcorneal pustules containing varying degrees of acantholytic cells.

Alternatives to corticosteroids and azathioprine for dogs include cyclosporine (10 mg/kg/day) as a single agent. Cyclosporine inhibits activated T-cells and some cytokines. This drug can cause gastritis (vomiting), diarrhea and renal failure (rare and difficult to prove). Famotidine administered 30 minutes prior to cyclosporine can reduce or eliminate vomiting and nausea. Viral papilloma formation, hypertrichosis, gingival hyperplasia and bizarre skin eruptions have also been experienced in rare instances.

Luflunomide, a strong immunosuppressant, now available as generic, has been used rarely in dogs for treatment of auto-immune disease. It inhibits T and B cells, antibody synthesis and antagonizes several cytokines. The dosage is 2-6 mg/kg/day. Trough levels should be achieved at around 30ug/ml.

Cellcept (mycophenolate mofetil) is a relatively new immunosuppressant that has been used rarely in dogs for the treatment of auto-immune diseases. This drug has potent cytostatic effects on T and B cells. Cellcept also suppresses antibody formation. The dosage is about 20 mg/kg BID. Diarrhea is the main side effect and is dose dependent.

The exact pathomechanism of canine pemphigus foliaceus is not known but it is considered to be an auto-immune disease involving the production of auto-antibodies (Immunoglobulin G, rarely Complement 3). The autoantigen is a component of the desmosome (desmoglein) that is considered a normal structure and a part of the intercellular "bridging" that allows epidermal cells to remain connected. It is part of the cytoskeleton and allows the epidermis to be part of the skin tissue. As a result of this antibody deposition, the epidermal cells (keratinocytes) lose their cohesion and fall apart (acantholysis). In a very short time after this acantholysis (blister formation), the canine immune system recruits neutrophils that quickly migrate into the inter-keratinocyte space, thus producing the classic pustule seen clinically, as well as histologically. This is what occurs in humans, except for the influx of neutrophils.

There has been speculation that genetic factors play a role in humans, since certain genetic markers have been discovered that link certain individuals to pemphigus vulgaris (more severe form of pemphigus that involves mucous membranes). Although this has not been demonstrated or proven in dogs, a marked breed predilection occurs. Akitas, Chow Chows, Dachshunds, the Finnish spitz, Bearded Collies and others are considered predisposed. In people, there is an endemic form of pemphigus foliaceus reported in Brazil and is called "fogo selvagem" or "wild fire." Wild fire refers to the burning or even stinging sensation that some patients experienced when exposed to sunlight. Epidemiologists speculated a black fly served as a vector. This was believed to be true since most people who developed lesions were exposed to black fly bites, while others who were not exposed did not develop lesions. Some human patients with pemphigus foliaceus may develop blisters in uninvolved skin. UV-B may be the wavelength involved and may also be implicated in cases of experimentally-induced blisters in humans exposed to artificial UV-B light.

Other factors that have been implicated in the cause of pemphigus foliaceus in humans include drugs and neoplasia. The most common drugs implicated in human pemphigus foliaceus include penicillamine and penicillin type antibiotics. In people, paraneoplastic pemphigus foliaceus has been reported to occur in association with lympho-proliferative neoplasia. In the dog, there have been two reports of paraneoplastic pemphigus foliaceus and have been related to thymic lymphoma and splenic sarcoma. There has been some association in cats with the administration of methimazole and the onset of pemphigus foliaceus.

In conclusion, facial pemphigus foliaceus has a slightly different clinical (facially confined) distribution, deeper histologic changes (follicular acantholysis) and can be refractory to some treatments. Knowledge about the known immunopathogenesis, newer drugs and their mechanisms of action, and awareness of less expensive sources of certain drugs may allow successful treatments.

Dr. Vitale received his veterinary degree from Mississippi State University, College of Veterinary Medicine. He completed a residency in veterinary dermatology at the University of California, Davis and is a diplomate of the American College of Veterinary Dermatology. He is a clinical instructor/lecturer at UC-Davis and a staff dermatologist at East Bay Veterinary Specialists (formerly Encina Veterinary Hospital), Bay Area Veterinary Specialists and San Francisco Veterinary Specialists.