In considering the principles of “multimodal therapy” for canine allergic pruritus, a key concept is that the therapy plan should consist of a “foundation treatment”—which forms the basis of overall relief for the pet—and one or more “accessory treatments,” which help the foundation treatment to work. We often say that every dog with allergies has one key “foundation treatment”—one particular treatment that provides the most efficacy for that patient, and the best client satisfaction. This treatment is often a drug or biological, at least initially. Current treatments that fall into this group include corticosteroids, ciclosporin, oclacitinib, lokivetmab, and allergen immunotherapy. The best foundation treatment does vary from patient to patient, and situation to situation. Things to think about when choosing and using foundation treatments include:

• Efficacy—of course. Each of the above foundation treatments will probably work well for somewhere between 60–80% of dogs. However, it’s not the same 60–80% for each treatment! Unfortunately, at this point, there is no way to predict in advance which treatment will turn out to be the best one for a particular dog. This implies that trial-and-error is a necessary part of early treatment and clients must understand this.
• Administration and adherence—What does the owner prefer? What is easy for them to do?
• Owner preferences: for example, the biological treatments may resonate more with some owners than others.
• Adverse effect profile of each treatment.
• Safety, contraindications, and comorbidities for each treatment.
• Overall cost of the treatment—recognizing that this includes not only the cost of the treatment itself per year, but also recommended monitoring and re-examination costs.

Something Old: Corticosteroids as a Foundation Treatment

Corticosteroids are the most untargeted, broadest-acting treatment we have for inflammatory skin disease—which is of course why they work so well for many patients, and also why they have adverse effects. Systemic corticosteroids are perhaps unfairly maligned in treatment of allergic skin disease. Clearly, long-term use of systemic glucocorticoids is not ideal treatment, due to the ubiquitous short- and long-term adverse effects that develop. However, short-term use of oral glucocorticoids, for example for a couple of weeks to induce remission in a severely affected patient, may be a very acceptable part of treatment.

Don’t forget about topical corticosteroids! Despite recent appearance of many new options, topical corticosteroids are still the mainstay of first-line treatment of atopic dermatitis in people. They are very effective, easy to apply, inexpensive, and have few or no adverse effects if used carefully.

A common way that topical anti-inflammatory drugs are used for human atopic dermatitis (AD) is termed “proactive therapy.” With this principle, we recognize that treating skin “just until it looks better” is not ideal. Even at clinical normalcy, there still may be subclinical inflammation present that immediately reasserts itself if the medication is stopped—and then requires daily treatment again. Rather, in proactive therapy the topical is applied daily until clinical normalcy and then for some time (perhaps a week or two) after clinical normalcy. Then, the topical is applied proactively (i.e., even when the skin is normal) to the typically affected areas, usually twice weekly. Long-term, low-dose, intermittent application of topical anti-inflammatory therapy keeps the skin inflammation from re-erupting, and therefore the daily applications are typically no longer needed, at least as frequently. This results in much less drug being used over the entire course of the patient’s disease.

In North America, the useful veterinary corticosteroid spray products available include Genesis (Virbac; low-concentration triamcinolone—USA) and Cortavance (Virbac; hydrocortisone aceponate—Canada and Mexico). These moderate-potency, easy-to-apply spray steroids are especially useful for situations such as:

• Regional application in short-coated dogs, where they can actually be a very effective foundation treatment for some pets (though surprisingly, they are often effective in long-coated dogs also).
• Relief of “trouble spots” that seem refractory to another foundation treatment that is being used. Examples include pedal pruritus, anal pruritus, and pinnal pruritus.

The local adverse effect of most concern with topical steroids is alopecia and thinning of the skin. This effect occurs frequently with topical betamethasone products; such products should never be used more than 2–3 weeks total. Topical low-concentration triamcinolone, or hydrocortisone aceponate, are much less likely to cause this problem; the key to minimizing it is to minimize frequency of application. Here, the concept of “proactive therapy” really shines! Begin application at twice daily for a week, then once daily for a week or more, until the inflammation subsides “plus one week.” At that time, begin twice-weekly application as proactive therapy to prevent relapse. This treatment regimen is somewhat foreign to owners, who are used to applying medication only when their pet is symptomatic…so requires some explanation by the veterinary staff.

Ciclosporin: Forgotten Benefits?

Ciclosporin, a calcineurin inhibitor, is more targeted and safer long term than using oral steroids. Used frequently when it first came onto market for dogs around 15 years ago, the advent of newer treatments has led some clinicians to forget how very beneficial it can be for some patients. Its effect is to inhibit production of cytokines, including interleukin-2, that are involved in T-cell activation and regulation. In high doses, it is profoundly immunosuppressive, accounting for its original use in organ transplantation. In lower doses, we might call it “immunomodulatory,” as it seems to dampen down the immune response just enough to lessen allergic symptoms, while not raising any danger of opportunistic infections or other adverse effects. It does have the obvious problem of causing gastrointestinal upset in some patients, and uncommonly, it can cause gingival hyperplasia. But overall, assuming the patient tolerates it, it can be an excellent, effective foundation treatment for AD and in addition has a long record of safe use in dogs and cats. It does have a 2–4-week “lag period” from first administration to efficacy, making it unsuitable for periodic or occasional use. Ciclosporin does not require any specific periodic monitoring steps when used for AD. Though this drug has a reputation for being expensive, in many cases the somewhat costly starting doses can be tapered after 2–3 months of daily administration, to 50% or even 25% of the original starting dose. This dramatically reduces cost. The more recent advent of liquid oral formulations of ciclosporin is enabling more precise dosing at price points that can be very competitive with other medications.

Something New(ish): IL-31 and Oclacitinib

Oclacitinib, a JAK1 inhibitor, has been studied in a variety of models of pruritus and has shown the ability to suppress pruritic responses rapidly and effectively, in some cases better and quicker than prednisolone. Results in head-to-head studies against either prednisolone or ciclosporin show the drug to be equally effective in control of itch and inflammation, and to have a very rapid onset of action with relief sometimes apparent within hours of oral administration. Oclacitinib is indicated for control of acute or chronic allergic pruritus in dogs over 12 months of age. Recommended dosing consists of twice-daily administration for up to 14 days (important language, as this means twice daily for anywhere between 0 and 14 days), followed by once-daily dosing for longer-term use. A few dogs seem to worsen when switched from twice to once daily, probably related to the short half-life of the drug (4 h in the dog). Overall, it appears that at least 60–70% of allergic dogs receiving the drug have rapid, substantial, and prolonged relief of their clinical signs. There is no specific organ toxicity associated with oclacitinib, therefore no specific laboratory monitoring is advocated, though good medical practice dictates that all dogs receiving this drug should be examined at least once annually. The drug has been limited to use in dogs 12 months or older, mostly because in one high-dose safety study with 6-month-old laboratory dogs, generalized demodicosis developed in some patients that were given 5x the label dose. Oclacitinib can be used safely along with antibiotics, antihistamines, antifungal drugs, NSAIDs, allergen-specific immunotherapy, and many other medications, and vaccination of treated dogs is effective. It does not appear to interfere with serologic or intradermal allergy tests. As with other treatments targeting the immune system, it should not be used in the face of a severe infection, demodicosis, or with active malignancy.

Recent practical experience with oclacitinib by US dermatologists has provided insights as to how best to use the drug. First, two rare adverse effects have been seen, even at the label dose: demodicosis, and slightly lowered WBC count. Until we know more, most dermatologists advise the following examinations if the drug will be used longer term: (1) Recheck exams at 2 months, 6 months, and then annually; (2) at each recheck exam, check for lesions or alopecia, and if any are present, scrape for Demodex mites, and perform a complete blood count; (3) serum chemistries and urinalysis are not necessary, though are often recommended as part of general annual health evaluation. Oclacitinib may not work very well on the pruritus associated with skin infection, either staphylococcal or yeast.

The Newest Modality: Monoclonal Antibody Therapy with Lokivetmab

Therapies continue to become more and more targeted. The newest type of therapy in veterinary medicine is monoclonal antibody (mAb) treatment. This therapy has been used in people for about 20 years, and was always considered something that would never be financially practical for dogs or cats. However, improvements in techniques and processes now make it completely possible for this new and dramatically different type of treatment to be accessible for pets. Monoclonal antibody treatments involve treatments with injections of laboratory-produced antibody proteins that target harmful molecules in the pet’s body. Because these are proteins that exist normally in the pet, they are not rejected by the immune system, and are not toxic to any organ. They persist for many weeks or even months in the pet’s body after subcutaneous injection. These treatments are being developed for a variety of pet diseases, such as cancer, pain, and inflammatory disease. The first anti-itch mAb, lokivetmab, targets and eliminates IL-31 from the dog’s body. After a single injection, the treatment typically works within a day or two, and can last as long as 8 weeks.

What about safety? First, because these products are peptides or proteins, they are not metabolized by the liver or kidneys, as with a drug, and are not expected to have specific organ toxicity. They are merely degraded into their constituent amino acids, which are recycled for other uses in the body. There is also the possibility that these molecules could become immunogenic. This appears to happen in a very small number of individuals, based on human experience, and the same will probably prove true in veterinary medicine. If antibodies are generated which react against the therapeutic substance, at the very least it will be inactivated. At worst, continued administration could result in allergic reactions. In the specific case of lokivetmab, data from the manufacturer indicate about 3% of dogs will develop “anti-drug antibody” which will render subsequent injections ineffective, though allergic reactions are exceptionally uncommon.

Accessory Treatments: The Old and the New

With canine allergic skin disease, the foundation treatment alone typically does not provide optimal relief. Along with finding the best foundation treatment for each pet, accessory treatments are enormously helpful for most dogs, both for increasing efficacy and decreasing amounts of other medications that may be required. So—what works? Here are some things to think about:

• Parasite control: many dogs with AD will have concurrent flea sensitization. Thus, routine prophylactic antiparasitic treatment is advised for all canine AD patients.
• Recurrent staphylococcal and yeast dermatitis is a nearly universal feature of canine AD. The pruritus caused by the infection itself can be more intense than the actual allergy. Moreover, infection-related pruritus has a reputation for being quite resistant to treatment with anti-allergy drugs, including all of the new options. Therefore, all dermatologists strongly advise paying attention to infection control (meaning both treatment and prevention of relapse) in dogs with AD. It is a critical part of treatment in all dogs.
• Relating to the above, it is very possible to eliminate active superficial staphylococcal infections (even resistant strains) from the skin by using topical products as the primary treatment, without antibiotics. For primary topical treatment of an existing superficial pyoderma, daily treatment is necessary until the infection is cleared, which typically takes 4 weeks or more. Antimicrobial topicals are also the first line of defense for prevention of relapse in patients with recurrent pyoderma due to allergy or other causes. For preventive maintenance, topicals are typically used 2–3 times weekly. As far as ingredients, the most studied and proven formulations are those containing 2–4% chlorhexidine. Combination with azole antifungal ingredients (miconazole or ketoconazole) is helpful. Other specific topical formulations now contain ingredients that promote the action of endogenous antimicrobial peptides in skin.
• Essential fatty acid (EFA) supplementation—via diet or otherwise: EFA supplements remain a cornerstone of conservative management. Their effects may occur through their weak anti-inflammatory actions, through possible effects on epidermal barrier function, and most importantly through their medication-sparing effects. Because they are relatively inexpensive, safe, and easily administered, many dermatologists advise that, ideally, all atopic pets should receive enhanced levels of EFA in their diet. Typically, daily doses in the range of 40–100 mg/kg of omega-3 anti-inflammatory fatty acids, administered via supplement or as part of the dietary formulation itself, are recommended to achieve this benefit.
• Nutritional considerations: beyond being a source of EFA supplementation, modern “skin benefit” diets often contain other ingredients that may enhance barrier function and reduce inflammation, thereby adding to relief at least by reducing other medication requirements. Evidence for efficacy of these diets is limited at this point, but it does exist—both in cutaneous models and in clinical feeding trials.
• Don’t forget the ears! Atopic otitis is a very common problem in many dogs with AD. Otic inflammation leads to increased secretion of cerumen, leading to overgrowth of normal ear flora such as Staphylococcus and Malassezia and eventual relapsing ear infections. Allergic ear disease has a strong reputation for being “treatment resistant” to some of the newer drugs. Foundation therapies that are very effective at controlling AD on the majority of the body sometimes fail to control the ears very well. Proactive therapy to the rescue! Daily application of corticosteroid-only ear drops for several weeks, until the inflammation has completely subsided and then perhaps a week longer, can be followed by twice-weekly application to prevent relapse of the inflamed ears. In countries where available, Cortavance has been used effectively (though off-label) for this purpose (0.25 ml per ear, twice weekly). In the USA, the authors routinely use either 0.1% dexamethasone drops or 0.1% mometasone furoate drops. The latter is now widely available in an inexpensive generic form.

New Concepts to Consider: Targeting and Progressive Therapy

Our recent understanding of the pathogenesis of AD stresses that it is an immensely complex process involving many different cell types, inflammatory and immunologic processes, cytokines and chemokines, and other inflammatory mediators. In particular, many of these processes are orchestrated via networks of cytokines. Exactly which cells, processes, and mediators are responsible for clinical signs and patient discomfort likely vary by individual and by stage of disease.

In parallel with this concept, we must recognize that foundation treatments vary greatly in how targeted they are with respect to, for example, cytokine networks. Corticosteroids are very untargeted, in that they affect production of many cytokines by many cell types. This is why they work so well, but also why they have adverse effects. Ciclosporin is more targeted, and oclacitinib even more so. The most targeted treatment we have currently is lokivetmab, which affects only a single cytokine.

Putting these two concepts together: a dog with relatively early, uncomplicated AD with minimal lesions and mild to moderate pruritus may be simpler to address than a dog with severe pruritus, longstanding disease, secondary complications, and chronic skin changes. The latter patient may have dozens of cytokines wreaking havoc. In this case, is it fair or reasonable to expect that a very targeted therapy will be effective? It may be, or it may not be—and if it is not, the reason might be that it is simply too targeted for that patient at that time. Moving up towards something less targeted may provide a solution in this instance. Once the condition is better controlled, moving back down to more targeted treatments may provide long-term benefit with a better adverse effect profile.