Dermatology: latest findings in companion animal skin disease

The past year, 2021, has definitely been very dedicated to the cat and its allergic conditions.

Unlike for human and canine atopic dermatitis (CAD), a very low number of publications were published regarding the immunopathogenesis of feline allergic syndrome.

For that reason, it is always exciting when new investigations are developed and questions regarding the mysteries of the allergic disease in cats are answered.

Allergic dermatitis in cats is quite exceptional, not only in what concerns the clinical signs, but also with regards to its pathomechanisms.

Cats potentially lack immunoglobulin E (IgE) involvement, and differ in the immunological profile when compared to people and dogs1.

In dogs and humans, interleukin-31 (IL-31), a pruritogenic cytokine, has drawn a lot of attention for its role in pruritus and atopic inflammation2.

It was found that the serum IL-31 concentration in atopic dogs was increased compared to that in healthy dogs3,4and a specific IL-31 neutralizing monoclonal antibody was found to reduce IL-31-induced pruritus in these animals5. In cats, questions exist if IL-31 would have a similar role in the development of pruritus and if, similarly to dogs, molecules for the blockade / inactivation of this cytokine would be as effective as it is in canine patients.

Several studies have been carried out to investigate the role of IL-31 in allergic skin disease in cats.

In one study, recombinant feline IL-31 was injected in healthy cats, which resulted in the development of pruritus6.

One abstract also demonstrated higher circulating serum concentrations of IL-31 in cats with allergic dermatitis when compared to healthy controls7. Altogether, these studies suggest that targeting IL-31 could be a promising treatment option.

Last year, a group of investigators developed research to determine whether IL-31 would have a clear role in feline allergic dermatitis. They evaluated the concentrations of IL-31 in the skin and serum of cats affected by allergic dermatitis and asthma1.

Other Th2 cytokines were also investigated. IL-31 was found in low quantities or even undetectable in most skin samples1.

Although serum IL-31 was detected in a larger number of cats with allergic dermatitis than healthy cats, and concentrations appeared to be higher in cats with allergies, this difference was not statistically significant.1.

Cats affected by asthma also exhibited insignificantly higher concentrations of IL-31 in the serum1. This study provides some evidence that the allergic condition in cats can be quite distinct from the disease in dogs1. Although IL-31 appears to play quite a different role in allergy in cats, it does not rule out that targeting molecules within the IL-31 pathway may still be valuable1. In fact, in the study presented by Fleck et al (2013), oclacitinib effectively treated IL-31-induced pruritus in cats6.

Immunotherapy

Atopic dermatitis (AD) is one of the most common canine skin diseases, affecting 3 per cent to 15 per cent of the population8.

To date, allergen-specific immunotherapy (ASIT) is the only treatment for atopic dermatitis in dogs that appears to have the potential to normalize the dysregulated immune response and thus slow the progression of the disease9.

It is, however, ineffective in some dogs and only partially effective in many cases10.

Commercial serum allergen-specific IgE tests are commonly used in veterinary medicine for the formulation of ASIT prescriptions for dogs with AD; however, it is not uncommon for these in vitro tests to deliver inconsistent results with a dog’s history of disease (for example, when dogs show strong positive reactions to seasonal allergens when they are not specially symptomatic in that time of year).

In humans, IgE reactivity against highly antigenic, carbohydrate structures commonly found on plant and insect allergens was identified11. These structures, known as cross-reactive carbohydrate determinants (CCD)12were considered a source of cross-reactivity in IgE serological tests, leading to false positive reactions for in vitro allergen tests and to the inclusion of irrelevant allergens in ASIT formulation11.

In a study performed in atopic dogs, anti-CCD IgE was detected in 24 per cent of the sera samples. These dogs had strong serological reactivity to grass pollens13.

In another study, results of an intradermal test (IDT) and a serum test for allergen-specific IgE, with and without blocking anti-CCD IgE, were compared to assess the agreement between the tests performed14.

In dogs with negative anti-CCD IgE samples, the agreement between the results of the serum test and the IDT was substantial, while dogs with positive anti-CCD IgE samples showed no agreement between serum and skin testing14.

Blocking anti-CCD IgE in those samples resulted in a fair agreement between the tests14. Also, anti-CCD IgE positive sera had multiple positive results for grass and weed allergens, and blocking decreased them markedly14. Overall, the results of these studies suggest blocking anti-CCD IgE before serological testing could improve the relevance and accuracy of allergen specific IgE tests.

Consequently, better-targeted immunotherapy formulations can be developed with a greater efficacy of ASIT in canine patients15.

Oclacitinib

Oclacitinib is a Janus-kinase inhibitor (JAKinib) approved for the treatment of canine pruritic and allergic skin diseases16.

JAKinibs have broad anti-inflammatory and immunosuppressive effects through alteration of lymphocytes and natural killer cell proliferation, differentiation, function and / or survival, and through inhibition of receptors responsible for signaling of multiple inflammatory mediators16.

In humans, JAKinibs are approved for the treatment of multiple immune mediated diseases such as rheumatoid arthritis and psoriasis17. In dogs, oclacitinib has also been used off-label to successfully treat several autoimmune and immune-mediated conditions.

In 2017, Aymeric and Bensignor presented a case of a five-year-old German shepherd cross-breed with refractory subepidermal blistering dermatosis18.

This dog had been treated with prednisolone at 1.2mg / kg twice daily; however, developed severe adverse effects and relapse, when the prednisolone dose was reduced.

A complete resolution of clinical signs was noted after one month of oclacitinib therapy at 0.5mg / kg twice a day and no relapse was observed after 12 months of treatment18.

Oclacitinib has also been shown to be effective in the management of vasculopathic conditions, which are presumed to be of immune-mediated origin. Vercelli and Cornegliani first described the effectiveness of oclacitinib in idiopathic ear-tip vasculitis unresponsive to previous treatments19.

In 2018, Pulsoni et al described treatment success in two dogs with juvenile onset ischemic dermatopathy20and later Levy et al described four cases of juvenile-onset ischaemic dermatopathy that were refractory treatment, and rapidly and durably responded to oclacitinib administration21.

Recent reports published revealed the efficacy of oclacitinib also in hyperkeratotic erythema multiforme in two dogs and in a case of pemphigus foliaceus in cat22,23.

Oclacitinib’s mechanism of action in these cases is unknown and only speculative; however, its effectiveness in the presented conditions makes this therapeutic option very promising when managing cutaneous immune-mediated conditions.

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