Updates on JAK Inhibitors for Veterinary Dermatology

Canine atopic dermatitis is a hereditary, typically pruritic, and predominantly T-cell–driven inflammatory skin disease involving interplay between skin barrier abnormalities, allergen sensitization, and microbial dysbiosis. According to the International Committee on Allergic Diseases of Animals, the updated definition of canine atopic dermatitis emphasizes the different dynamics of the syndrome and the need for multimodal management strategies.¹

The prevalence of canine atopic dermatitis differs according to the breed of dog, and breed predisposition varies according to geographic region. Worldwide, however, the breeds most predisposed to canine atopic dermatitis are boxers, bulldogs, pugs, Labrador retrievers, and West Highland white terriers.²

The underlying pathophysiology of canine atopic dermatitis is complex, incompletely understood, and beyond the scope of this article. However, to understand the role of the Janus kinase (JAK) inhibitors in the treatment of canine atopic dermatitis, this article revisits the role of the inflammatory response. For example, an atopic dog sensitized to house dust mite allergens has an exaggerated and aberrant response from T helper 2 lymphocytes, which then release proinflammatory cytokines (e.g., interleukin [IL]-2, IL-4, IL-5, IL-6, IL-13, IL-31), which lead to neuronal itch stimulation and ultimately the incessant pruritus visible and audible to the client. The key component of ongoing pruritus and inflammation in most dogs is the IL-31 cytokine, which is a critical target of JAK inhibitors.³ JAK inhibition can provide pruritic relief to the patient and improve the quality of life of both the dog and client. The JAK inhibitors oclacitinib and now ilunocitinib are everyday treatments in small animal practice.

JAK Inhibitors

The JAK family is composed of intracellular, nonreceptor tyrosine kinases (TYKs) that transduce cytokine-mediated signals. The name is derived from Janus, the Roman god of duality, because the JAKs have 2 phosphate-transferring domains.⁴ When a cytokine binds to an extracellular cytokine receptor, JAKs phosphorylate the receptor and create docking stations for the signal transducer and activator of transcription (STAT) signaling proteins. After docking, the STAT proteins are phosphorylated further and released into the cytoplasm to form a dimer. The STAT dimer enters the cell nucleus and binds DNA to initiate transcription of cytokine genes, many of which regulate immunity, inflammation, and hematopoiesis.^4-6 JAK inhibition blunts the intracellular signaling cascade and subsequent downstream gene transcription.

The JAK family is composed of 4 isoform members: JAK1, JAK2, JAK3, and TYK2. The JAK-STAT pathway is found in many cells, including those in cutaneous epithelium, nervous tissue, and the immune system, and the pathway has been implicated in numerous autoimmune and inflammatory disease processes, such as atopic dermatitis⁷ and rheumatoid arthritis in humans.⁸ The JAK-STAT pathway is essential for cytokine signaling in immunity, inflammation, and hematopoiesis. Cytokine receptors are associated with different combinations of JAK enzymes (e.g., JAK2/JAK2 versus JAK1/JAK3), and JAK-inhibitor drugs exhibit varying degrees of affinity for each isoform, which could lead to effects on multiple organ systems.^5,6,9

Understanding the affinity differences enables the clinician to recognize potential adverse effects and the value of monitoring (e.g., CBCs when there is potential for myelosuppression) (TABLE 1).⁷

Oclacitinib (Apoquel)

Oclacitinib (Apoquel, Zoetis) was the first JAK inhibitor to be FDA-approved for dogs, receiving approval in May 2013. Oclacitinib is a nonselective inhibitor of predominantly JAK1 and has a high oral bioavailability (89%) unaffected by food coadministration.¹⁰ The drug half-life of 4 to 6 hours lends itself to dosing by mouth every 12 or 24 hours.^11,12 The label dose indicates an induction period of dosing every 12 hours for 14 days, followed by every 24 hours as maintenance therapy.

Some dogs that received oclacitinib experienced increased pruritus when dosages were adjusted from every 12 to every 24 hours. A recent retrospective study of client-owned dogs found that prolonged extralabel twice-daily dosing resulted in acceptable efficacy for 72% of dogs in the study, and the study authors recommended routine laboratory testing for dogs receiving oclacitinib, considering the potential adverse effects.¹²

It is critically important to recognize the risks of extralabel dosing and the role of regularly scheduled physical examinations, CBCs, and chemistry profiles for dogs receiving  such regimens. When oclacitinib is adjusted from twice-daily to once-daily dosing, a short course of prednisolone effectively reduces the probability of rebound pruritus.¹³

A case report of 2 German shepherd dogs with perianal fistulae described successful treatment with oclacitinib at a higher dose than labeled.¹⁴ Given its immune-modulating properties, oclacitinib has been successfully used to treat several immune-mediated dermatopathies, such as chronic cutaneous lupus erythematosus variants, ear tip ulcerative dermatitis, ischemic dermatopathy, and pemphigus foliaceus.^15-18

Ilunocitinib (Zenrelia)

Ilunocitinib (Zenrelia, Elanco), a nonselective JAK inhibitor, was approved by the FDA in September 2024. Ilunocitinib has high affinity for JAK1, JAK2, and TYK2. A recent summary of ilunocitinib’s pharmacokinetic data revealed a half-life of approximately 5 hours with good oral bioavailability, and it maintained effective plasma concentrations over 24 hours, supporting once-daily dosing.¹⁹ Field studies also supported once-daily dosing of ilunocitinib based on drug efficacy.²⁰ A placebo-controlled, double-masked, randomized clinical trial assessing 268 dogs from 25 veterinary clinics found that 83% of the pruritic dogs that received ilunocitinib once daily achieved treatment success.²¹

Although ilunocitinib represents another pharmacologic option for targeting the pathogenesis of itch via the JAK pathway, there are important safety considerations with the immune response. A study initially designed to evaluate the effect of ilunocitinib on response to modified live and inactivated vaccines when administered to research dogs at 3 times the label dose changed course due to infectious disease outbreaks during the study period.²² Although the study itself was confounded by the outbreaks, 4 of the 6 treated dogs failed to mount an adequate immune response to rabies vaccine during the study period, which represents a public health risk that was communicated to veterinarians via an official Dear Veterinarian letter.²³ Accordingly, ilunocitinib carries a boxed warning on the product label stating “Discontinue Zenrelia for at least 28 days to 3 months prior to vaccination and withhold Zenrelia for at least 28 days after vaccination.”²⁰

Although both oclacitinib and ilunocitinib are viable options for treating canine atopic dermatitis, practitioners should recognize differences in the respective JAK affinities and overall adverse effect profiles of the 2 drugs (TABLE 2).^10,21,24

Literature Updates

The literature is burgeoning with updates related to JAK inhibitors and the roles they play in veterinary medicine. A recent review article examining the effect of oclacitinib on veterinary medicine over the past 10 years determined that based on the literature thus far, oclacitinib plays a key role in managing the acute and chronic states of canine atopic dermatitis without significantly increasing the incidence of malignancies.¹⁰ A new chewable formulation of oclacitinib was FDA-approved in June 2023 and offers efficacy similar to that of the original tablet formulation.²⁵ However, a veterinary medicine news alert from North Carolina State University detailed 2 cats experiencing acute kidney injury necessitating hemodialysis after ingesting unknown quantities of chewable oclacitinib tablets.²⁶ A retrospective study using the Pet Poison Helpline revealed that after the chewable tablet was introduced onto the market, the helpline noticed an uptick in overdose exposure reports for dogs and cats with multisystemic signs.²⁷

Since the ilunocitinib foray into the veterinary world in September 2024, it has offered another pharmacologic strategy for managing the pruritus associated with canine atopic dermatitis. Because it is still quite recent, the amount of literature is less than that for oclacitinib. However, 1 randomized, double-blinded study found ilunocitinib to be noninferior to oclacitinib for controlling pruritus in dogs with atopic dermatitis.²⁸

JAK Inhibitors in Cats

There is limited evidence supporting the use of oclacitinib in cats, and veterinarians must exercise caution when considering an extralabel prescription for a cat. One prospective, noncontrolled study found that oclacitinib was effective for controlling the clinical signs of feline atopic skin syndrome at an extralabel dose higher than the label dose for dogs.²⁹

Summary

JAK inhibitors represent a valuable tool in the veterinarian’s arsenal due to their profound effects on mitigating pruritus in dogs. There are 2 FDA-approved products available for veterinary use: oclacitinib (Apoquel) and ilunocitinib (Zenrelia). As the drugs remain on the market and the current understanding of their scope of effect expands, veterinarians must remain cognizant of the drug labels, pertinent adverse effects, and monitoring implications. Although JAK inhibitors offer pruritic relief for dogs, extralabel use reports might include extralabel doses, and clinicians should be prepared to adjust monitoring expectations (e.g., physical examinations, CBCs, chemistry panels) accordingly before formulating a therapeutic plan and monitoring strategies with the JAK inhibitors.