An embarrassment of riches: An update on the symptomatic treatment of canine atopic dermatitis

Veterinarians have, in recent years, been witness to major advances in the treatment of canine atopic dermatitis (AD). While the principles of therapy remain unchanged, the options for treating the inflammation and pruritus that characterize AD have greatly increased. The wealth of choices can feel like an “embarrassment of riches:” an overabundance of good things, leading to more options than one knows what to do with. This update provides a summary of the current therapies and guidelines for using them to treat this very common disease.

Canine AD is defined as a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features, associated most commonly with IgE antibodies to environmental allergens (1). Successful treatment of AD is multimodal and must adapt to changes in the patient’s condition. It consists of treating acute flares of the disease as well as managing the chronic condition (2). Client communication and education are crucial, as affected dogs can be successfully managed, yet rarely cured.

Although the treatment plans are highly individualized depending on a patient’s clinical signs, the principles of therapy for AD include (1,2):

• reduction of pruritus and inflammation with symptom-relieving treatments (the subject of this review),

• allergen-specific immunotherapy, a long-term disease-modifying intervention,

• treatment and prevention of secondary bacterial and yeast skin and ear infections,

• improvement of skin hygiene and barrier function, and

• identification and avoidance of flare factors, including environmental allergens.

The 4 symptom-relieving interventions for AD with good evidence of high efficacy discussed in this article are glucocorticoids (oral and topical), cyclosporine, oclacitinib, and lokivetmab. Due to their different mechanisms of action, benefits, and side-effect profiles, they all have a role in the treatment of AD. Although many other treatments including antihistamines, fatty acids, topical tacrolimus, interferons, misoprostol, pentoxifylline, vitamin E (1), and vitamin D (3) have shown some efficacy for AD, their use as monotherapy is uncommon. Innovative therapies such as vaccination against interleukin (IL)-31 (4) or other novel treatments may increase our already impressive arsenal in the future.

Glucocorticoids

Oral glucocorticoids such as prednisone, prednisolone, and methylprednisolone have been a staple of therapy for AD for decades. They exert their myriad anti-inflammatory effects by repressing inflammatory genes such as those for cytokines, adhesion molecules, pro-inflammatory enzymes, and receptors (1) and provide a potent broad-spectrum “hammer” to quickly and reliably reduce inflammation in atopic skin. Because most dogs with AD respond well to oral glucocorticoids, a poor response should prompt us to consider alternative diagnoses or complications such as skin infections (2). The usefulness of systemic glucocorticoids for chronic AD is limited by long-term adverse effects with which we are very familiar (1). However, glucocorticoids remain an excellent choice for treating acute flares for periods of several days to weeks in otherwise healthy dogs. Although side-effects are common, they are often tolerable to clients if the treatment duration is short and if they have been adequately prepared. Dogs vary in their susceptibility to glucocorticoid side-effects. A commonly recommended starting dose of prednisone for dogs is 0.5 to 1 mg/kg body weight (BW) per day for several days, followed by a taper (1). I often start with lower doses (< 0.5 mg/kg BW per day) in large dogs with good results and fewer adverse effects. Glucocorticoids can be safely combined with lokivetmab, but long-term combination therapy with cyclosporine or oclacitinib is usually avoided.

Oral glucocorticoids.

Uses

• short-term use for allergic flares

• otitis externa, particularly with hyperplasia or ulceration

• severe inflammation, e.g., pododermatitis

• severe secondary changes, e.g., lichenification

Advantages

• potent anti-inflammatory and antipruritic effects

• consistently effective

• rapid onset

• low cost

Disadvantages

• many well-recognized adverse effects

Contraindications

• many, including diabetes mellitus, severe infections, demodicosis

Monitoring

• clinical examinations, periodic urinalysis (possibly urine cultures), complete blood (cell) count (CBC), serum biochemistry

With the new treatments available for AD, why reach for oral glucocorticoids? They are still the most effective agents for reducing severe inflammation quickly, or for treating skin and ears with severe secondary changes such as lichenification and ceruminous gland hyperplasia. Topical glucocorticoids can be very useful for the management of localized signs of AD such as pododermatitis and otitis externa with a lower risk of systemic adverse effects. They can also be combined with other therapies. Otic topical glucocorticoids such as hydrocortisone (ProOtic HC; Pro Concepts Animal Health, Toronto, Ontario) or in compounded formulations (e.g., Burow’s solution), can be used for the treatment and prevention of ear infections in dogs with allergic otitis externa. Hydrocortisone aceponate (Cortavance Topical Spray Solution; Virbac Canada, Cambridge, Ontario) is a potent dermal glucocorticoid spray with a low rate of percutaneous absorption. Used as labeled (for 7 consecutive days), it can be used to treat acute localized flares of AD. Several studies confirm the efficacy and safety of this product for longer periods. A study comparing Cortavance and oral cyclosporine used up to 84 d (daily, or less often if possible) showed no differences in the scores for efficacy, tolerance, or ease of administration (5). Another study showed that proactive twice weekly treatment was well-tolerated and effective in extending the period between relapses of clinical signs (6). Patients treated for longer than the recommended period should be carefully monitored for cutaneous atrophy (7), which in my experience is more common when topical glucocorticoids are applied to inguinal and axillary skin.

Cyclosporine.

Uses

• maintenance anti-inflammatory therapy; use when glucocorticoids would otherwise be chosen

• chronic otitis externa, particularly with hyperplasia

• severe inflammation, e.g., pododermatitis

• severe secondary changes, e.g., lichenification

Advantages

• broad-spectrum anti-inflammatory

• usually well-tolerated long-term

• normalizes skin to help reduce secondary infections

• labeled from 6 mo of age

• dose reductions often possible

Disadvantages

• slow onset, not useful for flares

• gastrointestinal side effects more common than with other treatments, but usually self-limiting

• high cost for large dogs at daily dosing

• many drug interactions

Contraindications

• include neoplasia, serious infections

Monitoring

• clinical examinations including oral examinations (gingival hyperplasia), periodic urinalysis (possibly urine cultures), CBC, serum biochemistry

Common errors

• routinely reducing the dose in all patients after 1 mo, even if only partial improvement has been noted (daily dosing can be continued as needed)

Cyclosporine

Cyclosporine (Atopica; Elanco Canada, Guelph, Ontario), available in Canada for more than a decade, is labeled for the control of clinical signs of AD in dogs 6 mo of age and older. It revolutionized our ability to treat atopic dogs by giving us the first effective symptom-relieving drug that freed many dogs of their reliance on steroids. Cyclosporine has proven to be a useful and safe (8) alternative to long-term glucocorticoid therapy. Cyclosporine exerts its effects primarily through lymphocytes, giving it broad-spectrum anti-inflammatory activities. The remission of clinical signs is markedly slower than with the other therapies but its overall efficacy in reducing pruritus and skin lesions is similar to that of oclacitinib after several weeks have elapsed (9). Co-administering lokivetmab can be helpful for rapidly reducing pruritus. Alternatively, oclacitinib (10) or oral glucocorticoids can be added for the first 1 to 3 wk. However, the long-term co-administration of these 2 drugs is not recommended.

Has cyclosporine become obsolete with the arrival of newer therapies for AD? Absolutely not. Due to its broad-spectrum effect on inflammation, it remains a valuable part of our treatment arsenal.

Oclacitinib.

Uses

• anti-pruritic and anti-inflammatory, for short- or long-term use

Advantages

• effective anti-pruritic activity

• very rapid onset

• usually well-tolerated

• pharmacologic drug interactions unlikely

Disadvantages

• minimum age 12 mo

• may be less effective when severe inflammation, lichenification, otitis, pododermatitis are present

• increased pruritus can be seen when reducing (from twice daily) to once-daily therapy

Contraindications

• include neoplasia, serious infections

Monitoring

• clinical examinations, periodic CBC, serum biochemistry, urinalysis

Common errors

• attempting to reduce the dose to alternate-day therapy (unlikely to be effective due to short half-life)

• relying on oclacitinib exclusively for AD, at the exclusion of other therapies or adjunctive treatments (e.g., for concurrent infections)

Oclacitinib

The line-up of treatments for AD increased in 2016 with the arrival of a highly effective and much-anticipated addition, oclacitinib (Apoquel; Zoetis Canada, Kirkland, Quebec). Apoquel is approved in Canada for the control of pruritus associated with allergic dermatitis and the control of AD in dogs at least 12 mo of age. This Janus Kinase 1 inhibitor inhibits the activity of various pro-inflammatory and pruritogenic cytokines at their receptors. Among these is IL-31, one of the critical cytokines mediating pruritus in dogs. The primary biological function of IL-31 in mammals appears to be the induction of itch (11). However, IL-31 also has pro-inflammatory and barrier-disrupting roles in other species in which it has been studied, which may further contribute to its importance in AD (11).

Oclacitinib has provided veterinarians with a novel, effective, and well-tolerated treatment for AD (9,12,13). A key benefit of the drug is its impressively rapid efficacy (9), which is comparable to that of oral glucocorticoids. In contrast to glucocorticoids, oclacitinib is well-tolerated by most dogs, even when used for long periods.

Lokivetmab

Since June 2017, lokivetmab, or canine atopic dermatitis immunotherapeutic (Cytopoint; Zoetis Canada) has been available in Canada as an aid in the reduction of clinical signs associated with AD in dogs. This therapy is unique in that it is a caninized monoclonal antibody that targets and inhibits the activity of IL-31. Its spectrum of activity is narrower than that of oclacitinib since it does not impact other cytokines.

Lokivetmab.

Uses

• predominantly anti-pruritic, for short- or long-term use

Advantages

• effective anti-pruritic activity

• very rapid onset

• well-tolerated

• can be combined with other treatments for AD including oclacitinib

• no minimum age

• no contraindications for concurrent illness including neoplasia, infections, and demodicosis

• convenient

• laboratory monitoring not routinely needed

Disadvantages

• high cost for large dogs

• may be less effective when used alone if severe inflammation, lichenification, otitis, pododermatitis are present

Contraindications

• none, unless adverse effects have been noted

Monitoring

• clinical examinations

Common errors

• prescribing it only for “desperate” cases

Lokivetmab is administered by subcutaneous injection every 4 to 8 wk. It has been shown to be a safe (14) and effective (15,16) treatment for canine AD. One should not consider lokivetmab as an “injectable Apoquel:” despite its activity on the same key cytokine, the 2 treatments are very different. Perhaps surprisingly, lokivetmab can work well even in dogs responding poorly to oclacitinib (17). Moreover, it can be safely combined with oclacitinib — or any other treatments for AD — when additional anti-pruritic activity is needed. My observation is that this extremely useful therapy is often overlooked, perhaps due to its arrival on the heels of oclacitinib.

How do I incorporate these 4 therapies in my practice to treat the “embarrassment of itches” that I see every day? Always as part of a multimodal approach that might include allergen-specific immunotherapy, infection prevention, allergen avoidance, and barrier enhancing measures. I expect to find a symptom-relieving combination that will work well for most dogs. But I do not expect to find it the first time, every time. A pruritic pitbull terrier with mild inflammation and recurrent pyoderma (Figure 1) might do well with oclacitinib or lokivetmab and regular chlorhexidine shampoo and spray. A Westie with extensive lichenification and inflammation despite control of Malassezia infection (Figure 2) might do better with cyclosporine (possibly combined with lokivetmab). And the optimal therapy might be different for the next similar-looking pitbull or Westie I see, with my “first choice” therapy failing but another working very well. I expect, and explain to clients, that establishing an acceptable maintenance protocol for each dog will require repeated visits. I provide a tracking calendar and a pruritus scale for owners (available from the Canadian Academy of Veterinary Dermatology website, www.cavd.ca) to monitor improvement in relation to treatments. The embarrassment of riches can lead to therapeutic dilemmas when I treat itchy dogs, but has also made their treatment more successful and rewarding than ever before.

Figure 1.

Atopic pitbull terrier with mild cutaneous changes.

Figure 2.

Atopic West Highland white terrier with severe chronic lichenification and inflammation.