Can We Treat Cushings in Horses?

Hello Summarians!

I decided to change things up a bit. Today we have a theme issue. Specifically, a drug safety and efficacy issue. These are questions and the assumed answers that we often take for granted. It is great to see some follow-up research evaluating these parameters.

Enjoy! … and please pass along to a friend if you learned something new.

How Safe is Apoquel in Dogs

Allergic and atopic dermatitis affect up to 15% of dogs and represent some of the most frequently diagnosed conditions in canine practice. Pro-inflammatory cytokines, many of which signal through the JAK/STAT pathway, play central roles in the pathophysiology of these disorders. By binding to specific cell surface receptors, cytokines activate paired Janus kinase enzymes to regulate gene expression. Among the four JAK isoforms—JAK1, JAK2, JAK3, and TYK2—JAK1 is critically involved in transmitting signals for cytokines linked to allergy, inflammation, and pruritus, including interleukins 2, 4, 6, 13, and 31. Recognizing that inhibition of JAK1 could selectively interrupt these pathways while sparing other essential functions, researchers at Pfizer Animal Health pursued oclacitinib, a small molecule designed to preferentially block JAK1 activity. 

Oclacitinib’s development paralleled advances in human medicine, where JAK/STAT inhibitors were being explored for T cell–mediated diseases. In dogs, oclacitinib was engineered to disrupt pro-inflammatory and pruritogenic cytokine signaling without markedly affecting JAK2-dependent processes such as hematopoiesis. Pharmacokinetic studies demonstrated that twice-daily oral administration at 0.6 mg/kg achieved plasma concentrations above the half-maximal inhibitory threshold (IC₅₀) for JAK1-dependent cytokines yet remained below levels that would inhibit JAK2. After two weeks, transitioning to once-daily dosing maintained efficacy against JAK1 targets while minimizing interference with JAK2-mediated functions. These findings underpinned the approved regimen—0.4–0.6 mg/kg twice daily for 14 days, followed by 0.4–0.6 mg/kg once daily—which balances rapid relief of pruritus with a favorable safety margin. 

Early clinical trials confirmed both the efficacy and tolerability of oclacitinib. Dogs treated with oclacitinib experienced a significant reduction in itching within 24 hours of the first dose, and comparative studies showed similar effectiveness to cyclosporine and prednisolone, but with a potentially faster onset. In longer-term investigations, dogs maintained on oclacitinib for up to two years continued to benefit without accumulating new safety concerns. Laboratory evaluations corroborated that higher-than-recommended exposures could impair immune function, leading to secondary infections; however, such outcomes were rare when dosing guidelines were followed. Exploratory work, including a small study combining oclacitinib with topical therapies for otitis externa, found no unexpected adverse events, and observational data did not link oclacitinib use to increased urinary tract infections, a known risk with some immunosuppressive drugs. 

Since its approval by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2013, oclacitinib has become widely adopted in veterinary practice. Pharmacovigilance (PV) monitoring, covering more than 91 million treated dogs between 2013 and 2021, has captured roughly 21,800 adverse event reports, yielding an estimated reporting frequency of 0.025%. This rate classifies overall events as “rare” (fewer than one in 4,000 dogs), with each individual reaction falling into the “very rare” category (fewer than one in 10,000 dogs). The most commonly reported concerns—vomiting, diarrhea, lethargy, anorexia, and elevated liver enzymes—mirror those observed during controlled trials and are consistent with expectations for this patient population. Reports of skin disorders, seizures, polydipsia, and demodicosis also appeared but did not occur at rates suggesting new or unanticipated risks. Notably, while early reports alluded to cases of rapidly growing histiocytomas, subsequent cohort analyses found no statistically significant increase in neoplasia among oclacitinib-treated dogs compared to those receiving other systemic therapies. 

Throughout postapproval surveillance, the oclacitinib label has been updated only modestly. By December 2020, after seven years of PV data, no changes were made to the “Precautions” section, and new “Warnings” emphasized immune modulation, observed neoplastic conditions (benign and malignant), and the importance of weighing risks and benefits when treating dogs with histories of recurrent serious infections or neoplasia. A new “Post-Approval Experience” section lists adverse events reported since market release—terms drawn from the Veterinary Dictionary for Drug-Related Affairs (VeDDRA) system—while cautioning that not all events could be causally linked to the drug and that their frequencies may not be reliably estimated. In parallel, a chewable oclacitinib formulation was introduced in 2023, with pharmacokinetic bridging studies confirming bioequivalence; although long-term PV data for this formulation are not yet available, its active ingredient remains unchanged. 

More recently, in September 2024, the FDA approved ilunocitinib (Zenrelia), a nonselective JAK inhibitor for the same indications as oclacitinib. Zenrelia carries additional boxed warnings related to vaccine-induced disease risk and impaired vaccine response, underscoring oclacitinib’s more targeted mechanism as an important differentiator. 

After a decade of both investigational trials and real-world use, oclacitinib’s safety profile in dogs appears consistent and well-characterized. Controlled studies had already anticipated the majority of adverse events, and PV monitoring has not unveiled any unexpected demographic or pharmacologic susceptibilities. Long-term administration does not seem to carry cumulative risks beyond those identified early in its development, and its benefits in rapidly alleviating pruritus remain clear. Consequently, oclacitinib continues to offer a favorable risk–benefit balance for controlling allergic and atopic dermatitis in canine patients. 

Nederveld, S.M., Krautmann, M.J. and Mitchell, J. (2025), Safety of the Selective JAK1 Inhibitor Oclacitinib in Dogs. J Vet Pharmacol Therap, 48: 135-145. https://doi.org/10.1111/jvp.13503 

Bottom line — Pretty Safe.

Can We Really Treat PPID in Horses?

The United States Department of Agriculture has reported an increase in the number of equids aged 20–29 years from 7.6% to 11.4% of the total equine population between 2005 and 2015, reflecting an aging equine population. Similar trends were observed in the United Kingdom and Australia, with a significant portion of the equid population being 15 years or older. As equids age, there is a rise in medical diagnoses such as osteoarthritis, asthma, neoplasia, and endocrinopathies, with Pituitary Pars Intermedia Dysfunction (PPID) being the most common endocrinopathy in older equids. The prevalence of PPID in a population of 70,000 equids across UK veterinary practices was 2.9%, and clinical signs such as hair coat changes were reported in over 20% of equids aged 15 and above. However, despite these high prevalence rates, less than 5% of owners recognized PPID in their equids, and fewer than 70% of those affected were receiving treatment. 

The approval of Prascend® (pergolide mesylate) in 2011 provided a reliable treatment for PPID, which has been shown to improve both clinical signs and endocrine test results in affected horses and ponies. The study aimed to assess the long-term effects of Prascend on clinical responses, medical problems, and owner satisfaction. The results showed that long-term treatment of PPID with pergolide leads to clinical improvement in nearly all surviving equids, with over 60% showing normalization of endocrine test results. Owner satisfaction was high, with most owners reporting that treatment improved their equid's quality of life, although the study did not demonstrate a direct effect on prolonging lifespan due to the absence of a cohort of untreated PPID-affected equids for comparison. 

The study revealed that over 60% of equids continued to have normal results for up to 5–6 years without needing an increase in dosage, challenging previous assumptions that PPID treatment would require dose escalation over time. Medical problems associated with pergolide were similar to those observed in the initial clinical efficacy study, with a transient decrease in appetite being the most common side effect. Other issues, such as laminitis, muscle wasting, and abnormal shedding, were noted as signs of advancing age or PPID, though pergolide did not appear to directly address laminitis. Gastrointestinal issues like colic and diarrhea were also reported, but these were generally self-limiting and not attributed directly to the drug. 

The study's limitations included the reliance on the Oral Dexamethasone Suppression Test (ODST) as the primary diagnostic tool for PPID and potential biases in survey responses due to recall bias and the provision of free medication. Despite these limitations, the study found that pergolide treatment significantly improved the quality of life for PPID-affected equids, though it did not demonstrate that treatment extended lifespan. The findings provide valuable information for veterinarians advising equid owners on long-term PPID management, emphasizing the need for careful communication about treatment expectations. 

Schott, H.C., II, Strachota, J.R., Marteniuk, J.V. and Refsal, K.R. (2025), Long-Term Response of Equids With Pituitary Pars Intermedia Dysfunction to Treatment With Pergolide. J Vet Intern Med, 39: e70109. https://doi.org/10.1111/jvim.70109 

Bottom line — Significantly improved quality of life.

How Safe is Previcox in Horses

This study assessed the long-term effects of firocoxib, a selective COX-2 inhibitor, on biochemical and hematologic values in horses. While firocoxib is widely used in equine medicine for managing conditions like osteoarthritis, especially in older horses, its long-term effects beyond the labeled 14-day treatment period were previously unknown. 

The study compared horses receiving long-term firocoxib with those not on the drug. The firocoxib group was older, with a higher prevalence of Arabian horses, reflecting the common use of the drug in older, chronically lame horses. The results showed minimal changes in laboratory values for the firocoxib group. A small increase in plasma sodium and total protein concentrations was observed, but these changes were clinically insignificant. There was also a slight decrease in total white cell count, which, while minimal, could be linked to potential gastrointestinal effects like subclinical colitis, commonly associated with NSAID use. 

Interestingly, there was no significant difference in serum creatinine or blood urea nitrogen (BUN) levels between the two groups, suggesting that long-term firocoxib use did not lead to kidney issues as seen with some other NSAIDs in different species. However, the study acknowledged several limitations, including the retrospective design, the potential for biased data due to incomplete records, and the age difference between the groups, which could have influenced the findings. Despite these limitations, the results indicate that long-term firocoxib administration in horses is not associated with clinically significant changes in biochemical and hematologic variables. 

This study’s findings provide some reassurance regarding the safety of long-term firocoxib use in horses, though further prospective studies are needed to confirm these results and better understand the drug's long-term impact. 

Buzelato Carli, I. and Fielding, L. (2025), Long-Term Firocoxib Use in Horses. J Vet Intern Med, 39: e70117. https://doi.org/10.1111/jvim.70117 

Bottom line — Seems to be safe long term.

Just putting things in perspective …