1. General Considerations

   1. Autoimmune skin diseases are rare in large animals.
   2. Pemphigus foliaceus has been reported in horses and goats.
   3. Bullous pemphigoid has been reported in horses and Yucatan mini pigs.
   4. Discoid lupus erythematosus and systemic lupus erythematosus have been reported in horses.

2. Pathogenesis

   1. The pathogenesis of each of the autoimmune skin diseases mentioned below is the same described for dogs and cats in a previous section of Volume 2. Remember that drugs can trigger some of these diseases; therefore, a thorough drug history is important.

3. Clinical Signs

   1. Pemphigus foliaceus:
      1. It is a rare disease described in horses and goats.
      2. It is the most common form of pemphigus and the most common autoimmune skin disease of horses.
      3. There is no apparent age, breed, or sex predilection.
      4. Anecdotal reports indicate that triggering factors such as drug administration, systemic diseases, or stress precedes the onset of pemphigus foliaceus in horses.
      5. In horses, skin lesions usually begin on the face or limbs including the coronary band, and become widespread. More than 50% of the cases have varying degrees of edema of the distal extremities and ventrum and it may be the first sign in some cases. Limb edema may occur in the absence of surface lesions.

1. 1. 6. In goats, skin lesions usually begin on the ventrum and perineum, then become widespread with very severe lesions on the face and pinnae.
      7. The primary lesions are subcorneal or intracorneal pustules. However, these lesions are transient and the clinician usually sees tufted hairs associated with crusts, scales, oozing, annular erosions bordered by epidermal collarets. Alopecia and erythema are also often seen.

1. 1. 8. Some horses show localized or more often generalized extensive exfoliative dermatitis.

1. 1. 9. Pruritus and pain are variable.
      10. A juvenile or neonatal form with a better prognosis compared to adult horses has been reported.
      11. Over 50% of the horses and occasionally some goats have concurrent signs of systemic illness (i.e. depression, lethargy, weight loss, poor appetite, and pyrexia).

1. 2. Bullous pemphigoid:
      1. Bullous pemphigoid has been rarely reported in horses of all ages (5-14 years) and breeds.
      2. Signs usually develop slowly over several weeks,
      3. The primary lesions are vesicles or bullae. These lesions will rupture very easily leaving crusts, deep erosions and more often ulcerations.

1. 1. 4. The areas affected are the mucocutaneous junctions (lips, vulva, anus, eyelids), oral cavity, nasal mucosa and intertriginous areas (most commonly axillary and groin regions).

1. 1. 5. Pain and pruritus are variable.
      6. Severely affected horses may be anorectic, depressed, lose weight and febrile.
      7. It has also been reported in Yucatan minipigs, affecting mainly their dorsum.

1. 3. Systemic Lupus Erythematosus:
      1. Systemic lupus erythematosus is a multisystemic autoimmune disorder that has been rarely recognized in horses.
      2. There are no reported age, breed, and sex predilections.
      3. The clinical signs are variable.
      4. Cutaneous changes have included lymphedema of the extremities, panniculitis, mucocutaneous ulceration, alopecia, generalized exfoliative dermatitis, leukoderma, and scaling of the face, neck, and trunk.
      5. Extracutaneous abnormalities have included polyarthritis, thrombocytopenia, peripheral lymphadenopathy, proteinuria, fever, depression, anorexia, and weight loss.
      6. Sun exposure aggravates the disease.

1. 4. Discoid Lupus Erythematosus:
      1. Discoid lupus erythematosus has been rarely recognized in horses.
      2. There are no apparent breed and sex predilections.
      3. Affected horses range from1 to 14 years of age.
      4. It is a relatively benign skin disease without systemic involvement. Affected horses are otherwise healthy.
      5. Patchy erythema, alopecia, scaling, and crusting are usually localized to the face, periocular areas, nostrils, ears, and neck. The perineal, perianal and genital areas may be affected.
      6. Leukoderma and leukotrichia may be seen within lesions.
      7. Pruritus and pain are usually mild to absent.
      8. Sun exposure aggravates the disease.

4. Diagnosis

   1. The information obtained from a thorough patient’s history and clinical signs is important to obtain a diagnosis or a sensible list of differential diagnoses.
   2. Nikolsky sign is usually positive in bullous pemphigoid and epidermolysis bullosa.
   3. Cytologic exam:
      1. Pemphigus foliaceus:
         1. Direct smears of the exudate collected from intact pustules, from recent erosions, and/or from the exudate underneath a crust, reveal numerous acantholytic keratinocytes, numerous non-degenerate neutrophils or eosinophils, and no intracellular bacteria (however, they can be seen if secondary infection is present).
         2. Occasional acantholytic keratinocytes can be present in any suppurative condition, but when seen in clusters or large numbers in several microscopic fields they are strongly suggestive of pemphigus. In horses, dermatophytic infections caused by Trichophyton spp. have been associated with profound acantholysis; therefore, it is recommended to perform special stain of skin biopsy and fungal culture to rule out dermatophytosis in any case suggestive of pemphigus foliaceus in horses.
      2. Bullous pemphigoid, epidermolysis bullosa, discoid lupus erythematosus, and systemic lupus erythematosus:
         1. Cytologic exam does not demonstrate acantholytic keratinocytes.
   4. Clinical Pathology:
      1. More than 50% of the horses with pemphigus foliaceus manifest some combination of non- regenerative anemia, neutrophilia, hypoalbuminemia, and elevations of serum globulins.
   5. Skin biopsy: formalin fixed samples.
      1. Pemphigus foliaceus:
         1. Intact pustules are the ideal sample. Biopsy a recent crust and erosion if pustules are not present. Remember to not surgically prep the skin before biopsying and to biopsy through the crust (i.e. include the crust in your sample since acantholytic cells may be imbedded in the crust).
         2. Multiple biopsies taking samples from different stages of disease development will greatly increase the chances of demonstrating diagnostic histopathological changes.
         3. Pemphigus foliaceus is characterized by subcorneal or intragranular acantholysis with resultant cleft and pustule formation. Hair follicles may also be affected.
         4. Neutrophils and/or eosinophils may predominate within the pustule. These inflammatory cells will accompany the acantholytic keratinocytes.
      2. Bullous pemphigoid:
         1. Numbers a and b under “Pemphigus foliaceus” are also applicable for bullous pemphigoid.
         2. Histologically lesions are characterized by subepidermal vacuolar alteration and subepidermal cleft and vesicle formation.
         3. Dermal inflammatory infiltrates are usually mild to moderate and perivascular.
         4. Acantholytic keratinocytes are not present.
      3. Discoid lupus erythematosus and systemic lupus erythematosus:
         1. Skin biopsy reveals hydropic and/or lichenoid interface dermatitis.
         2. Multiple biopsies taking samples from different stages of disease development will greatly increase the chances of demonstrating diagnostic histopathological changes.
         3. Acantholytic keratinocytes are not present.
   6. Direct immunofluorescence (skin biopsy samples are fixed in Michel’s solution) or immunohistochemistry (skin biopsy samples are fixed in formalin):
      1. Pemphigus foliaceus:
         1. Diffuse intercellular deposition of immunoglobulin (and occasionally complement) within the epidermis.
         2. Direct immunofluorescence has been reported to be positive in equine dermatophilosis as well. Results must be interpreted in conjunction with the patient’s history, clinical signs, cytological exam, and histopathology.
      2. Bullous pemphigoid:
         1. Linear deposition of immunoglobulin and usually complement at the basement membrane zone of affected skin or mucosae.
      3. Discoid lupus erythematosus and systemic lupus erythematosus:
         1. Deposition of immunoglobulin or complement, or both, at the basement membrane zone.
   7. Indirect immunofluorescence (serum is collected for this test):
      1. It is usually not requested routinely to diagnose autoimmune skin diseases because the results are often negative. Additionally, this test is not widely available.
   8. Clinical pathology:
      1. Perform a CBC, chemistry profile, urinalysis and joint fluid analysis if you suspect systemic lupus erythematosus or if the animal is systemically ill.
   9. Antinuclear antibody test (ANA):
      1. It is generally positive for systemic lupus erythematosus and negative for the other autoimmune skin diseases.

5. Treatment: Pemphigus foliaceus, bullous pemphigoid, discoid lupus erythematosus, and systemic lupus erythematosus.

1. 1. Treatment of autoimmune skin diseases is often difficult requiring high doses of systemic glucocorticoids with or without other potent immunomodulating drugs.
   2. Additionally, therapy is often maintained for prolonged periods if not for life because autoimmune skin diseases cannot be cured.
   3. Client education is essential to obtain a successful outcome.
   4. High dose of systemic glucocorticoid is the initial treatment of choice:
      1. Prednisolone: 1.0-2.0 mg/kg given orally twice daily.
      2. Dexamethasone: 0.2-0.4 mg/kg given orally once daily.
   5. Disease control is usually achieved within 7 to 10 days, at which point alternate-morning therapy is begun and the dose is slowly reduced to the lowest possible dosage.
   6. When systemic glucocorticoids are unsatisfactory, the addition or substitution of other immunomodulating drug may be required for an adequate disease control.
   7. Gold salts (aurothiomalate, Myochrisine®) or azathioprine can be added to the glucocorticoid regimen or used in place of glucocorticoids. Remember that these drugs have a long lag phase (i.e. azathioprine 4 to 6 weeks; gold salts 6 to 12 weeks). Pentoxifylline, which improves tissue oxygenation and has an anti-inflammatory effect can also be used as adjunctive therapy in horse cases. This is a very safe drug.
      1. Azathioprine: 2.0 mg/kg q 24h until remission of signs then every 48 hr.
      2. Gold salts: 1 mg/kg intramuscularly per week until remission, then once a month.
      3. Pentoxifylline: 10-12 mg/kg q 12h.
   8. Remember to monitor for potential side effects when using azathioprine and gold salts drugs (same tests and protocol described for dogs and cats – refer to previous section of these notes).
   9. Sun avoidance is an important part of the treatment regimen of autoimmune skin disorders.

References

Knottenbelt DC. Chapter11: Immune-mediated/allergic diseases. In: Pascoe’s Principles & Practice of Equine  Dermatology. 2009. W.B. Saunders, p. 253-297.

Medeiros, Gildenor X, Riet‐Correa F. Epidermolysis bullosa in animals: a review. Vet Dermatol 2015; 26(1): 3-e2.

Scott, DW. Color atlas of farm animal dermatology 2008. John Wiley & Sons.

Scott DW. Immunologic Disease. In: Large Animal Dermatology 1985.  W.B. Saunders, Philadelphia, p307-317.

Scott DW. Miller WH. Chapter 9: Immune-mediated disorders. In: Equine Dermatology 2003. W.B. Saunders, St. Louis, p. 475-547.

Vandenabeele, SIJ et al. Pemphigus foliaceus in the horse: a retrospective study of 20 cases. Vet Dermatol 2004; 15(6): 381-388.