Overview of the diagnosis and treatment of autoimmune skin disorders in horses

Immune-mediated diseases can be categorized into primary (autoimmune), wherein antibodies or lymphocytes mistakenly target endogenous proteins; and secondary (immune-mediated), wherein an inappropriate inflammatory response occurs in the presence of foreign antigens such as drugs or supplements, viruses, bacterial toxins, or vaccines (1).

Pemphigus foliaceus, with antibodies against specific junctional adhesion protein between epidermal keratinocytes (desmocollin and desmoglein; albeit not clearly elucidated in horses), is the most common primary immune-mediated dermatitis in veterinary dermatology (1). Cutaneous autoimmune diseases are rare and often poorly described thus complicating diagnosis. Furthermore, primary immune-mediated dermatitis is often complicated by a secondary microbial infection, thereby challenging diagnostics. Similarities in clinical patterns can be observed between autoimmune dermatitis and some infectious skin conditions, e.g., bacterial pyoderma or dermatophytosis due to Trichophyton spp., in which release of proteases leads to cleavage of intercellular bonds (2). Parasitic infestations can also be secondary (e.g., demodicosis) or concomitant. Therefore, skin cytology should be performed and ectoparasites ruled out to prevent over-diagnosis of autoimmune skin diseases. Immunomodulatory and/or immunosuppressive therapy is usually required for authoimmune (primary) or imune-mediated (secondary) conditions.

This brief review aims to define a comprehensive diagnostic approach to primary and secondary immune-mediated dermatitis in horses and provide therapeutic options.

DIAGNOSIS OF EQUINE SKIN IMMUNEMEDIATED DERMATITIS

For diagnosis, a thorough dermatological history is essential, including previous diseases. Recent events might have contributed to immune-mediated disease, e.g., Streptococcus equi infection or a vaccine that can cause purpura haemorrhagica (3). Progression of skin lesions may provide valuable insights. For example, lesions with spontaneous improvement and exacerbation are more indicative of autoimmune diseases rather than infections. Seasonality must be documented, because an exacerbation of skin lesions in summer may be explained by a photoaggravated pemphigus foliaceus or discoid lupus erythematosus (Figures 1, 2).

FIGURE 1.

Discoid lupus erythematosus in an adult Belgian draft horse. (a) — Alopecia, erythema, erosions, and crusts are localized in the white-haired area of the nose, secondary to UV radiation from the sun. (b) — Alopecic, crusty, and depigmented lesions, secondary to inflammation, affect the eyelids.

FIGURE 2.

Miniature horse (10 y) with pemphigus foliaceus (crusts were hidden under haircoat).

A medical condition affecting several individuals in contact is rarely immune-mediated, but more suggestive of underlying infectious, parasitic, dietary, or environmental causes. Age of disease onset is important, e.g., pemphigus foliaceus usually has a more favorable prognosis before 12 mo of age (Figure 3) (4). Furthermore, skin lesions early in life can indicate an underlying genetic disorder, e.g., junctional epidermolysis bullosa (vesiculo-bullous dermatosis), which, although not an autoimmune disease, can manifest with clinical signs resembling such dermatoses (5,6). An exhaustive inventory of drugs and supplements administered should be listed; those most often reported to cause cutaneous drug reactions in horses are trimethoprim sulfa, penicillin, phenylbutazone, ivermectin, diuretics, and phenothiazines (Figure 4) (7).

FIGURE 3.

Pemphigus foliaceus in an American paint foal. Note the severe alopecic and crusty lesions localized to lower limbs, which may heal spontaneously by 1 y of age.

FIGURE 4.

Serpiginous crusty pattern on the lateral thorax of a 24-year-old Icelandic horse with a suspected cutaneous adverse drug reaction to pergolide.

Next, a complete dermatological examination should be conducted. The distribution of skin lesions varies depending on the immune-mediated dermatitis and may occasionally extend to mucous membranes and/or mucocutaneous junctions. Primary lesions, which can help in establishing a differential diagnosis, typically manifest as erythema, vesicles, bullae, and pustules. Secondary lesions, prevalent in many skin conditions, include erosions or ulcers, crusts, and oozing. Systemic clinical signs are sometimes noticed in some immune-mediated dermatitises. Not only the skin lesion description but also distribution can aid in distinguishing an immune-mediated disorder from other forms of dermatitis. For instance, superficial bacterial pyoderma may be widespread but typically presents as multifocal and asymmetrical, whereas autoimmune diseases tend to be more symmetrical. The distribution of skin lesions within the group of immune-mediated dermatitis also varies. For example, pemphigus foliaceus commonly affects the face, neck, trunk, and limbs, although a generalized distribution is also possible, and discoid lupus erythematosus targets primarily the face (8). Urticarial lesions, typically associated with allergies, can indicate other conditions, including erythema multiforme (Figure 5) (7). Cutaneous and mucosal ulcers may suggest vasculitis, a bullous disease (e.g., bullous pemphigoid; Figure 6), or even pemphigus vulgaris. Mucosal ulcers often signal a more severe condition, with increased risk of secondary infection.

FIGURE 5.

A 7-year-old Lusitano horse with an erythema multiforme presented for generalized donut shape edematous lesions mimicking urticaria.

FIGURE 6.

Bullous pemphigoid in a 22-year-old American paint horse with mucosal ulcers localized into the oral cavity (a) and alopecic, ulcerated, and crusty lesions localized to the right hindquarter (b).

If any skin lesions are present, it is strongly advisable to conduct basic dermatological sampling to accurately characterize ongoing dermatitis. Skin scrapings for detecting ectoparasites, and skin cytologies for identifying infection, inflammation, or tumoral cells can assist in refining the diagnosis.

In the absence of ectoparasites, broad-spectrum antiparasitic therapy is recommended if parasitic dermatosis is suspected (7). Skin cytologies are useful for detecting bacteria (or yeast) and degenerate neutrophils, indicative of a primary or secondary skin infection, as well as other cells suggestive of pemphigus foliaceus, such as intact neutrophils, eosinophils, and acantholytic keratinocytes.

Diagnosis of immune-mediated dermatitis through conducting skin biopsies is usually based on the results of dermatohistopathology in the context of suggestive clinical findings. Obtaining a diagnosis is ideal, as often these diseases require long- or short-term immunosuppressive or immunomodulatory treatment. A precise diagnosis not only helps with prognostic information but also facilitates selection of appropriate treatment. Prior to performing skin biopsies, it is important to resolve any existing skin infections (by applying topical or giving systemic antimicrobial therapy) since inflammation triggered by infection could alter histological findings, potentially complicating diagnosis of immune-mediated diseases (9). Ideally, oral or topical glucocorticoids should be discontinued for ≥ 2 to 3 wk before obtaining skin biopsies, since the anti-inflammatory effect can change the inflammatory pattern and remove characteristic cells from the epidermis that are crucial for diagnosis (9). If the patient cannot be weaned off glucocorticoids, the pathologist should be notified, and a second set of biopsies considered if the histological diagnosis is inconclusive.

For skin biopsies (9):

1. Do not pre-scrub skin, to avoid altering epidermis or inflammatory changes.

2. Primary lesions should be prioritized (e.g., macules, papules, pustules, vesicles, bullae, nodules, plaques, urticarial papules).

3. Secondary lesions are biopsied if primary lesions are absent or inaccessible (e.g., crusts, epidermal collarettes, erosions, ulcers, fissures).

4. Any crusts, even if detached from the epidermis, should be included in the submission. If pemphigus foliaceus is present, crusts are partially composed of acantholytic keratinocytes, thus facilitating diagnosis.

5. If ulcers are present, a peripheral biopsy is recommended, if the epidermis is intact. Ulcers are devoid of epidermis, whereas intact epidermis can have distinct cellular changes, thereby guiding diagnosis.

6. Take ≥ 3 punch skin biopsies (6 to 8 mm), ideally with the lesion centered.

A comprehensive history and detailed lesion description should be clearly documented, plus any potential differential diagnoses. Consider taking photographs of skin lesions to provide further clinical information for the pathologist.

TREATMENT OF EQUINE SKIN IMMUNE-MEDIATED DERMATITIS

Typically, treatments focus on immunosuppression and/or immunomodulation, occasionally necessitating antimicrobial therapy to control secondary infections, in addition to supportive care. Depending on the horse’s history, some actions should be prioritized, such as discontinuing potentially harmful medications and addressing the underlying cause, if possible. Medication and dosage should match disease severity.

Topical therapy

If skin lesions are localized in the absence of systemic clinical signs, topical treatment should be considered, if feasible. Without bacterial skin infection, the drug of choice for addressing an immune-mediated disorder is glucocorticoid. Many topical products contain glucocorticoids (variable potency). Topical veterinary products with glucocorticoids licensed for skin use in Canada include: 1% hydrocortisone spray (CortiPro; ProConcepts, Mississauga, Ontario); hydrocortisone aceponate spray (Cortavance; Virbac, Cambridge, Ontario); gentamicin sulfate and betamethasone valerate spray (Topagen spray; Merck Animal Health, Kirkland, Quebec); fusidic acid and bethamethasone gel (Isaderm Gel; Dechra Veterinary Products, Pointe-Claire, Quebec), and a cream with triamcinolone acetonide, nystatin, neomycin, and gramicidin (Theraderm; Bimeda, Cambridge, Ontario) (10). Nearly all veterinary otic preparations in Canada with glucocorticoids and antibiotics can also be applied directly on skin. For a mild secondary bacterial infection, a glucocorticoid and antibiotic combination may be beneficial.

Topical glucocorticoids are classified by potency. Less potent glucocorticoids are preferred for mild inflammation or maintenance in chronic dermatitis, but the most potent (betamethasone or triamcinolone) are used in severe inflammatory disorders, especially if acute. Otic preparations in Canada with stronger glucocorticoids are Mometamax (momethasone furoate; Merck Animal Health), Otomax (betamethasone valerate; Merck Animal Health), and Aurizon (dexamethasone acetate; Elanco Animal Health, Guelph, Ontario) (10). It is usually recommended that topical glucocorticoids be applied twice daily until remission (2 to 4 wk), before decreasing the frequency of application. Another anecdotally used topical option for treating immune-mediated dermatitis is tacrolimus 0.1% (Protopic; Astellas, Markham, Ontario), a calcineurin inhibitor. However, the interval to remission can be longer than when glucocorticoids are used (1).

Systemic therapies

The most accessible, efficient, and cheapest option is oral glucocorticoids. Horses do not metabolize prednisone well, so prednisolone or dexamethasone should be used (11). The recommended doses of dexamethasone and prednisolone for skin immune-mediated disorders are 0.02 to 0.4 and 1 to 4 mg/kg, respectively, q24h (7,12,13). Potential side effects include hypothalamic pituitary-adrenal axis suppression, hepatopathy, muscle wasting, hyperglycemia, polyuria, polydipsia, altered bone metabolism (12); therefore, a conservative starting dose is recommended unless the disease is extensive and severe. In the absence of a response, the dose can be increased after a few days to weeks.

After achieving remission, reduce the dosage by ~25% every 3 to 4 wk of treatment. Whether it is feasible to completely discontinue the medication depends on the condition and its progression. Otherwise, identify the minimum effective dose that controls skin disease and limits side effects. Glucocorticoids could cause laminitis due to catabolic, apoptotic, and vascular effects, but a clear association has not been proven (12,14). Still, particular attention should be paid to laminitis symptoms during corticosteroid treatment, especially in horses with other associated risk factors (12).

Glucocorticoids and other immunomodulatory/immunosuppressive drugs can be administered concomitantly to minimize duration of systemic glucocorticoid treatment. Once disease control has been achieved, glucocorticoid is weaned off first. Other immunomodulatory/immunosuppressive drugs can be maintained, and doses can be gradually tapered after cortisone cessation if the disease is under control.

Concomitant immunomodulatory and/or immunosuppressives drugs reported in horses include azathioprine and pentoxifylline, the most used, and aurothioglucose (gold salts) (1,12).

Azathioprine (1 to 3 mg/kg, q24 to 48h) inhibits purine (component of RNA and DNA; 1,7,13). Bioavailability is low in horses, but it can be used to decrease glucocorticoid dose in several autoimmune disorders (12). Blood tests are recommended during treatment as thrombocytopenia, leukopenia, and anemia have been reported (7).

Pentoxifylline (10 to 15 mg/kg, q12h) is a methylxanthine derivative used to reduce pro-inflammatory cytokines (1,7,13) and a rheological agent mainly used for vasculitis and vasculopathies in animals. Its anti-inflammatory actions are explained by inhibition or downregulation of Tumor Necrosis Factor (TNF)-α; influence on other inflammatory cytokines (interleukin (IL)-1,4,6,12); and decrease activity of natural killer (NK) cells, T- and B-lymphocytes (7).

Mycophenolate mofetil is a purine inhibitor that inhibits recruitment of inflammatory cells (15). A safe dosage has not been determined and 10 mg/kg, q12h causes severe side effects within just 7 d. Therefore, it is not recommended for use in horses (15).

Oclacitinib, an antipruritic drug approved for canine atopic dermatitis, was recently shown to be effective in controlling allergic pruritus in horses (0.25 to 0.5 mg/kg, q24h (16,17). Cases reports indicated a beneficial effect of oclacitinib in canine immune-mediated diseases (18). This has potential, but additional studies are needed.

Chemotherapeutic drugs, e.g., cyclophosphamide and vincristine, are anecdotally reported in equine auto-immune disorders not related to skin (12).

Other adjunctive therapies

Omega-3 fatty acids can be administered for anti-inflammatory effects. An effective dose has not been established in horses, but their use appears to be beneficial for cutaneous and respiratory allergic disorders (7,19).

Sun exposure should be limited, even avoided, especially in cases of photo aggravated or photoinduced dermatitis (pemphigus, bullous diseases, lupus erythematosus). Repeated sunscreen application on affected skin areas (especially light or pink-colored skin) may prevent or reduce recurrence.

Efforts should be made to limit secondary cutaneous microbial infection. Use a chlorhexidine-based antibacterial shampoo, spray, or mousse (≥ 2%) particularly if the skin barrier is disrupted. Moisturizing skin may promote restoring and maintaining skin barrier function.

CONCLUSION

The diagnostic approach for cutaneous autoimmune diseases in horses follows a relatively consistent approach. This includes systematic steps such as eliminating microbial infections and parasitic infestations, before performing skin biopsies. If possible, refrain from using systemic or topical glucocorticoids before diagnosis, as they can mask clinical signs and characteristic histopathological changes. Following diagnosis, immunomodulatory or immunosuppressive therapy may be administered, with gradual tapering once remission is achieved. Initial dosage of the selected drug depends on disease severity. However, severity of disease is not always directly proportional to the dose required to control skin lesions. With extensive skin lesions, there is an increased risk of secondary skin infections, necessitating antimicrobial preventive measures. Prognosis is determined not only by the diagnosis but also by response to treatment and potential side effects. Fortunately, immune-mediated skin disorders in horses are uncommon, if not rare.