Pemphigus foliaceus in cats

Introduction

Pemphigus foliaceus (PF), the most common autoimmune dermatosis in cats (1), typically presents with pustular and crusting lesions (1–3). Implicated in the pathogenesis of PF are autoantibodies targeting antigens likely associated with desmosomes or other intercellular linker proteins (4–6) that maintain adhesive bonds between epidermal keratinocytes; impairment of these intercellular adhesions results in acantholysis (intercellular separation) (5–7). When acantholysis occurs in the upper epidermis, intracorneal and subcorneal pustules arise (5,7). Although the major target antigen causing feline PF has not been identified, recent detection of anti-keratinocyte autoantibodies in PF-affected cats at a higher rate than in healthy cats is a step toward identifying the major target antigen (4). The target antigen is suspected to differ from that reported in dogs (desmocolin-1) (4,8). Desmoglein-1, the major target antigen in human PF, is currently considered the most relevant potential major target antigen in feline PF (8).

Clinical presentation

In cats, as in dogs, PF most commonly affects middle-aged individuals (1,3,6,9). Unlike in dogs, for which there is a breed predisposition in Akitas and chows, there is no true breed predisposition in cats, although PF is more often reported in the domestic shorthair than in other breeds (1–3,9). Further, PF does not exhibit a sex predisposition in either species (1,2,6).

There are several potential triggers for PF in cats, including medications, vaccines, and concurrent disease (1). There are multiple reports of cats developing PF within a few weeks after vaccination, specifically for rabies (1,9). There have been numerous possible drug associations mentioned in the literature; however, in many instances, direct causation cannot be established, as the implicated drugs were not reintroduced to affected animals (6,9). Doxycycline was strongly suspected as the trigger in 1 cat, as accidental reintroduction caused a disease flare (1). Cimetidine, enilconazole/neomycin/triamcinolone/amoxicillin, and itraconazole/lime sulfur were also suspected triggers in 3 cats in which PF resolved spontaneously after withdrawal of the offending medication (1). Cefovecin, clindamycin/carprofen, and ipodate were implicated in the cases of 3 cats, all of which needed treatment beyond withdrawal of the offending medication. In the case of cats treated with cefovecin and clindamycin/carprofen, immunosuppressant therapies were eventually withdrawn (1). Other medications indicated as possible triggers for PF, albeit with less convincing evidence, include methimazole, ronidazole, penicillin G, vitamin B12, oxytocin, and radioactive iodine (1,9). Thymoma and leishmaniosis have been identified as disease processes with potential to trigger PF in cats (1).

Lesions associated with feline PF include pustules, crusts, erosions, ulcerations, and alopecia (3,7,9). Due to their transient nature, pustules are less common than crusts, which often span multiple hair follicles (2,6). Lesions most commonly affect the head/face (including nose, pinnae, and eyes), claw folds, and paw pads, and are typically bilaterally symmetrical (Figure 1) (1–3). Lesions can also affect the periareolar and perianal regions (1,3). Typically, lesions affect multiple locations (1,3). However, there are several reports of cats presenting only with crusting lesions and infection around the claw folds, known as paronychia (Figure 2) (1,10).

Figure 1.

Cat with pemphigus foliaceus exhibiting crusting lesions affecting the periocular region, muzzle, and chin.

Photograph courtesy of Frédéric Sauvé, DVM, MSc, DiplACVD.

Figure 2.

Paw of a cat with pemphigus foliaceus exhibiting crusting lesions affecting the claw fold, consistent with paronychia.

Photograph courtesy of Frédéric Sauvé, DVM, MSc, DiplACVD.

Pruritus affects ~65 to 80% of cats with PF (1,3,6,9). Systemic clinical signs are also common and include fever, lethargy, and anorexia (1,3,6,9). Systemic clinical signs appear to be more frequent in cats than in dogs, in which systemic signs most often occur in cases of severe and widespread disease (1,2). Lameness has also been reported in pets when lesions involve paws or claw folds (9).

Diagnosis

Diagnosis is based on clinical signs, microscopic confirmation through cytology and histopathology, and exclusion of other possible differential diagnoses (1,3).

Cytology is most beneficial when a smear is obtained from an intact pustule but cytology can be done using material from underneath crusts (3). Cytology findings include nondegenerate neutrophils, acantholytic cells, and microorganisms such as bacteria or yeast if secondary infection is present (2). Acantholytic cells typically appear as round, darkly staining cells with central nuclei (Figure 3) (2,6).

Figure 3.

Cytological sample from a case of pemphigus foliaceus. Note the large, circular, acantholytic cells with darkly staining nuclei among the neutrophils.

Photomicrograph courtesy of Frédéric Sauvé, DVM, MSc, DiplACVD.

Biopsies are best taken from intact pustules; however, if those are not present, crusted lesions should be obtained (3). On histopathology, there are usually pustules located in the superficial epidermis (intracorneal or subcorneal) (3,6,7,11). Pustules are primarily composed of neutrophils and acantholytic cells, which can present as individual cells or rafts of multiple cells, although eosinophils can also be noted (2,3,11). Dermal inflammation is predominantly neutrophilic but mast cells and plasma cells can be seen with some frequency, although eosinophils are not commonly part of the dermal inflammation (3,9). The epidermis is hyperplastic with the stratum corneum exhibiting orthokeratotic hyperkeratosis (3).

Differential diagnoses for superficial epidermal pustules in cats with acantholysis are limited but include pustular dermatophytosis and subcorneal pustular dermatitis caused by Staphylococcus spp., although the latter has not been well-described in cats (1,2). Although fungal cultures are often recommended in the literature as part of the diagnostic work, case reports suggest they are not routinely done (3,9). Bacterial cultures based on cytology results should also be considered, to guide antimicrobial therapy.

General blood work, including a complete blood (cell) count (CBC) and serum biochemistry panel, along with FIV/FeLV testing, are warranted before starting immunosuppressive treatments. Changes on blood work tend to be nonspecific (3). Leukocytosis and neutrophilia are the most common changes (3,7,9), whereas monocytosis, lymphopenia, eosinophilia, or anemia may also be present (3,9).

Treatment

Immunosuppression is the mainstay of PF treatment (7). Glucocorticoid monotherapy is the most common initial therapy for cats, with complete remission achieved in most animals (1,7,9). Prednisolone is the most commonly used glucocorticoid, but other options include triamcinolone and dexamethasone (1,7). In 1 case series (3), triamcinolone was more likely to induce remission and had less frequent adverse effects than prednisone. Unfortunately, it is not possible to compare the response to triamcinolone to that of prednisolone, which has greater bioavailability in cats, due to low case numbers in more recent case series (1,3,9). High-dose oral glucocorticoid pulse therapy, similar to that recommended for dogs, has been used in cats, but there is a perceived lack of benefit, as the interval to disease remission and the cumulative dose of glucocorticoid did not vary greatly from standard treatment protocols (1). Previously recommended doses for treatment were as high as 6.6 mg/kg per day, but lower doses (2 mg/kg per day) are equally effective at inducing remission (1,9,10). The most common adverse effects of glucocorticoids include polyuria, polydipsia, and polyphagia; the most serious adverse effects are diabetes mellitus, upper respiratory infections, urinary tract infections, and steroid hepatopathy (1,9). Injectable glucocorticoids should be used cautiously due to their anecdotally higher risk of causing severe adverse effects such as diabetes mellitus (9). Non-glucocorticoid options for treatment may need to be considered in animals not responding to glucocorticoids, in those with comorbidities that preclude the use of glucocorticoids, in those with severe adverse effects secondary to glucocorticoids, and in those in which glucocorticoids cannot be tapered to a dose considered safe for long-term use (7).

Other non-glucocorticoid treatments used as monotherapy or in combination with steroids with varying results include cyclosporine, chlorambucil, and gold salts. Cyclosporine (Atopica for Cats; Elanco, Mississauga, Ontario) is a calcineurin inhibitor labeled for management of feline allergic skin disease (12). Case series reported variable results for its use in the treatment of feline PF (1,9,12). As a monotherapy, it was efficacious for some, but not all, cases, with some case series suggesting a longer interval to disease remission (1,6,9,12). As an adjunct therapy, cyclosporine had efficacy comparable to that of chlorambucil in terms of interval to disease remission and overall disease response (12). The same case series reported it could also provide a glucocorticoid sparing effect, allowing systemic glucocorticoids to be reduced or eliminated (12). Although other case series reported on cyclosporine as an adjunct therapy, it is difficult to draw conclusions due to limited case numbers (1,9). Gastrointestinal clinical signs are the most common adverse effects of cyclosporine, but there are also rare reports of fulminant systemic disease (toxoplasmosis and mycobacterium) and neoplasia (12). Although there were isolated cases of neoplasia in cyclosporine-treated animals, increased prevalence of neoplasia was not reported in published clinical trials (13). Cats treated with cyclosporine should be tested for FIV/FeLV and have toxoplasma titers determined before initiation of treatment, to prevent treatment-induced development of clinical signs associated with these infectious diseases. Cats should also be kept indoors and not fed raw diets, and attempts should be made to taper cyclosporine to the lowest effective dose (12).

Chlorambucil is an alkylating agent often used as an adjunct treatment for its glucocorticoid-sparing effects or in cases of refractive disease (7). Although it can be used as a monotherapy for PF, it is difficult to draw conclusions about efficacy because of limited numbers of pets treated with chlorambucil monotherapy in recent case reports (1,9). Myelosuppression is a possible severe adverse effect and warrants routine blood work (7). Gold salts are mentioned in several case series as a possible treatment but are no longer commercially available (9).

Decisions regarding initial and maintenance treatment are usually based on multifactorial considerations of clinician preference, comorbidities, severity of disease, and response to treatment (9). Regardless of drug choice, the objective of initial therapy is to promptly achieve disease remission or resolution of the majority of lesions. Further, the objective of maintenance treatment is to determine the lowest effective dose that prevents relapse and decreases occurrence of adverse effects.

There are several alternative treatment options. Topical glucocorticoids can be used but should be reserved for localized disease (7). Prolonged use of potent topical steroids results in cutaneous atrophy or alopecia, and systemic absorption is possible (7). Topical steroids can be used with other therapies; e.g., a recent case report outlines the successful management of PF with topical hydrocortisone acetate and oral pentoxifylline (14). Oclacitinib (Apoquel; Zoetis, Parsippany, New Jersey, USA) is another alternative therapy described in 2 case reports in which the animal’s concurrent comorbidities precluded the use of glucocorticoids or immunosuppressive agents (15,16). In both reports, oclacitinib provided clinical improvement with subsequent dosage reductions within a generally short interval (15,16). Although no major adverse effects were reported and results appeared favorable, this use of oclacitinib was off label as safety studies have not yet been done in cats (15,16). More research into the use of oclacitinib for immune-mediated diseases is needed before it can become a treatment recommended by dermatologists.

Prognosis

Pemphigus foliaceus in cats generally has a good prognosis (1,6). One case series suggested that 90% of affected cats achieve disease control within 1 mo, with the interval to disease control varying only slightly depending on treatment protocol (1). This contrasts with dogs, in which reaching disease remission is less likely and often takes much longer (1). Most cats do, however, require long-term therapy and most often experience relapse with tapering or discontinuation of therapy (1,9). Relapse can also occur as part of the waxing and waning disease process (9). Thus, even with a good prognosis, client education regarding financial cost, time commitment, and emotional burden should be undertaken (9). Notably, in a quality-of-life survey for the owners of cats with PF, more than 60% of owners perceived that their cat was stressed by veterinary visits. The use of anxiolytics before appointments should be emphasized to improve both client and patient experience (9). However, euthanasia or death associated directly with PF or adverse effects of treatments appears less common in cats than in dogs (1).