Background: Canine atopic dermatitis (CAD) is an incurable inflammatory and pruritic allergic skin disease that starts in young dogs and requires lifelong management. There have been limited choices for the management of CAD, but over the past few years two, more-targeted, therapies have been developed.
Aim of the article: This article aims to review the use of these newer therapies and how they fit into the management of this complex disease.
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Peter Forsythe qualified from the Royal (Dick) School of Veterinary Studies, University of Edinburgh in 1983. In 2001, he founded the Dermatology Referral Service, based in Glasgow and Aberdeen in Scotland. He is an RCVS-recognised specialist in dermatology and an honorary lecturer in dermatology at Glasgow Veterinary School.
Hilary Jackson qualified from the Royal (Dick) School of Veterinary Studies, University of Edinburgh in 1985. After a spell in general practice she did a residency in dermatology followed by eight years working as a professor of dermatology at North Carolina State University. She is currently a director of the Dermatology Referral Service with clinics in Glasgow and Aberdeen.
Key learning outcomes
After reading this article, you should understand:
The basic mechanisms of action of oclacitinib and lokivetmab;
Where oclacitinib and lokivetmab fit in to the short- and long-term management of canine atopic dermatitis;
Dose regimes, adverse effects and monitoring for dogs receiving lokivetmab and oclacitinib;
That sublingual immunotherapy is an alternative route of administration for allergen-specific immunotherapy;
The efficacy and potential adverse effects of sublingual immunotherapy.
Canine atopic dermatitis (CAD) has been defined as ‘a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated with immunoglobulin (Ig)E antibodies most commonly directed against environmental allergens’ (Halliwell 2006). It is a complex disease. Affected dogs may have impaired skin barrier function and immune dysregulation, which predisposes them to percutaneous allergen sensitisation and secondary yeast and bacterial infections.
CAD is an incurable condition that starts in young dogs and requires lifelong management. The clinical diagnosis is made be assessing the history, presenting signs and ruling out other pruritic skin diseases, particularly ectoparasitic infestations. An elimination diet trial should be performed in any dog presenting with non-seasonal signs to rule out involvement of food allergens. Intradermal and/or serological testing can identify the presence of allergen-specific skin sensitising or circulating IgE, respectively, but as positive results may be seen in healthy dogs and negative results in suspected atopic dogs, these are not tests for atopic dermatitis per se but are used for the purposes of allergen avoidance or selection of allergens for allergen-specific immunotherapy.
For many decades, there were limited choices for the management of CAD and glucocorticoids were the mainstay of treatment. Although inexpensive and usually effective in controlling pruritus, unacceptable adverse effects are common. Injectable allergen-specific immunotherapy has been used for more than 50 years to desensitise dogs with known hypersensitivities with some success. Ciclosporin was licensed for the management of CAD 15 years ago and has been a valuable additional treatment with fewer adverse effects when compared with glucocorticoids. The last few years have seen the introduction of two additional, more targeted, immunomodulatory and antipruritic therapies – oclacitinib and lokivetmab. Additionally, the use of an alternative, sublingual method of delivering allergens for allergen-specific immunotherapy is becoming more widespread.
Management of canine atopic dermatitis
It is important to appreciate that management of CAD is multimodal; no two cases are the same and treatment may vary with season. During investigation of the disease, short-term control of pruritus may be required; for example, during the initial stages of an ectoparasite or elimination diet trial. This should always be discontinued to assess the efficacy of the trial itself. Long-term treatment is instituted once a specific diagnosis has been made and following a full discussion with the owner regarding management options.
The options for treatment fall into five categories:
Management of flare factors such as secondary yeast or bacterial infections;
Skin and coat care to restore barrier function;
Targeted allergen-specific management, such as allergen-specific immunotherapy or allergen avoidance;
Pharmacotherapy – the use of drugs to control the signs of pruritus associated with CAD;
Biological therapies such as lokivetmab.
It is out with the scope of this article to discuss the in-depth management of CAD and readers are directed to excellent review papers on this subject (Hensel and others 2015, Olivry and others 2015, Santoro 2018).
Oclacitinib – a new pharmacotherapy for CAD
Oclacitinib (Apoquel; Zoetis) is a novel janus kinase (JAK) inhibitor that downregulates the production of cytokines involved in atopic dermatitis (Gonzales and others 2014). Effector molecules engage with specific cell surface receptors stimulating intracellular signalling pathways which are dependent on JAK enzymes, resulting in the production of cytokines. There are several families of JAK and oclacitinib is most active against JAK1. JAK1-dependent cytokines include the pro-inflammatory cytokines interleukin (IL)-1, IL-2, IL-6, IL-13 and IL-31. IL-31 is a cytokine that has been shown to induce pruritus in the dog.
Thus, oclacitinib has both anti-inflammatory and anti-pruritic effects.
Oclacitinib is approved for the treatment of pruritus associated with allergic dermatitis in dogs. The recommended dose is 0.4–0.6 mg/kg every 12 hours for 14 days followed by 0.4–0.6 mg/kg every 24 hours. It is not licensed for long-term twice daily use, dogs under 12 months of age or that weigh less than 3 kg.
Oclacitinib has been shown to have a rapid onset of effect and be as effective as ciclosporin and prednisolone and significantly better than placebo in the control of pruritus and skin lesions associated with CAD (Cosgrove and others 2013, Gadeyne and others 2014, Little and others 2015). Clinical experience has shown that when the drug is effective, most clients report a significant improvement within 24 to 48 hours of starting the treatment. Around 60 to 65 per cent of cases can be expected to show a 50 per cent or greater reduction in pruritus and skin lesions.
Oclacitinib has a short half-life in the dog and as a result of this clinical experience has shown that many cases are well controlled with twice daily therapy but there is often some recurrence of pruritus on reduction to once daily treatment, although most cases are still obviously improved compared to pretreatment (Souza and others 2018). For this reason, and because oclacitinib is only licensed for once daily treatment when used long term, we will often initiate treatment on a once daily basis, as this avoids the inevitable client concern when there is some recurrence of pruritus when treatment is reduced from twice to once daily. Furthermore, a rebound effect of clinical signs has also been noted following abrupt withdrawal of treatment and this clinical impression has been borne out by experiments in a mouse model (Fukuyama and others 2017). The rebound effect is attributable to an increase in pruritogenic cytokines, facilitation of intracellular signalling (after JAK inhibition is withdrawn), and an increased sensitivity of cutaneous nerve endings to these cytokines.
When to use
Oclacitinib has proven to be a useful additional treatment for the management of CAD and has both short- and long-term applications.
Short-term use of oclacitinib
The short half-life of oclacitinib makes it useful during the work-up phase of atopic dermatitis. We frequently use it to manage pruritus during an elimination diet trial. It may be administered on an intermittent or continuous basis. When used intermittently, it is usually given once daily for three to four days at a time to control unacceptable levels of pruritus and repeated as required. When used continuously, it is necessary to withdraw treatment to assess response to the elimination diet. The short half-life is beneficial in this respect as withdrawal of treatment usually results in rapid recurrence of pruritus unless there has been a response to the diet.
Due to its immunomodulatory effects the use of oclacitinib should preferably be avoided when treating microbial infections, although a short course may be employed at the start of antimicrobial therapy if it is necessary to manage pruritus.
Drug withdrawal for allergy testing
A period of drug withdrawal (one to three weeks) is recommended for dogs on antihistamines and short-acting oral glucocorticoids, respectively, before intradermal testing to avoid interference with test results (Olivry and others 2013). A similar period of glucocorticoid withdrawal is advised for serum allergy testing. Oclacitinib does not affect the results of intradermal or serum allergy testing and may be used as an alternative treatment for pruritus during this period.
Management of pruritus during the induction phase of allergen immunotherapy
Allergen-specific immunotherapy is generally considered the treatment of choice in most non-seasonally affected atopic dogs. However, it can take up to 10 to 12 months for any improvement to become apparent and should be administered for this length of time before making any final decision on efficacy. Pruritus often has to be managed during this period and oclacitinib may be used either continuously or on an intermittent basis, as required. However, it is important to discontinue treatment to truly assess the response to immunotherapy.
Management of atopic flares
Oclacitinib may also be given as a short-term treatment to manage uncomplicated atopic flares during peak allergy seasons in dogs, which are otherwise adequately managed for most of the year with allergen-specific immunotherapy.
Management of other pruritic skin disease
Oclacitinib is also useful for the short-term management of other pruritic diseases such as flea allergy dermatitis, although it should not be used as a panacea for any pruritic skin disease in lieu of making a specific diagnosis.
Oclacitinib administered once daily may also be used as a long-term treatment for CAD if effective (Fig 1). The decision to use this treatment long term should be an informed decision made by the owner. To date, oclacitinib has proven to be a safe treatment when used for up to two years (Cosgrove and others 2015), but discussion with the owner should include the fact that the very long-term effects of this treatment are not yet known. Many dermatologists consider that conditions complicated by significant inflammation, scarring and changes to the epidermal barrier, such as pedal furunculosis or chronic otitis externa, do not respond well to oclacitinib as a monotherapy.
Adverse effects and contraindications
In general, oclacitinib is well tolerated and short-term side effects are uncommon. The most commonly recognised adverse effects in one study were urinary tract infection (UTI)/cystitis (11.3 per cent of cases treated), vomiting (10.1 per cent), otitis (9.3 per cent), pyoderma (9.3 per cent) and diarrhoea (6.1 per cent). In addition, 19 per cent of dogs developed new dermal, epidermal or subcutaneous masses that did not have a specific diagnosis established. These signs were not seen with any expected increase in frequency compared to the general population and it may be appreciated that some of these signs would be expected in a dog suffering from atopic dermatitis (Cosgrove and others 2015). The incidence of histiocytomas is reportedly increased in dogs receiving oclacitinib (High and others 2017).
A recent study concluded that UTI was not an expected adverse effect in dogs treated with oclacitinib and that routine urine culture was not indicated in the absence of signs suggestive of UTI. However, unexplained proteinuria occurred in 10 per cent of dogs (Simpson and others 2017).
We have seen several cases of demodicosis in dogs treated long term with oclacitinib, which is to be expected in dogs receiving a T cell-specific immunomodulatory therapy.
This drug should not be used in dogs with evidence of immunosuppression or in dogs with evidence of progressive malignant neoplasia. We have seen cases of cutaneous lymphoma mistakenly diagnosed as atopic dermatitis and administered oclacitinib resulting in a marked and rapid deterioration of clinical signs (Fig 2).
Weight gain has also been observed in some dogs during long-term oclacitinib therapy. The reason for this is not clear but does not seem to be associated solely with a reduction in scratching.
Monitoring oclacitinib therapy
The data sheet advises that oclacitinib is an immune-modulating drug and may increase susceptibility to neoplasia and infection. Therefore, it is recommended that dogs receiving long-term therapy with oclacitinib should be monitored with periodic complete blood counts and serum biochemistry. In our practice a full physical examination and blood work and urinalysis are performed every three to six months depending on the individual case.
As previously discussed, many cases are well controlled on twice daily treatment, but pruritus increases to an unacceptable level when reduced to once daily. This apparent rebound of pruritus may resolve, but not consistently, and the question arises as to whether it is safe to administer this treatment twice daily long term. There are theoretical reasons why this should not be considered safe. Oclacitinib has effects not just against JAK1 but also JAK2 and JAK3, albeit to a lesser extent. These enzymes are involved in pathways affecting erythropoiesis, myelopoiesis, platelet production, granulopoiesis, T-cell differentiation and some antiviral and antitumour cytokines, among others. Thus, the effect of overdosing this drug over a prolonged period of time could potentially have severe adverse effects.
Concurrent administration with other medications
There are no contraindications to administration of oclacitinib with ecto- and endoparasiticides, antimicrobials and non-steroidal anti-inflammatories.
The long-term use of oclacitinib along with other immunosuppressive therapies such as glucocorticoids and ciclosporin has not been evaluated; however, there would be concern about the induction of severe immunosuppression when using such combinations long term as different immune pathways are targeted.
The short-term use of oclacitinib with ciclosporin has been investigated in healthy beagles. Oclacitinib was administered at a dose of 0.4–0.6 mg/kg every 12 hours for two weeks and then every 24 hours for one week along with ciclosporin at the recommended dose; this resulted in no significant adverse clinical, haematological or biochemical effects and thus appears to be safe (Panteri and others 2016). Thus, oclacitinib may be used to control pruritus during the induction phase of ciclosporin therapy.
Reasons for apparent lack of efficacy
There are several reasons why oclacitinib may appear to be ineffective. Pruritus can result from the activation of many pathways which may not involve IL-31 and oclacitinib will not be effective in such cases.
Oclacitinib is not effective in controlling pruritus associated with secondary bacterial (Fig 3) and yeast infections, and in our practice this is the most common reason for apparent lack of efficacy in referred cases. Infections should be identified and treated before starting oclacitinib. Secondary infection should be suspected in any case that has been well controlled but suddenly relapses. Indeed, there may be an increased incidence of pyoderma in dogs being treated with oclacitinib.
Lokivetmab – a new biological therapy for CAD
Lokivetmab (Cytopoint; Zoetis) is a caninised monoclonal antibody produced in mice that, like oclacitinib, also targets IL-31, but unlike oclacitinib, it acts extracellularly by targeting and neutralising IL-31 before it can bind to a cell-bound receptor. In the UK, it is licensed for the clinical manifestations of CAD. It has no direct effects on other cytokines and so is considered a more targeted therapy than oclacitinib with an improved safety profile.
It has been shown to be as effective as ciclosporin for the control of pruritus and inflammation in CAD over a period of three months with a more rapid onset of action (often within 24 hours) (Moyaert and others 2017). In one study 77 per cent of dogs treated had a greater than or equal to 50 per cent reduction in owner-assessed levels of pruritus and clinical improvement was noted within 24 hours in 56 per cent of dogs treated (Souza and others 2018). In the same study it was noted that response to oclacitinib is to some degree a good predictor of whether the case will response to lokivetmab, although many cases that had a poor or no response to once daily oclacitinib still responded to lokivetmab.
Dose and licensing
Lokivetmab is administered by subcutaneous injection. In the UK the recommended dose is 1 mg/kg, repeated every four weeks, if necessary. With subsequent administrations this interval may be increased with some dogs only requiring repeated injections every three to four months. Occasional cases require dosing every three weeks, although this is an off-licence use of this treatment. If there is a poor initial response to treatment it is worth trying a second injection a month later, but treatment should not be continued if this does not result in a satisfactory response. It is only licensed for the management of CAD and thus it is important to have a specific diagnosis and should not be used empirically as a treatment for any case of pruritus.
It should not be used in dogs weighing less than 3 kg as it is not licenced for use in dogs under this bodyweight.
In practice, lokivetmab has also proven to be a useful, albeit moderately expensive, additional treatment for the management of CAD with rapid onset of action.
Lokivetmab has a prolonged duration of action and so is perhaps less useful for control of pruritus during an ectoparasiticide or elimination diet trial. If it is used, the clinician should appreciate that to assess response, the diet will need to be continued after the effect of the lokivetmab could be expected to have worn off. In some cases, pruritus can remain in remission for two months or longer following treatment.
It is not uncommon to see dogs presenting with signs of atopic dermatitis at a few months of age and the approach to diagnosis is the same in these cases. Dogs that do not respond to a diet trial will require treatment to control pruritus. Allergen-specific immunotherapy is one such option for treatment but it is recognised that some younger patients may test negative on intradermal or serological testing and should be retested when they are over one year of age (Fadok and others 2014). Lokivetmab may be a preferable alternative to glucocorticoids or ciclosporin to control pruritus in these cases until the dog is old enough for intradermal or serology testing and, furthermore, lokivetmab does not seem to affect the results of intradermal testing (Souza and others 2018).
It may be an appropriate therapy for the management of seasonally allergic dogs, and is particularly useful for owners that find it difficult to administer oral medication.
We have also used lokivetmab for the short- to medium-term control of pruritus in dogs starting allergen-specific immunotherapy.
Lokivetmab may be considered as a long-term option for the management of CAD. Again this should be following full and frank discussion with the owner regarding the necessity for lifelong treatment, the duration of action of therapy, the necessity to manage secondary infections, possible adverse effects and cost. This is a relatively new treatment and the long-term effects are not yet known. It should be stressed here that lokivetmab is very specific and effective at controlling pruritus. For those individuals with significant chronic changes of the skin and/or ear canals this is not an ideal monotherapy due to the lack of anti-inflammatory action of the agent.
Administration to dogs with concurrent disease
Lokivetmab has been administered to atopic dogs with concurrent diseases including demodicosis, hyperadrenocorticism, hypothyroidism, diabetes mellitus, pancreatitis, protein losing nephropathies, and malignant neoplasia (Souza and others 2018), with no apparent interference or exacerbation of the disease course. It should be considered the treatment of choice for the rapid management of pruritus in atopic dogs with these diseases.
Adverse effects with lokivetmab are uncommon but include vomiting, diarrhoea, lethargy, urinary incontinence and pain at injection site (Souza and others 2018). Rare hypersensitivity reactions resulting in anaphylaxis, urticaria and angio-oedema were reported in a small percentage of dogs treated with lokivetmab. It is also recognised that a small percentage of cases may develop an antibody response to the product, which will result in lack of efficacy after a period of use.
Co-administration with other treatments
Lokivetmab has been administered with a wide variety of additional medications including endo- and ectoparasiticides, antimicrobials, anti-inflammatories, antihistamines, glucocorticoids, ciclosporin and oclacitinib, allergen-specific immunotherapy, and prophylactic vaccines without any adverse effects (Michels and others 2016, Souza and others 2018). It is recommended that if any injection is to be administered at the same time as treatment with lokivetmab, the two should not be mixed and should be administered at different sites.
Sublingual allergen-specific immunotherapy
Many dermatologists consider allergen-specific immunotherapy to be the treatment of choice for the management of CAD. It is the only treatment which modifies the immune response to specific allergens. Subcutaneous injectable immunotherapy (SCIT) has been used for decades and is beneficial in around 60 per cent of cases, being used as a sole therapy in perhaps half of those cases. It is relatively inexpensive, particularly in large dogs and has no long-term adverse effects.
Sublingual immunotherapy (SLIT) is a form of allergen-specific immunotherapy where the allergens are administered into the oral cavity and absorbed across the oral mucosa rather than being given by subcutaneous injection. SLIT is considered a safe and efficacious treatment for the management of allergic diseases in people (DeBoer and others 2016). SLIT is now starting to be used for the management of CAD and has been shown to be well tolerated. It is generally more expensive than SCIT.
The allergens are administered in a glycerinated solution using a pump dispenser that delivers an aliquot of liquid under the dog’s tongue (Fig 4). Treatment is administered every 12 hours. Different protocols are available but the concentration is gradually increased over a period of months.
Efficacy seems to be similar to that of SCIT with a response rate of 50 to 60 per cent (DeBoer and Morris 2012, DeBoer and others 2016), although experience in our practice is that SLIT may have a more rapid onset of effect. In one unpublished study 49 per cent of cases that had not responded to SCIT showed a beneficial response to SLIT (DeBoer and Morris 2012).
In our practice to date, 158 dogs have received SLIT and after an initial nine months of treatment, 73 dogs have had a response that justified continuation of therapy. It should be noted that for some cases where therapy was not continued owner compliance was the issue.
Adverse effects are uncommon but include increased pruritus, lethargy, vomiting, diarrhoea and mild angioedema. In some of our cases administration of a less concentrated formulation resulted in resolution of pruritus induced by treatment. Gastrointestinal signs have resolved with temporary discontinuation of therapy.
There are no published studies detailing the safety or otherwise of administering other treatments and vaccines along with SLIT. However, in our experience, there have been no adverse reactions to concurrent administration of glucocorticoids, ciclosporin, oclacitinib, lokivetmab, antimicrobials and non-steroidal anti-inflammatory drugs.
This form of immunotherapy requires compliant owners. It is important that the treatment is administered twice daily. Our experience is that some clients are initially enthusiastic about this modality then request a switch to conventional SCIT because they find twice-daily administration of treatment to be too onerous.
Overall assessment of SLIT
SLIT is an additional safe and effective management option for CAD and should certainly be offered to clients wishing to start allergen immunotherapy as an alternative to SCIT. It is particularly useful for dogs (and owners) that are resistant to injections. However, it is important that owners appreciate that this is long-term therapy and that twice-daily administration is required. Any owners who doubt their ability to maintain this protocol may be better to use SCIT.
CAD is a common disease which requires long-term multimodal treatment. These new therapies – oclacitinib, lokivetmab and SLIT – are welcome additions for effective and safe case management. They may not control pruritus in every dog and the individual should be carefully assessed for the suitability of each treatment and the client appraised of realistic expectations and potential side effects.
Competing interests Peter Forsythe has received lecture fees from Zoetis.
Hilary Jackson has received consultancy fees from Stallergenes Greer.
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