Feline pemphigus foliaceus

Introduction

Pemphigus foliaceus (PF) is an autoimmune, vesicobullous to pustular skin disease recognized in many species, most notably dogs, cats, horses and humans. Clinical lesions in small animals typically include pustules and crusts, erosions and ulcers, as well as alopecia (Figure 1) (Figure 2a) (Figure 2b) 1. The disease is characterized histologically by acantholysis (the breakdown of desmosomes) and loss of adhesion between keratinocytes 2.

The first report of seven cases of feline PF was published in 1982 3 and to the best of the authors’ knowledge only two papers of a larger case series (>10 cats) have been published since then 4 5. Five forms of pemphigus are recognized in dogs and cats: pemphigus foliaceus, pemphigus erythematosus, panepidermal pustular pemphigus, pemphigus vulgaris and paraneoplastic pemphigus 1 6 7. In contrast to humans, who are frequently affected with pemphigus vulgaris (a deep form of pemphigus), PF is the most common form in dogs and cats 1.

Many cases of PF need long-term medical treatment with immunosuppressive drugs. While glucocorticoids are often used in feline patients, only limited and contradictory data for the need for, and choice and efficacy of, alternative medications are available 1 8 9.

Incidence, prevalence and predispositions

In most cases, the underlying cause for PF cannot be identified 1. The production of autoantibodies against adhesion molecules may result from an abnormal antigen stimulation or an exaggerated immune response 1. While genetic predispositions in humans and dogs exist, no such data has been published in cats. Breed and sex predispositions for feline PF have not been reported but domestic short-haired cats are said to be most commonly affected, and the age at disease onset, although reported to have a median of 5 years, can be highly variable 4 5. One study calculated a prevalence of 0.5% for feline PF over a 10-year period, so the disease seems to be rare in cats 4.

Pathology and possible triggers 

Keratinocytes develop structural molecules for either cell-to-cell (desmosomes) or cell-to-matrix adhesion (hemidesmosomes or anchoring fibril complexes). Autoantibodies against these proteins lead to intra- or sub-epidermal splitting with individual acantholytic keratinocytes or rafts of cells (Figure 3) and subsequently clinical signs of blistering. Depending on the autoantibody, blisters develop in the superficial or deeper layers of the epidermis. Deep lesions are seen with pemphigus vulgaris (with antibodies directed against desmoglein 1 and desmoglein 3) and with paraneoplastic pemphigus (with antibodies against desmoglein 3 and plakins). Superficial variants include pemphigus foliaceus (targeting desmoglein 1 in humans, and desmocollin 1 in dogs) and Ig-A pemphigus (targeting desmocollin 1 and 3) 10.

The exact pathomechanism of acantholysis in feline patients is still unclear 1. Autoantibodies bind one of two members of the cadherin group (responsible for cell-to-cell adhesion), and calcium seems to be a crucial element. This binding leads to an activation of intracellular mechanisms; it is thought that the protease urokinase plasminogen activator converts plasminogen to plasmin, resulting in the destruction of intercellular bridges and acantholysis 1 11 12. Complement has been suggested as a possible co-factor, although symptoms may occur without complement involvement.

Adverse drug reactions and other skin diseases have been reported to be trigger factors for some pemphigus variants in both human and animals 3 11 13. In some regional outbreaks, infectious triggers have been presumed 1. Black flies (in combination with viral diseases and environmental factors) were reported as an insect vector for human PF (Fogo selvagem) in South America 14. Another study noted that dogs which later developed PF frequently had a previous history of flea bite hypersensitivity 15, although this should be taken with caution due to the high incidence of flea bite hypersensitivity in dogs within the study area 2. Case reports of leishmaniasis as a possible trigger for canine PF have also been published 16.

Adverse drug reactions have been suspected as a trigger factor for PF in dogs and cats for a long time 5 17 18 19 but definitive identification of a medication as a trigger for a specific disease is very hard to achieve, and many authors will use an “adverse drug reaction probability scale” 20. One review retrospectively applied this scale to published case reports and studies and concluded only a “possible“ drug relation in almost all cases 2.

Clinical appearance

The primary lesion of PF in domestic animals is a pustule 2. The pustules are multifocal and rupture shortly after developing, leading to crusty erosions. Pruritus is variable, but (if present) may lead to secondary ulceration 4 21. Yellowish crusts and erosions on the face, ears, and feet are the main feature of PF in cats (Figure 1) (Figure 2a) (Figure 2b) 3 5 22. These pustules can be large and follicular or non-follicular, and may extend over several hair follicles (which is uncommon for bacterial folliculitis). While lesions in some feline patients are restricted to the head, face (Figure 2a) (Figure 2b) and inner pinnae (Figure 1), other cats show generalized disease 2. However severe generalized disease in cats is less commonly seen 2 5. In some cases PF mainly or exclusively targets the pads or ungual folds 2 3 4 5 22. Affected pads may be scaly or may develop crusts and erosions. Paronychia with a creamy to cheesy exudate is a PF feature unique to cats. Complete alopecia and generalized exfoliative erythroderma have been described with feline PF 9. Lethargy, anorexia, limb edema or fever are restricted to patients with severe, widespread erosions or ulcers 4.

Diagnostic findings

With appropriate history and clinical changes, impression smears should be obtained from intact pustules or areas underneath freshly removed crusts 4 21. Acantholytic keratinocytes, i.e., clustered, rounded keratinocytes with a dark blue “fried egg“ appearance, in combination with intact neutrophils or sometimes eosinophils, are suggestive for PF (Figure 3) 4 21 but are not pathognomonic. Acantholytic keratinocytes with neutrophils have also been reported with severe pustular Trichophyton dermatophytosis in dogs and horses and severe bacterial pyoderma and leishmaniasis in dogs 16 23 24.

Histopathology in combination with the clinical appearance and history is currently the gold standard to diagnose feline PF. Histopathologically, intraepidermal pustules with active acantholysis and without evidence of infection are consistent with PF (Figure 4) 1. In contrast to bacterial folliculitis, the pustules may be large and extend over multiple hair follicles 2 23. More chronic lesions show a mild dermatitis reaction with erosive epidermitis and serocellular crusting. Classically, acantholytic keratinocytes are observed as large eosinophilic cells in the serocellular crusting (Figure 4).

Direct immunofluorescence of skin biopsies may show a “chicken-wire” pattern of intercellular immunofluorescence (in cats predominantly due to intercellular IgG) 4. Indirect immunofluorescence for circulating serum IgG autoantibodies has been attempted unsuccessfully in feline PF patients 4. Affected cats may present with moderate to marked leukocytosis and neutrophilia, mild (non-regenerative) anemia, mild hypoalbuminemia and elevated globulins 1.

Treatment and outcome

Initial approach

The majority of cats with PF require immunosuppressive drugs, so a definite diagnosis is necessary prior to commencing treatment 1.

Glucocorticoid monotherapy which downregulates inflammatory cytokines and autoantibodies is often effective 8; prednisolone (2-5 mg/kg q24H) or triamcinolone (0.6-2 mg/kg q24H) is typically recommended (5,8). In one large study triamcinolone showed a higher remission rate (15/15 cats) than prednisone (8/13 cats) and less adverse effects 5. Since oral prednisone is not well-absorbed or metabolized (into prednisolone) in cats, prednisolone should be used in preference. A daily prednisolone dosage of 2 mg/kg q24H led to clinical remission in 37 cats with PF in one study, but other authors reported a lower (35-50%) success rate 1 8 9. Some cases may respond better to methylprednisolone or dexamethasone 1. Common glucocorticoid adverse effects in dogs (polyphagia, polyuria, polydipsia, weight gain and behavioral changes) are interestingly less frequent and less prominent in cats 8, although transitional or persistent diabetes mellitus and bacterial skin and bladder infections may be observed 1.

One study reported 9/11 cats (82%) with PF were treated successfully with a combination of prednisone and chlorambucil 5. Chlorambucil is an alkylating agent which affects cross-linking of DNA, resulting in a down-regulation of T- and B-lymphocytes 1 and is given at 0.1-0.2 mg/kg PO q24-48H. There can be a lag phase (2-4 weeks) before improvement is noted, so it is often combined with systemic glucocorticoids in the early treatment phase 5. Breaking the chlorambucil tablets should be avoided due to the exposure risk for staff and clients 1. Besides gastrointestinal (GI) adverse effects, patients should be monitored for signs of myelosuppression; such monitoring should occur more frequently in the early stages of therapy.

Calcineurin inhibitors, such as ciclosporin, bind to the intracellular immunophilins and thus inhibit cytokines such as interleukin-2 and T-helper and cytotoxic T-cells. Oral ciclosporin is usually administered at 7-8 mg/kg q24H and often initially combined with oral glucocorticoids. In one retrospective study 12 cats were treated with a combination of glucocorticoids and chlorambucil (n=6) or ciclosporin (n=6) 9. All six patients maintained with ciclosporin for PF management were weaned off systemic glucocorticoids and remained in remission, while glucocorticoid therapy could only be discontinued in one of six cats receiving chlorambucil. The most common adverse effects are GI signs. Prior to systemic ciclosporin therapy, a serum antibody titer for Toxoplasma should be obtained in free ranging cats or animals fed raw meat, as fatal outcomes have been reported in recently infected cats on ciclosporin therapy 25. A positive toxoplasmosis titer prior to ciclosporin therapy is currently regarded as protective against such events.

Azathioprine, an immunosuppressive agent frequently recommended in canine PF, is often associated with fatalities in cats, even at low doses, and therefore should not be used for feline PF.

Vitamin E at 250 mg q24H or essential fatty acid supplementation are frequently recommended as adjunctive therapy based on anecdotal evidence, although there are no studies published supporting such use.

Relapsing or refractory cases

While most patients respond to at least one of the above-mentioned therapeutic options, conventional therapy is unsuccessful in some patients. Switching the type of glucocorticoid or using an aggressive (three day) intravenous pulse therapy protocol may be beneficial 1. Alternatively, a combination of different immunosuppressive drugs at lower dosage may be attempted 1.

Chrysotherapy (administration of gold salts such as aurothioglucose) has been used in dogs and cats with PF. It is recommended that a small test dose (1 mg IM) of the chosen drug is first tried, before commencing weekly injections at 1 mg/kg until remission is achieved. This dose is then administered every 4-6 weeks as a maintenance therapy. A successful response to aurothioglucose in four out of ten cases of feline PF has been reported (the other six cats responded well to prednisolone 4. Skin eruptions, erythema multiforme and proteinuria are the main adverse effects for patients on gold therapy, and regular monitoring and urinalysis is recommended.

Topical tacrolimus (0.1% ointment) has improved focal lesions of PF in both canine and feline patients. Local erythema and stinging are described as possible adverse reactions of topical calcineurin inhibitors, particularly when applied on ulcerated skin.

Mycophenolate mofetil blocks the de novo purine synthesis (especially guanine) and thus selectively inhibits the proliferation of the guanine-dependent B and T lymphocytes, as well as consequently the production of antibodies, with comparably low adverse effects. Studies on its usage in human and veterinary autoimmune diseases show promising results. The current recommended dose for cats is 10 mg/kg q12H. The most frequently reported adverse reactions are GI signs, but there are rare cases of bone marrow suppression with a concurrent increased risk of infection. The potential for renal or hepatic toxicity seems to be relatively low.

In some patients euthanasia may be considered due to limited response to or adverse effects of treatment, or an owner’s financial or psychological limitations. In one study, four of 30 cats (13%) were euthanized due to the severity of the disease, treatment failure or adverse effects 5. An early referral to a veterinary dermatologist after a first treatment failure may result in a better outcome.

PF is an uncommon autoimmune, blistering skin disease that occurs in many different species. While the clinical appearance and the underlying etiology can vary, in most feline patients the typical lesions are pustules and crusts on the face, inner pinnae and footpads, as well as paronychia. Diagnosis is based on clinical history, appearance and histopathology. Immunosuppressive treatment is needed in most cases and can be long-term, expensive and frustrating due to relapses, adverse effects, treatment duration and costs.