What's new with an old problem: Drug options for treating the itch of canine allergy
Canine atopic dermatitis is a common and frustrating skin disease. Here are three treatments compared and contrasted, including two standards and one relatively new kid on the block.
Canine atopic dermatitis is a common and frustrating skin disease. Here are three treatments compared and contrasted, including two standards and one relatively new kid on the block.
Canine atopic dermatitis due to environmental allergies is a common skin disease in dogs. Until recently, the most frequently administered systemic drugs for treating pruritus associated with canine atopic dermatitis were glucocorticoids and cyclosporine (Atopica-Novartis Animal Health). However, a new medication, oclacitinib (Apoquel-Zoetis), has been approved as an antipruritic therapy.
In this article, we briefly compare and contrast glucocorticoids, cyclosporine, and oclacitinib as antipruritic therapies for canine atopic dermatitis.
CANINE PRURITUS
Don't forget to download this algorithm to help you pinpoint the cause of a dog's pruritus.
Over the last decade, there have been major advances in our understanding of the pathophysiology of canine atopic dermatitis.1 It is beyond the scope of this article to provide an in-depth review of the diagnostic approach to canine pruritus, etiologic causes of pruritus, or the pathophysiology of canine atopic dermatitis, but click here to download an algorithm on the diagnostic approach to pruritic dogs.
The treatment of canine atopic dermatitis is multimodal and usually includes topical therapy, allergen-specific immunotherapy, the avoidance of flare factors (preventing flea infestations), epidermal barrier repair, and the appropriate administration of systemic antipruritic drugs.2 It is important to note that controlling pruritus is a key component in maintaining a good quality of life for dogs with canine atopic dermatitis and their owners.3 Communication and client education about the complexity of canine atopic dermatitis and commitment to multimodal therapy is essential.
Glucocorticoids have well-documented efficacy for the treatment of pruritus associated with canine atopic dermatitis.2,4,5 The long-term administration of glucocorticoids is associated with widely recognized complications, so strategies to reduce the dosage and frequency of administration are important. While antihistamines administered alone have poor evidence for efficacy in pruritus reduction,5 the concurrent administration of prednisolone and trimeprazine can have a corticosteroid-sparing effect.6 Essential fatty acids might also have a corticosteroid-sparing effect, although the optimal dose and formulation are debated.7
The 2001 introduction of a veterinary-specific cyclosporine provided veterinarians with a drug alternative to glucocorticoids. Compared with prednisone, cyclosporine has similar efficacy with respect to pruritus control and fewer side effects at a dose of 5 mg/kg once daily.8-10 In 2013, oclacitinib was approved for use as an antipruritic drug for canine pruritus, adding another option for the treatment of pruritus in dogs with atopic dermatitis. Click here to see Table 1, which summarizes the comparisons of these three medications.
GLUCOCORTICOIDS
Glucocorticoids bind to cytosolic glucocorticoid receptors, forming a complex that acts on nuclear glucocorticoid response elements to either promote or suppress transcription of a wide variety of genes.11 Inhibition of proinflammatory cytokine production, decreases in eosinophil and mast cell formation in bone marrow, and decreased T cell activation are a few of the ways by which glucocorticoids likely act to control cutaneous inflammation and resultant pruritus.11,12
Documented efficacy
Oral glucocorticoids have long been the foundation of treatment of pruritus associated with canine atopic dermatitis.12 In a summary review of five randomized controlled trials in which four of the studies administered oral glucocorticoids as a positive treatment control, a 50% or greater reduction in pruritus and lesion scores was noted in 40% to 80% of dogs.4 Various dosing and tapering regimens were used, but overall owners assessed the responses as “good to excellent.”4 An update to that review includes two more randomized trials in which oral glucocorticoids were administered as a positive treatment control; 67% to 86% of the dogs experienced more than 50% reduction in pruritus or lesion scores.5
Side effects
Polyuria, polydipsia, and polyphagia are common immediate side effects of oral glucocorticoid administration. These are generally mild and decrease as the dose is tapered.
Long-term side effects include-but are not limited to-muscle atrophy, corticosteroid-induced hepatopathy, delayed wound healing, and increased susceptibility to skin or urinary tract infections. Because the clinical signs of corticosteroid-induced polyuria and polydipsia are indistinguishable from polyuria and polydipsia caused by diabetes mellitus and bacterial cystitis-associated inflammation is often masked, regular veterinary examinations with laboratory monitoring, including urinalysis and bacterial urine culture, are advised.13 Gastric ulceration, calcinosis cutis, adult-onset demodicosis, and diabetes mellitus are also possible consequences of long-term glucocorticoid administration.
Indications, dosing, and usage
There are indications for both short-term and long-term administration of oral glucocorticoids in treating canine atopic dermatitis. Acute flares of atopic dermatitis should ideally be controlled with topical glucocorticoids and topical antimicrobial therapy if secondary infections are detected.2,14 Severe clinical signs might necessitate oral therapy. Prednisone or prednisolone are typically administered at 0.5 to 1 mg/kg orally twice daily until pruritus resolves and are then gradually tapered based on clinical response.
Longer courses of oral glucocorticoids are indicated when pruritus returns rapidly when tapering is begun or when exposure to allergens is ongoing. In these cases, the lowest effective dose administered at the lowest effective frequency that avoids corticosteroid-associated side effects should be chosen. A standard target dose is 0.25 to 0.5 mg/kg orally every other day.2,4,12,14 The administration of long-acting repositol glucocorticoids should be avoided.12
Contraindications
Glucocorticoids should not be administered systemically to animals with suspected or known gastrointestinal ulceration, diabetes mellitus, congestive heart failure, deep pyoderma, cutaneous or systemic fungal infections, or atypical bacterial infections.13 Concurrent administration with nonsteroidal anti-inflammatory drugs should be avoided, and administration with concurrent immunosuppressive therapy should be done cautiously.
CYCLOSPORINE
Cyclosporine is a fungal-derived macrolide immunomodulatory agent. By inhibiting calcineurin, a T cell activation enzyme, cyclosporine therapy results in decreased T cell-mediated cytokine production. Cyclosporine also decreases mast cell and eosinophil survival and cytokine secretion in addition to limiting epidermal antigen-presenting cell activation.15 All of these actions provide an overall reduction in proinflammatory mediators and inflammatory cell action.
Documented efficacy
There are multiple reviews of cyclosporine's use, safety, and treatment efficacy for a variety of conditions in veterinary medicine.5,10,15,16 A review of cyclosporine's efficacy for the treatment of canine atopic dermatitis indicates that about 70% of dogs show greater than 50% reduction in pruritus and atopic dermatitis lesion scores.9
Side effects
The most common short-term side effects are vomiting and diarrhea, occurring in 25% to 31% and 15% of dogs, respectively, in a recent review of 15 trials including 759 dogs.10 Cyclosporine's adverse effects can be dose-dependent, so if gastrointestinal signs are problematic, dose reduction should be attempted before therapy is discontinued. Anecdotal clinical experience supports storing the capsules in the freezer and administering them with a meal to reduce vomiting.17 While drug administration one hour before a meal or two hours after is advised on the Atopica product insert, one small study demonstrated no reduction in the drug's clinical efficacy for treating canine atopic dermatitis when was administered with a meal.18
Long-term side effects of cyclosporine therapy are uncommon. Gingival overgrowth (also called gingival hyperplasia) was reported in less than 2% of dogs in the previously mentioned review.10 Dog breeds prone to developing gingival overgrowth, including boxers, Great Danes, collies, Dalmatians, and Doberman pinschers, may be more likely to develop it as a side effect of cyclosporine therapy.19 Dosage reduction and regular dental cleanings slow the development of gingival overgrowth.
For dogs with pruritus that is not controlled with a lower cyclosporine dose, azithromycin, in either compounded 8.5% toothpaste or orally administered capsule (10 mg/kg daily), has been demonstrated in one study to clinically reduce gingival sulcus depth.20 The exact mechanism by which azithromycin had that effect in this study is unknown; possibilities include antimicrobial effects, local reduction of inflammation, and decreased fibroblast protein synthesis.
The Atopica product insert states that because this drug is an immunosuppressant it can increase a dog's susceptibility to infection and the development of neoplasia. As with glucocorticoids, cyclosporine can predispose patients to urinary tract infections.21 In one study, 30% of dogs receiving cyclosporine for inflammatory skin disease had at least one urine culture result positive for bacteria.21 These results did not always correlate with clinical signs or bacteriuria, so urine culture should be performed in addition to urinalysis.21
Indications, dosing, and usage
Atopica is labeled for the control of atopic dermatitis in dogs. The label dosage for control of pruritus associated canine atopic dermatitis is 5 mg/kg orally once daily. Response usually occurs within four to six weeks. Tapering of the dose frequency can be started after 30 days or when the maximum clinical response is noted; 40% to 50% of dogs achieve good control with every-other-day therapy.9
Dogs should be given the modified (microemulsion) formulation of cyclosporine because the unmodified formulation (Sandimmune-Novartis) has highly variable bioavailability.14,22 Numerous compounded formulations are available, but potency and efficacy are variable.15 Recommendations are to initiate therapy with the veterinary-licensed product to document positive response to therapy before administering a generic formulation. The administration of compounded formulations is not recommended. Atopica is contraindicated for use in dogs with a history of neoplasia.
OCLACITINIB
Oclacitinib is a selective Janus kinase (JAK) inhibitor. It specifically inhibits interleukin-31 signal transduction. Activated T cells and keratinocytes release interleukin-31, which binds transmembrane receptors on cutaneous neurons, and through JAK activation triggers an action potential that results in a pruritic response, known as neuronal itch stimulation.1,23 Interleukin-31 is a key cytokine for neuronal itch stimulation. The interleukin-31 receptor is also present on peripheral blood mononuclear cells and keratinocytes. Activation by interleukin-31 promotes the release of proinflammatory cytokines, perpetuating inflammation and pruritus.23,24
Documented efficacy
In preapproval trials, oclacitinib therapy produced rapid reductions in pruritus. The onset of action was more rapid than glucocorticoid therapy's was.25 Oclacitinib was compared with both prednisolone (0.25 mg/kg or 0.5 mg/kg orally one dose) and dexamethasone (0.2 mg/kg intramuscularly one dose) in an interleukin-31 canine laboratory model of pruritus.25 Oclacitinib reduced pruritus by 80% in one to three hours while none of the glucocorticoids showed any effect on pruritus in that time frame.25 Prednisolone (0.5 mg/kg) demonstrated a 37% decrease in pruritus at 12 hours.25
In a preapproval clinical trial of 436 dogs with allergic dermatitis, 65% of oclacitinib-treated dogs showed significant improvement in pruritus scores seven days after beginning therapy, compared with 21% improvement for placebo-treated dogs.26 This drug has not yet been evaluated in independent clinical trials.
Side effects
Side effects reported in initial studies affected less than 3% of dogs and included vomiting, diarrhea, anorexia, and polydipsia. Most of these side effects were mild and resolved without treatment, although oclacitinib therapy was discontinued in some dogs.26
As with any immunomodulatory therapy, there is the potential for increased risk of opportunistic bacterial or fungal infections. It is important to note that the Apoquel product insert states that oclacitinib therapy might increase a dog's susceptibility to infection, including demodicosis, and may exacerbate neoplastic conditions.
Indications, dosing, and usage
Apoquel is labeled for the control of pruritus associated with allergic dermatitis and for the control of atopic dermatitis in dogs more than 12 months old. It is dosed at 0.4 to 0.6 mg/kg orally twice daily for up to 14 days, and then once daily. The drug's rapid onset is useful for situations in which immediate relief of pruritus is needed. For example, oclacitinib could be given for relief of pruritus due to flea allergy dermatitis while the owner starts an integrated flea control program.
Oclacitinib should not be administered in place of other immunosuppressive therapy, such as glucocorticoids or azathioprine, for treating autoimmune disease or cancer chemotherapy. Like cyclosporine, oclacitinib can be given to patients to alleviate pruritus before intradermal allergy testing as neither drug interferes with intradermal test results, unlike glucocorticoids. Oclacitinib should not be administered to animals less than 12 months of age or those with severe infections.
CONCLUSION
While the introduction of oclacitinib adds a valuable pruritus treatment tool, pruritic dogs still need a thorough diagnostic work-up to rule out nonallergenic causes of itch. Canine atopic dermatitis is a lifelong disease that requires lifelong management. Communication about these facts is critical for the establishment of realistic client expectations. A systematic and individualized treatment approach for each patient is important.
Ideally, pruritus due to canine atopic dermatitis can be treated with nondrug therapy such as allergen-avoidance, topical therapy, and allergen-specific immunotherapy, with oral immunomodulatory medications reserved for flare-ups. However, in severe cases, long-term medication is needed. It is important that medication tapering is attempted only after clinical signs have maximally improved and other components of the treatment plan are instituted.
Editor's note: The authors participated in the Apoquel Early Experience program funded by Zoetis.
Elizabeth A. Layne, DVM
Karen A. Moriello, DVM, DACVD
Department of Medical Sciences
School of Veterinary Medicine
University of Wisconsin
Madison, WI 53706
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