History

A 3-year-old approximately 450-kg (990-lb) Quarter Horse gelding was referred to the University of Georgia's Large Animal Teaching Hospital because of fever, signs of depression, inappetence, extensive alopecia, and crusting of the skin of 1 month's duration. One month prior to referral, crusts and marked edema of the lower portions of the horse's limbs were evident. Cytologic examination of the moist underside of crusts taken from the skin of the lower aspects of the limbs performed at that time revealed infection with Dermatophilus congolensis. Appropriate systemic and topical treatments with antimicrobials, along with administration of NSAIDs, did not resolve the dermal lesions and had no influence on the horse's other clinical signs. The dermal lesions spread over the horse's entire body and onto the head during that treatment period. Subsequent IM injections of isoflupredone acetate (10 to 20 mg) given every 5 to 7 days resulted in rapid resolution of all clinical signs and temporary improvement of the crusted dermal lesions. The extensive alopecia improved during the course of this treatment.

Clinical and Gross Findings

At the referral evaluation, the horse was not febrile and had no signs of depression; however, it had been treated IV with glucocorticoids within the preceding 12-hour period. The lower portions of all 4 limbs were mildly to moderately edematous and covered with numerous tightly adhered crusts that had some areas of serum leakage. Larger and thicker crusts were present over the horse's entire trunk and head. Removal of the crusts exposed macroscopically normal-appearing skin. Overall, the density of hair in the horse's coat was less than that expected for a healthy horse (hypotrichosis). The lack of fever and signs of depression and absence of deeper dermal lesions beneath the crusts were attributed to the recent glucocorticoid administration. Intermittent glucocorticoid treatment was discontinued, and the horse was observed for 3 days. At the end of this 3-day period, all previously described clinical signs returned, along with newly formed diffusely distributed small crusts with underlying erosions and ulcerations (Figure 1).

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Photograph of the right side of the neck and shoulder areas of a horse that was evaluated because of fever, signs of depression, inappetence, extensive alopecia, and crusting of the skin of 1 month's duration. Notice the extensive, loosely adherent, superficial crusts; hypotrichosis (thin hair) is evident in the lower right portion of the image.

Citation: Journal of the American Veterinary Medical Association 237, 9; 10.2460/javma.237.9.1041

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Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page →

Histopathologic and Cytologic Findings

The horse was lightly sedated, and 5 skin biopsy specimens were obtained with an 8-mm-diameter biopsy punch from lesions on the neck after administration of a local anesthetic agent. Cytologic examination of impression smears made from the underside of randomly selected crusts revealed numerous variably degenerate neutrophils and acantholytic cells but no microorganisms. Histologic examination of sections of the skin biopsy specimens revealed mild to moderate orthokeratotic hyperkeratosis of the epidermis. Large, subcorneal and intragranular pustules were evident; the pustules were typically composed of 5 to 10 layers of keratinized squamous epithelium overlying a large aggregate of neutrophils, sloughed keratinocytes, and pyknotic cellular debris. Within the granular layer of the epidermis, there was marked acantholysis that was characterized by complete separation of epidermal keratinocytes, both individually and in small aggregates (Figure 2). The dermis appeared largely unaffected; however, in some sections, there was a mild neutrophilic infiltrate at the dermal-epidermal interface that extended into the superficial dermis, where dermal collagen fibers were mildly expanded by clear spaces (edema). In sections stained with Gram or Gomori methenamine silver stain, no bacterial or fungal organisms were detected microscopically.

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Photomicrograph of a section of a subcorneal pustule in a skin biopsy specimen obtained from the neck of the horse in Figure 1. The pustule contains acantholytic cells (which frequently formed rafts [black arrows]), neutrophils, and necrotic debris. H&E stain; bar = 50.0 μm.

Citation: Journal of the American Veterinary Medical Association 237, 9; 10.2460/javma.237.9.1041

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Morphologic Diagnosis

Marked, multifocal, suppurative epidermitis of haired skin (with subcorneal and intragranular pustules and acantholytic cells), consistent with pemphigus foliaceous.

Comments

Although pemphigus foliaceous (an autoimmune disease) is uncommon in humans, dogs, cats, horses, and goats,¹ it is nevertheless the most frequently reported autoimmune dermatosis in horses.² There are no apparent sex or breed predilections in horses, but familial cases in dogs and humans have been described.³ Pemphigus foliaceous has been diagnosed in horses at 2 months to 20 years of age.²

The diagnosis of pemphigus foliaceous is based on history, physical examination results, and distinctive cytologic and histopathologic findings. Primary skin lesions are characterized by superficial pustules, which may be very fragile and transient. Therefore, affected animals typically have extensive dermal crusting or scaling, along with variable degrees of secondary alopecia. Erosions are usually present underneath crusted lesions but may be absent as a result of recent immunosuppressive treatments. Skin lesions commonly develop initially on the face or limbs, and their distribution often becomes generalized within 1 to 3 months. In some horses, lesions may remain restricted to the coronary band. Preputial and mammary gland areas are often affected. Skin lesions can be exacerbated by warm, humid, and sunny weather. More than 50% of affected horses also have systemic clinical signs, including lethargy, anorexia, signs of depression, weight loss, and fever, although the mechanisms for the development of those systemic effects remain unclear.^1,2 On the basis of the gross features of pemphigus foliaceous in horses, differential diagnoses include dermatophytosis, dermatophilosis, bacterial folliculitis, multisystemic eosinophilic epitheliotropic disease, seborrhea, drug eruption, and epitheliotropic lymphoma.² Despite the similarities in the clinical appearance of these conditions, the cytologic and histologic features narrow the differential diagnosis list to pemphigus foliaceous, pyoderma, and blistering dermatophytosis.

The histopathologic characteristics of pemphigus foliaceous include the presence of marked acantholysis within or superficial to the granular cell layer (stratum granulosum) of the epidermis with subsequent formation of extensive clefts, vesicles, or pustules. Neutrophils or eosinophils may predominate within the pustules.² Superficial crusts that contain sloughed acantholytic cells may also be present. Special stains should be used to exclude the presence of bacterial and fungal organisms. However, as a general rule, distribution of vesicles and pustules over an extensive area of the epidermis is a typical feature of pemphigus foliaceous, whereas more focal collections of inflammatory cells and debris are associated with infectious processes.⁴ To preserve the architecture of these fragile lesions for microscopic examination, it is critical that affected skin areas are not scrubbed or clipped prior to biopsy sample collection. If trimming of long hair is necessary, it is best undertaken manually with scissors.

With regard to the development of pemphigus foliaceous-related lesions, there are 2 proposed mechanisms, both of which involve formation of autoantibodies. One mechanism involves production of immunoglobulins against desmoglein 1, a 150-kDa glycoprotein of the cadherin group of adhesion molecules.² When antibodies are bound to desmoglein 1, the formation of intercellular bridges between keratinocytes (desmosomes) is inhibited, resulting in acantholysis. The other mechanism involves formation of IgG that binds to cholinergic receptors, which are responsible for keratinocyte adhesion and mobility.² When the cholinergic receptors are inactivated by antibody binding, desmosomes are disassembled and acantholysis occurs.² It is proposed that animals with pemphigus foliaceous may also form antibodies against syndecan-1, another pro-teoglycan on the keratinocyte surface, because humans with pemphigus vulgaris or pemphigus foliaceous have decreased expression of this crucial binding substance.⁵In rare instances, results of immunofluorescent or immunohistochemical staining for antibodies against des-moglein 1 are useful in confirming a diagnosis of pemphigus foliaceous.

The underlying cause of autoantibody formation in cases of pemphigus foliaceous is unknown. In humans and dogs, a genetic predisposition is suspected.² Certain drugs, including penicillamine and phenylbutazone, have been implicated as causative agents, as have UV light exposure and emotional stress.⁵ In humans, diet is thought to have a role in the development of pemphigus foliaceous because the molecular structure of many foods is similar to that of known pemphigus foliaceous-inducing drugs.² In South America, there is an endemic form of human pemphigus foliaceous (termed fogo selvagem), which is believed to be associated with viral infection that is transmitted via an insect vector.⁶

Most horses with pemphigus foliaceous must be treated aggressively with immunosuppressive agents (eg, oral administration of glucocorticoids, azathioprine, or both). Some affected horses respond well to chrysotherapy (treatment with gold salts). Occasionally, horses respond to initial induction treatment with either glucocorticoids or gold salts and remain in remission, requiring no further treatment.⁷ However, approximately 50% of horses with pemphigus foliaceous relapse, and each relapse is often progressively less responsive to treatment.² Exposure of skin to UV light may exacerbate the condition; thus, avoidance of sunlight exposure is an important component of treatment. Typically, young horses (< 1 year old) have less severe disease and a better response to treatment.² In the horse of this report, it was not determined whether the initial crusts on the lower limbs were a result of infection (as indicated by detection of D congolensis via cytologic examination 1 month prior to referral) or were the first clinical signs of pemphigus foliaceus, or a combination of both. In retrospect, the possibility that the horse's immune-mediated disease was triggered by the antimicrobials administered to treat dermatophilosis prior to referral cannot be completely excluded.⁸ Oral administration of dexamethasone (0.16 mg/kg [0.07 mg/lb]) once daily was initiated immediately after skin biopsy samples were obtained from the horse; the dosage was gradually tapered over time. The horse's response to this treatment was rapid. After a treatment period of approximately 3 months, administration of dexamethasone was discontinued for approximately 6 weeks, during which time there was no recurrence of clinical signs.