In recent years, new therapies for canine atopic dermatitis have become available and at the same time, as more information on the pathomechanisms is published, the approaches to managing it are changing so to achieve the best outcomes.
Atopic dermatitis has complex pathomechanisms and multiple immunological pathways (Olivry et al., 2010; Bizikova et al., 2015; Olivry et al., 2015; Pucheu-Haston et al., 2015a; Pucheu-Haston et al., 2015b; Pucheu-Haston et al., 2015c; Santoro et al., 2015). Both innate and adaptive immune responses are responsible for the various lesions seen at different stages of the disease. The newer treatments like lokivetmab and oclacitinib are mainly targeted at Il-31, the cytokine associated with pruritus, whereas glucocorticoids and ciclosporin target a broader range of inflammatory mediators.
Depending on the severity of the clinical signs of atopic dermatitis, owner expectations and owner compliance, a mix of symptomatic treatment and/or proactive therapy (allergen avoidance, allergen-specific immunotherapy) for environment-associated allergic dermatitis may be implemented. From a clinical perspective these treatments are aimed at managing the pruritus and skin lesions and maintaining the epidermal barrier during the different stages of the disease.
Treatments can be divided into the “reactive phase”, given to deal with acute (Figure 1) and chronic pruritus and inflammation (Figure 2); and the “proactive phase”, used to maintain the skin lesion-free over the long term. Most dogs experience flare-ups, even when on proactive management, and so during this time reactive treatment is needed. The aim of the proactive treatments is to reduce the incidence of acute flare-ups by identifying and addressing flare factors.
Reactive treatment of acute flare-ups and chronic dermatitis in atopic dogs
The drugs of choice for acute flare-ups should be fast-acting, to rapidly reduce pruritus and inflammation, not just for the comfort of the patient, but also to prevent progression to chronic atopic dermatitis. Oclacitinib, lokivetmab and systemic and/or topical glucocorticoids are all useful, depending on whether the flare-up is localised or generalised. Antihistamines may also be included in this list. The evidence for their efficacy is patchy, but some owners do find them beneficial. Symptomatic treatments to manage chronic pruritus and dermatitis include oclacitinib, lokivetmab, glucocorticoids and ciclosporin.
Oclacitinib can rapidly reduce pruritus, in most cases within 12 hours of administration, thereby breaking the itch–scratch cycle in an acute flare-up. This rapid response helps prevent self-inflicted damage, subsequent infections and chronic changes in the skin. In dogs with seasonal atopic dermatitis, oclacitinib can be used to control the pruritus as needed.
An open study (Cosgrove et al., 2015) reported an improvement in quality of life with oclacitinib use, but more than 5 percent of dogs given oclacitinib had side-effects, mostly gastrointestinal upsets, urinary tract infections, otitis, pyoderma and development of skin masses. Bearing in mind that most dogs require lifelong management for atopic dermatitis, the possibility of these adverse effects should be discussed with the owners. Oclacitinib is contraindicated in dogs with immune suppression, hyperadrenocorticism, demodicosis and with progressive malignant neoplasia.
Lokivetmab is a caninised anti-canine monoclonal antibody. It has an extended duration of effect, acts within days and is repeated at four-weekly intervals as needed. In a blinded placebo-controlled study (Michels et al., 2016a), lokivetmab was shown to reduce pruritus, erythema and the severity of signs associated with atopic disease. It appears to be safe, with no reports of acute hypersensitivity reactions (Michels et al., 2016b) and the incidence of vomiting, diarrhoea, lethargy and anorexia were similar in both the lokivetmab- and placebo-treated groups.
Glucocorticoids, such as prednisolone, or methylprednisolone, given at 0.5mg/kg once or twice daily can rapidly reduce pruritus. They are highly effective drugs and short-term use (five to seven days) to break an itch–scratch cycle has no lasting adverse effects.
The topical glucocorticoid spray containing hydrocortisone aceponate can be effective in the management of flare-ups in atopic dogs. It is particularly useful for managing localised lesions. This use is supported by a study in which once-daily application of hydrocortisone aceponate to lesions in 21 dogs with atopic dermatitis, for 7 or 14 days, significantly improved lesions and pruritus (Nam et al., 2012). Topical gels/creams containing betamethasone are also useful in managing localised pruritus and/or surface pyoderma associated with atopic dermatitis.
Calcineurin inhibitors such as topical 0.1 percent tacrolimus have been reported (Marsella et al., 2004; Bensignor et al., 2005) to reduce the severity of localised lesions and, in the author’s experience, it is particularly useful in localised lichenified areas that are not infected.
Ciclosporin administered orally, at 5mg/kg once daily until there is satisfactory control of clinical signs, which usually takes four to six weeks, is suited to some individuals. It is recommended that no dose adjustments should be made for at least the first four weeks. It can then be tapered to every other day, or less often, depending on individual response. Using the measurement of serum levels of ciclosporin to regulate the dosage is not advised, as data correlating serum levels to clinical efficacy is lacking in dogs. Because of the slow onset of the response to ciclosporin, dogs with severe pruritus often require concurrent administration of prednisolone. It is reported that giving prednisolone at 1mg/kg with ciclosporin at 5mg/kg daily for 14 days resulted in a quicker improvement in skin lesions and reduction in pruritus when compared to those dogs given ciclosporin alone (Dip et al., 2013). Therefore, concurrent short-term use of a glucocorticoid with ciclosporin should be beneficial in severely affected dogs.
Gastrointestinal disturbances are the most common side-effects associated with ciclosporin in dogs. Other undesirable side-effects, such as reduced appetite, gingival hyperplasia, papillomatous skin lesions, muscle cramps, coat changes such as hirsuitism and erythematous pinnae, have been reported. Ciclosporin is contraindicated in dogs of less than six months of age, less than 2kg in weight and with a history of malignant disorders.
Proactive management to prevent the incidences of acute flares
Management of flare factors includes flea control and addressing any dietary triggers.
Allergen immunotherapy (AIT) is the only specific preventative therapy available for the management of atopic dermatitis. It is safe to use and can be used with other treatment modalities. It is beneficial in up to 75 percent of cases, but the time taken to show an improvement can be up to 10 months. A small percentage of dogs can be successfully managed on immunotherapy alone (Olivry et al., 2010).
AIT is made up, on a named patient basis, following intradermal and/or serological allergy testing. It is available as an injectable or oral therapy; both have been shown to be effective. The adverse effects are minimal, making it a safe way to ameliorate the clinical signs of atopic dermatitis. Over the years, administration using different protocols have been reported on (rush, traditional, low-dose and oro-mucosal), but realistically it should be individualised to the patient and the client. Many clients, for example, prefer to give the dogs four-weekly injections to once or twice daily oral drops. The frequency of treatment may also be modified to suit the individual response. There is a suggestion that an individual that has failed on injectable AIT may do better on the oro-mucosal formulation. AIT is usually recommended for life, as, at present, there is insufficient evidence to warrant stopping the treatment once an animal has been in remission for some years.
Serious adverse reactions such as anaphylaxis, urticaria and angioedema are extremely rare in animals treated with either the injectable or the oral forms. Transient facial pruritus and gastrointestinal upsets are associated with the oral form.
Skin and coat hygiene is important. Regular shampooing helps keep the skin surface clean by removing allergens and microbes and by hydrating the skin. Certain shampoos do have specific antipruritic effects, but even the simple act of bathing can reduce pruritus in some dogs. The choice of shampoo depends on the clinical findings, for example a chlorhexidine/miconazole shampoo is appropriate for bacterial and yeast infections, whereas oatmeal-based shampoos are indicated for managing pruritus. Some recent shampoo formulations contain synthetic antimicrobial peptides aimed at managing recurrent pyoderma.
Essential fatty acid supplements (EFAs) and specific diets that help maintain the epidermal barrier and immunity are also recommended as concurrent therapies for the management of atopic dermatitis. The general improvement in skin and coat condition helps maintain the epidermal barrier and can potentially reduce allergen penetration percutaneously and reduce microbial infections. EFAs may help some atopic dogs, but the results from studies vary and therefore one should not use them as a sole therapy for atopic dermatitis. Several EFA supplements and enriched diets for dogs are available in the UK.
Topical lipid formulations containing ceramides, cholesterol and EFAs may help some individuals in managing seborrhoea sicca, which can contribute to the pathogenesis of atopic dermatitis. A recently reported randomised controlled trial demonstrated the use of a topical spray containing plant-derived essential oils and fatty acids, and compounds with antimicrobial properties (manuka oil and N-acetyl cysteine), that resolved pyoderma in treated areas faster than in untreated areas (Bensignor et al., 2016).
In a recent study (Tamamoto-Mochizuki et al., 2019), lokivetmab administered at four-weekly intervals, as a proactive treatment, was reported to help one in four dogs. The study also reported increased intervals between flareups in dogs treated with lokivetmab.
To optimise the response to treatments, they need to be individualised depending on the chronicity of the disease, their potential adverse effects and the cost implications and taking into consideration the ability of the owner to implement them. For a successful long-term outcome, a combination of the various treatments should be adopted to maximise benefits and minimise adverse effects.