Introduction
Oclacitinib was approved in the United States in 2013 for the control of pruritus associated with allergic dermatitis and control of atopic dermatitis (AD) in dogs at least 12 months of age. Oclacitinib represented the first Janus kinase (JAK) inhibitor approved for use in dogs and is still the only one approved in veterinary medicine. JAK inhibitors are approved in human medicine to treat myelofibrosis, rheumatoid arthritis, and psoriatic arthritis in humans, as well as AD. A list of approved JAK inhibitors and examples of diseases for which they are used is provided (Table 1). Interestingly, a JAK inhibitor, baricitinib, approved for rheumatoid arthritis has received emergency use authorization for severe COVID-19 in children to decrease inflammation. Oclacitinib has become an important tool for veterinarians to manage allergies and provide relief to affected patients by targeting signaling of cytokines important for allergies.1 Although oclacitinib is not labeled for other species or to treat diseases other than allergies, veterinarians have used it empirically to treat other conditions.
Summary of approved Janus kinase (JAK) inhibitors.
| Jakinib | Selectivity | Species | Approved indications |
|---|---|---|---|
| Oclacitinib | JAK1 | Dog | Pruritus, atopic dermatitis |
| Ruxolitinib | JAK1, JAK2, JAK2V617F | Human | Myelofibrosis, polycythemia vera |
| Tofacitinib | JAK1, JAK2, JAK3 | Human | Rheumatoid arthritis, PsA, UC, polyarticular course JIA |
| Baricitinib | JAK1, JAK2 | Human | Rheumatoid arthritis, COVID-19 (emergency use authorization) |
| Upadacitinib | JAK 1 | Human | Rheumatoid arthritis, PsA, atopic dermatitis, UC |
| Fedratinib | JAK2, JAK2V617F | Human | Myelofibrosis |
| Abrocitinib | JAK 1 | Human | Atopic dermatitis |
| Delgocitinib | Pan JAK | Human | Atopic dermatitis |
| Figlotinib | JAK 1 | Human | Rheumatoid arthritis |
| Pacritinib | JAK2, JAK2V617F | Human | Myelofibrosis |
| Peficitinib | Pan JAK | Human | Rheumatoid arthritis |
JIA = Juvenile idiopathic arthritis. PsA = Psoriatic arthritis. UC = Ulcerative colitis.
JAK2V617F is an acquired, somatic mutation present in the majority of patients with myeloproliferative cancer.
For the purpose of this review, published literature was searched from May 2013 until December 2022. The keyword oclacitinib was used and 86 published articles were found. In addition to published research articles and case reports and proceedings from meetings were added.
Mechanism of Action and Pharmacokinetics in Dogs
Oclacitinib is a selective JAK1 inhibitor targeting the signaling of cytokines involved in pruritus and inflammation like IL-2, IL-4, IL-6, IL-13, and IL-31.1 In isolated enzyme test systems, oclacitinib inhibited JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) by 50% at concentrations (IC50) of 10, 18, 99, and 84 nm, respectively. Oclacitinib was most potent against the JAK1 enzyme, showing a 1.8-fold selectivity for JAK1 versus JAK2 and 9.9-fold selectivity toward JAK1 versus JAK3. In cell-based in vitro studies, oclacitinib did not have major effects on granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), IL-12, or IL-23 at the tested concentrations.1 In canine AD, cytokines produced by activated T-helper type (Th) 1, Th2, Th17, and Th22 cells as well as innate immune cells and keratinocytes after allergen exposure (Figure 1) are important.
Atopic dermatitis results from a combination of skin barrier damage and a skewed immune response to epicutaneously presented allergens. The inflammatory response is dynamic. Keratinocytes shape the immune response through the secretion of cytokines and contribute to the recruitment of lymphocytes by releasing chemokines. The initial Th2 response is important for the IgE production and supports a mastocytic and eosinophilic inflammation while later on other lymphocytic populations (Th1, Th17, and Th22) play a role. TARC = Thymus and activation-regulated chemokine. TSLP = Thymic stromal lymphopoietin.
Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0570
Pharmacokinetics of oclacitinib maleate showed rapid absorption in dogs and high absolute oral bioavailability ranging from 79% to 89%, which is not affected by food administration.2 The time to maximum concentration (tmax) is less than 1 hour, and the half-life ranges from 4.0 to 5.9 hours. These are properties that support a twice-daily or once-daily dosing regimen in dogs.2 Twice a day dosing (up to 2 weeks) provides plasma exposures that inhibit JAK1-dependent cytokines relevant in the disease process throughout the dosing interval.
A twice-daily regimen significantly improves pruritus and dermatitis and can be transitioned to a once-daily dosing for long-term management of clinical signs.3 Once-daily dosing generates plasma concentrations that are above the amount required to inhibit JAK1-dependent cytokines by 50% (IC50), effectively inhibiting proinflammatory JAK1-dependent cytokines (e.g. IL-2, IL-4, IL-6, IL-13, and IL-31) while not inhibiting non-JAK1–dependent cytokines such as GM-CSF and EPO (Figure 2, published in Clinician’s Forum in 2022). This selectivity provides a margin of safety between the inhibition of proinflammatory cytokines involved in the disease process versus those involved in normal functions such as hematopoiesis. The immunomodulatory effects of oclacitinib that allow for select functions of the immune system to be inhibited without broad suppression are likely due to both the selectivity of oclacitinib for JAK1-dependent cytokines and the chosen dosing regimen. Specifically, the once-daily dosing allows for temporary inhibition of JAK1-dependent cytokines and select functions of T cells for only part of the day.
Relationship between drug exposure and inhibition of cytokine function. The blue line shows the concentration of oclacitinib needed to inhibit the listed Janus kinase 1 (JAK1)–dependent cytokines. The potency of oclacitinib toward cytokines can be illustrated by generating dose-response curves that show the inhibitory effects of increasing concentrations of oclacitinib on cytokine function. Half maximal inhibitory concentration (IC50) can be determined from these curves, indicating the concentration of oclacitinib that inhibits the function of that cytokine by 50%. (Adapted from Incorporating Apoquel® chewable tablets into practice. In: Clinician’s Forum, a Clinician’s Brief supplement; 2022. Sponsored by an educational grant from Zoetis. Reprinted with permission from Embark Veterinary, Inc.)
Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0570
Effects of Oclacitinib on the Immune System
Several in vitro studies evaluated the effects of oclacitinib on various immune cell populations. To understand the clinical relevance of these studies it is important to note that maximum blood concentrations of oclacitinib after administration at labeled doses are around 1 μM, which equates to 337 ng/ml of oclacitinib). One study1 showed that oclacitinib inhibited IL-2-dependent proliferation of blood cells in a dose-dependent manner (IC50 = 63 to 189 nM), and a second study4 demonstrated oclacitinib did not inhibit concanavalin A–stimulated T-cell proliferation of canine lymphocytes. A third study5 showed that oclacitinib (0.1 to 1µM) caused a dramatic decrease in CD4+ and CD8+ T-cells in both T-regulatory and T-effector subsets. Using murine immune cells, the same investigators6 found a strong cytoreductive and proapoptotic effect with oclacitinib (0.1 to 1 µM) and reported a loss of both CD4+ and CD8+ T cells after exposure to oclacitinib. Oclacitinib did not affect the proliferation of CD4+ T cells or the number of interferon-γ (IFN-γ)- and IL-17-producing CD4+ and CD8+ T cells, suggesting oclacitinib has selective immunomodulatory effects focused on Th2 cells and not on Th1-mediated immunity.6
Oclacitinib in vitro suppresses cytokine production of IL-2, IL-15, proinflammatory cytokines (IFN-γ and IL-18), and the regulatory cytokine IL-10.4 However, these effects are seen only when high concentrations of oclacitinib were used (10 μM), which are over 10 times the concentration achieved using the labeled dose. Concentrations consistent with the labeled dose (1 μM) have no effect on cytokine production (IL-2, IL-10, IL-15, IL-18, IFN-γ, and tumor necrosis factor-α). However, in a study7 using peripheral mononuclear cells (PBMCs) isolated from allergic dogs and stimulated with house dust mite allergen, oclacitinib could inhibit the secretion of IL-31 (IC50 = 40 nM) from PBMCs.
A recently published study8 focused on T-regulatory cell numbers and serum IL-10 and transforming growth factor-β1 (TGF-β1) levels in atopic dogs treated with either cyclosporine or oclacitinib for 9 or more months and showed that, while cyclosporine significantly lowered the percentage of T regulatory lymphocytes compared to healthy dogs, no differences existed between oclacitinib and the healthy dog group. No significant differences were detected in IL-10 and TGF-β1 serum concentrations between healthy dogs and atopic dogs that were treated with oclacitinib or cyclosporine.
Collectively, these studies show that oclacitinib has selective immunomodulatory effects on immune cells and can reduce the production of the Th2 cytokine IL-31. Immunosuppressive effects occur at much higher concentrations (10 μM) that are not achieved when oclacitinib is prescribed at the doses used to treat dogs with AD.
Evidence of Clinical Efficacy for Canine Allergic Skin Disease and Comparison of Efficacy With Other Treatment Options
Oclacitinib is listed as an effective treatment for canine AD in the current published guidelines, both to control acute flares and for chronic management.9 The safety and efficacy of oclacitinib were investigated first, and then the efficacy was compared to other approved treatments for canine AD (Table 2).
Summary of studies evaluating oclacitinib for canine allergic skin disease
| Authors | Study type | Disease | Aim | Dose | n | Length study | Efficacy | Adverse effects |
|---|---|---|---|---|---|---|---|---|
| Cosgrove et al3 | Prospective placebo controlled | atopic dermatitis | Efficacy on pruritus and dermatitis and safety | Label dose | 299 | 112 d | At day 28, 66% of oclacitinib-treated dogs were considered a treatment success for reduction of pruritus compared with 4.0% of the placebo-treated dogs (P < .0001). | Most common adverse effects in both groups were gastrointestinal in the oclacitinib group, diarrhea (7/152) and vomiting (6/152) and in the placebo group, diarrhea (5/147) and vomiting 6/147). |
| At day 28, 49% of oclacitinib-treated dogs were considered a treatment success compared with 4.0% of the placebo-treated dogs (P < .0001) also for severity of dermatitis. | ||||||||
| Cosgrove et al3 | Prospective placebo controlled | Allergic skin disease | Efficacy pruritus and dermatitis and safety | Label dose | 436 | 28 d | Mean oclacitinib owner pruritus scores were significantly better than placebo scores (P < .0001) on each assessment day. The day 7 mean oclacitinib veterinarian dermatitis scores were also significantly better (P < .0001) than placebo scores. | Diarrhea and vomiting were reported with similar frequency in both groups. |
| Cosgrove et al10 | Retrospective open label | Allergic skin disease | Efficacy and effects on quality of life | Label dose | 247 | 401 d (mean) | > 50% reduction of pruritus in 63.9% of dogs, positive impact on quality of life in > 91%. | Urinary tract infection, cystitis, vomiting, otitis, pyoderma, and diarrhea |
| Little et al11 | Prospective randomized, controlled with cyclosporine | atopic dermatitis | Comparison of efficacy with cyclosporine | Label dose | 226 | 84 d | Faster onset of action of oclacitinib compared to cyclosporine in first 28 d and significant differences between treatments in the first month in favor of oclacitinib. On day 56, ciclosporin-treated dogs showed a similar decrease in pruritus to oclacitinib-treated dogs. | Three times as many adverse events attributed to gastrointestinal signs were reported in the ciclosporin group compared with the oclacitinib group. |
| Gadeyne et al12 | Prospective, randomized, controlled with prednisolone | Allergic skin disease | Comparison of efficacy with prednisolone | Label dose | 123 | 28 d | Both treatments produced rapid onset within 4 h. Mean reductions in pruritus and dermatitis scores were not significantly different between treatments except on day 14 (reductions were more pronounced for oclacitinib than prednisolone, P = .0193 for owner pruritus scores; P = .0252 for veterinarian dermatitis scores). | Similar frequency of adverse effects (eg, pyoderma, n = 6 in both groups) |
| Denti et al13 | Retrospective uncontrolled | atopic dermatitis | Efficacy and safety long term | Long-term twice-daily dose | 53 | Median 113 d | Excellent-to-good efficacy was observed in 38 dogs (72%). | Pyoderma (n = 14), gastrointestinal signs (n = 13), and otitis (n = 10) were most commonly reported. |
A prospective, randomized, placebo-controlled study14 enrolled 299 privately owned atopic dogs to receive either placebo or oclacitinib for 112 days. On days 14 and 28, clinicians reported a decrease in the extent and severity of dermatitis scores (canine atopic dermatitis extent and severity index [CADESI]) of 48.4% in the oclacitinib group compared with a 1.7% reduction and a 3.6% increase in placebo-treated dogs. After day 28, most of the placebo dogs (> 86%) had moved to an open-label study to receive oclacitinib. Differences in client-assessed pruritus (pruritus visual analog scale [PVAS]) and clinician-assessed CADESI were significant at all time points (P < .0001). The authors concluded that treatment was effective and rapid.
In a larger study,3 436 dogs diagnosed with allergic dermatitis with moderate to severe pruritus were randomized to either oclacitinib or placebo for 28 days. Oclacitinib (0.4 to 0.6 mg/kg twice daily) produced a rapid onset of efficacy within 24 hours. Owner-assessed PVAS scores were significantly better than placebo scores (P < .0001) on each assessment day. By day 7, 70.5% of oclacitinib-treated dogs compared to 23.2% of placebo achieved ≥ 50% reduction from baseline in pruritus, dermatitis, and PVAS scores. The conclusions were that oclacitinib was fast and effective.
Other medications used for the management of AD and pruritus in dogs include glucocorticoids, modified cyclosporine, lokivetmab, antihistamines, and essential fatty acids.9 In allergic patients, glucocorticoids are typically used for acute incidences of pruritus or otitis. The efficacy of oclacitinib was compared to prednisolone in a prospective randomized controlled study.12 Prednisolone was prescribed at 0.5 to 1.0 mg/kg once daily for 6 days and then every other day for 28 days, and oclacitinib was prescribed at 0.4 to 0.6 mg/kg orally twice daily for 14 days and then once daily for 28 days. There was a rapid onset of reduced dermatitis and pruritus within 4 hours for both treatments. Mean reductions in pruritus and dermatitis scores were not significantly different between treatments except on day 14, when reductions were more pronounced for oclacitinib than prednisolone.
The speed of action of oclacitinib was compared to that of glucocorticoids in a study15 using a model of itch in which research dogs were injected with IL-31 and then randomly allocated to receive either placebo, oclacitinib, oral prednisone, or intramuscular dexamethasone. Video surveillance was used to monitor and score pruritic behaviors in study animals. The results showed that prednisolone decreased pruritus when given 10 hours prior to observation, but when the treatment administration and observation were shortened to 1 hour, oclacitinib and dexamethasone were effective and prednisolone was not. Oclacitinib was effective within an hour, and the mean reduction of pruritus was greater than dexamethasone.15
Modified (microemulsion formulation) cyclosporine and topical tacrolimus (0.1% ointment) are calcineurin inhibitors used in the treatment of allergic and immune-mediated skin diseases. Generic cyclosporine with the wording “modified” is the equivalent of Atopica (dog product) and Neoral (human product). This formulation has better and more consistent absorption compared to the nonmodified formulation. Cyclosporine may take 2 to 4 weeks to relieve the symptoms of an allergic patient. The efficacy of oclacitinib was compared to oral-modified cyclosporine in a randomized controlled study11 that enrolled 226 dogs diagnosed with AD. Differences in efficacy were significant between groups in the first 28 days with oclacitinib group having less severe dermatitis and pruritus. These differences were no longer significant on day 56. Three times as many adverse events attributed to gastrointestinal signs were reported in the cyclosporine group compared to the oclacitinib group. The authors concluded that oclacitinib had faster efficacy and fewer adverse effects.
Lokivetmab (Cytopoint) is a caninized monoclonal anti-IL-31 antibody that is labeled for use in AD and allergic dermatitis in dogs and is administered via a subcutaneous injection every 4 weeks. Lokivetmab is indicated for use in dogs with pruritus and is effective in 73% to 88% of dogs.16,17 Rarely, some dogs may produce antibodies against the product resulting in treatment-induced immunogenicity.
One study18 compared the efficacy of oclacitinib, prednisone, cyclosporine, and lokivetmab in a colony of atopic beagles challenged with allergen for a month while controlling environmental conditions and diet. In this study, in the first 2 weeks, the severity of dermatitis in the prednisone- and oclacitinib-treated dogs were significantly lower than the controls. At the end of 1 month of allergen exposure, the oclacitinib- and lokivetmab-treated dogs had less erythema than the other groups. Interestingly also, oclacitinib- and lokivetmab-treated dogs had higher cutaneous hydration than the controls suggesting that possibly these treatments may have a positive effect on skin barrier parameters.
Additional Outcomes Monitored
Quality of life
In an open retrospective study,10 oclacitinib significantly improved the quality of life for the majority of treated dogs. Client’s quality of life also improved as the dog needed fewer trips to the veterinarian, the clients’ sleep was less disrupted, and their dog’s overall behavior improved.10
Adverse events
For managing pruritus, oclacitinib has less frequent side effects as compared with glucocorticoids and cyclosporine. Vomiting and diarrhea have been reported in the initial studies.3,9,10 Weight gain has been reported more often than weight loss in dogs on the medication (114 dogs gained 3.4% of body weight and anorexia in 0.9% of dogs).10
Demodicosis, pyoderma, and otitis were also reported in dogs receiving oclacitinib. A small study19 evaluated the management of otitis using twice-daily oclacitinib in 10 dogs with concurrent twice-daily topical application of enrofloxacin and Silvadene (Baytril Otic) for 14 days and reported a mean clinical score reduction of 81.7%. Histiocytomas, papillomas, and other cutaneous tumors have been reported in dogs receiving oclacitinib20 but do not appear to have increased incidence compared to dogs not receiving oclacitinib (16.5% on oclacitinib vs 12.8% not on oclacitinib).21
Evaluations of complete blood counts and serum biochemistries for patients on long-term oclacitinib reported mild leukopenia (most commonly neutropenia and rarely lymphopenia).3,8 Rare reports10 of changes in the serum biochemistry and urinalysis have been reported but do not often warrant cessation of therapy. In initial studies,10 symptoms of urinary tract infections were seen in 0.5% to 11.3% of dogs that were on chronic oclacitinib; however, quantitative bacterial cultures were not performed. A subsequent prospective study22 evaluated found no evidence of bacterial urinary tract infections in dogs on oclacitinib for up to 280 days. It is important to note that oclacitinib is not labeled for use in dogs < 12 months of age due to higher risk of pneumonia or demodicosis (Zoetis 2018).23 One of the authors (RM) has seen dogs develop hypothyroidism while on oclacitinib, but no study has specifically addressed the effect of oclacitinib on thyroid function.
Need for antibacterial therapy
In a retrospective study,24 the effect of oclacitinib on decreasing the need for antimicrobial therapy was examined and compared to other antipruritic therapies. The authors found that the odds of systemic antibacterial usage were significantly lower and odds of experiencing improvements in allergic dermatitis significantly higher for the oclacitinib group compared to other anti-pruritic therapies (eg, glucocorticoids, cyclosporine, and antihistamines). It is important to note that due to the retrospective nature of this study and the fact that limited information was provided regarding doses of the various treatments, it is possible that biases were introduced in the analysis of these patients. Regardless of the medication used, it is important to emphasize the need for a proactive approach in allergic patients as a way to minimize flares and ultimately minimize the development of infections. Atopic patients have low-grade inflammation also while they are not clinically manifesting disease, thus some form of long-term sustainable control of the disease is very beneficial in minimizing flares and pyoderma.
Effect on epicutaneous sensitization
As atopic dogs are known to develop new sensitizations over time, the question of whether the administration of oclacitinib would influence sensitization to a novel allergen was addressed using a colony of atopic beagles.25 Dogs were exposed to a novel allergen (Bermuda grass) while receiving oclacitinib and the time to develop sensitization was significantly delayed compared to the control group. Whether this effect can be a significant benefit when applied to a proactive approach to AD will need to be evaluated longitudinally in dogs with natural disease.
Long-Term Safety at Twice-Daily Administration
The licensed dose of oclacitinib is 0.4 to 0.6 mg/kg twice daily for up to 2 weeks and then once daily. In some patients, the once-daily administration may not be sufficient to control clinical signs; thus, owners keep their animals on twice-daily administration for extended periods of time. One recently published study13 addressed the safety of a prolonged twice-daily administration regimen. In this retrospective study, 53 client-owned dogs with AD had received twice-daily administration of oclacitinib (0.5-mg/kg dose, median treatment duration was 113 days). Oclacitinib was generally well tolerated and effective in most of the treated dogs (excellent to good response in 72% of dogs). Pyoderma, gastrointestinal signs, and otitis externa were the most frequent adverse events reported. In this study, blood work was done in 35/53 dogs. Statistically significant decreases in mean leukocyte counts were noted with treatment, although counts were within the reference range for most individuals. Three dogs developed increased cholesterol and developed demodicosis. The authors of that study concluded that twice-daily long-term administration is well tolerated and effective in most dogs, but regular clinical evaluation and blood work are advisable.
Oclacitinib and Neoplasia Concerns
Since the release of oclacitinib, there have been concerns regarding the incidence of malignancies in dogs receiving this drug. Some of the apprehension regarding oclacitinib and neoplasia has originated from reviewing the comparative use of JAK inhibitors in human medicine. When doing so, it is important to consider which JAK inhibitors oclacitinib is compared to, as the affinity of the various JAK pathways is different and what condition they are used to treat. Tofacitinib is an oral JAK1/JAK3 inhibitor with reduced JAK2 activity and has been used for the treatment of rheumatoid arthritis (RA), inflammatory bowel disease, transplant rejection, and psoriasis in humans.26 In humans with RA and other autoimmune diseases, independent of the type of treatment, there is an increased risk of certain malignancies.27 Another oral JAK1/JAK2 inhibitor, ruxolitinib, has been linked to increased incidence (17.1%) of basal cell carcinoma and squamous cell carcinoma compared to patients’ other therapies (2.7%).28
The other area of attention regarding association of oclacitinib and neoplasia has come from some of the early field studies and published reports3,14,29 regarding neoplasia in treated dogs. Two dogs in the oclacitinib-treated group were withdrawn from the study14 due to suspected or confirmed malignant neoplasia and subsequently euthanized, including 1 dog that developed signs associated with a heart base mass after 21 days and 1 dog that developed a grade III mast cell tumor after 60 days of oclacitinib. One dog in the placebo group also developed a grade I mast cell tumor and was removed from the study. After completing the field studies, 239 dogs were enrolled in an unmasked (no placebo control), continuation therapy study receiving oclacitinib for a mean time of 372 days (range, 1 to 610 days). Of these 239 dogs, 6 dogs were euthanized because of suspected malignant neoplasms. The association between oclacitinib and tumor formation in these cases is not known. It is also important to point out that association is different from causation.
A study21 looked at a comparison of malignancies and nonmalignant skin masses in 339 allergic dogs receiving long-term (> 6 months) oclacitinib with age- and breed-matched control populations on other forms of allergy therapy. The incidence of malignancies in the oclacitinib group (16.5%) versus controls (12.8%) was not statistically different (P = .1742). The incidence of skin masses in the oclacitinib group (56.6%) versus controls (58.3%) was not statistically different (P = .6743). The age of death/euthanasia in the oclacitinib group (11.2 years; n = 80) versus controls (11.8 years; 72) was not statistically different (P = .2077). There was no statistical significance regarding the dose of oclacitinib on the cumulative incidence of malignancy or masses.21 These results are to some extent reassuring, but it is important to point out the limitation of a retrospective study and that euthanasia is typically done at primary care rather than a specialty practice.
In another published long-term safety study,10 the most diagnosed common malignancy in 247 client-owned dogs was mast cell tumors (MCT). Mast cell tumors are a common skin cancer in dogs in general and were the most common tumor also found in the study21 listed above that compared an oclacitinib and a control group of dogs treated with other therapies for AD. Mast cell tumors were also found to be the most frequent malignancy in the control group, with no significant difference in incidence or risk ratio between the groups.21 Breed predisposition is very important in neoplasia development, particularly in MCT,30 and in both of these studies,10,21 several breeds were overrepresented including Labrador Retrievers, Golden Retrievers, Staffordshire Terriers, and Boston Terriers, which all have been reported to have an increased incidence of MCT.
In a more recent publication,31 oclacitinib was evaluated for its effect on cytokines that support mast cell tumor growth, specifically, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in 3 MCT cell lines (CoMS, CM-MC1, and VI-MC1). It was found that oclacitinib significantly decreased the release of IL-8 in the CoMS cell line and MCP-1 in the CoMS and VI-MC1 cell lines in clinically relevant concentrations and significantly decreased the proliferation of all 3 cell lines.31 These findings do not advocate using oclacitinib to treat mast cell tumors and further research is needed.
The incidence of lymphoma in dogs on oclacitinib has also received attention, especially in genetically predisposed breeds. In the Lancellotti study21 comparing oclacitinib to other allergy therapies, the cumulative incidence of noncutaneous lymphoma did not meaningfully differ between the exposed group and the nonexposed group, and interestingly, no Labrador Retrievers or Golden Retrievers in either group had lymphoma. A previous study32 suggested a relationship between canine AD and cutaneous lymphoma; however, there were only 2 cases observed in the Lancellotti study21 for the entire 660 allergic dogs.
In the previous long-term compassionate use oclacitinib study,10 the average time to detection of tumors was 7.9 months (range, 0.6 to 21.5 months), whereas the average time to detection of malignancy in the Lancellotti study21 was 24 months (range, 6.0 to 53.0 months). There is a report33 of a higher incidence of histiocytomas in patients receiving oclacitinib compared to patients receiving cyclosporine; however, the dogs receiving oclacitinib were significantly older (mean = 7.0 years) than dogs receiving cyclosporine (mean = 1.5 years). Furthermore, there was a significant difference in the duration of treatment between dogs with histiocytomas receiving oclacitinib (mean = 14.8 weeks) versus cyclosporin (mean = 4.8 weeks). In another study,14 the incidence of histiocytoma development in 283 dogs receiving oclacitinib was 3.9%. In the Lancellotti study,21 there were 19 histiocytomas identified in the oclacitinib group (5.6%) and 14 histiocytomas in the control group (4.4%), which was not statistically significant.
From the current data available, the incidence of malignancies and age of death in patients receiving oclacitinib long-term is not statistically different from patients receiving other long-term treatments for AD. Veterinarians should still continue to follow precaution and monitor patients for the development of neoplasia as each patient’s immune system is different. One of the authors (RM) has seen several young dogs receiving oclacitinib develop numerous fast-growing histiocytomas, some of which were behaving very aggressively. Whether this was caused by oclacitinib or would have occurred regardless of circumstances is unknown.
Oclacitinib Use for Allergic Skin Disease in Other Species
Use in feline atopic skin syndrome
Oclacitinib is not labeled for use in cats. At present, there are 4 peer-reviewed reports34–37 of oclacitinib safety and/or efficacy for feline atopic skin syndrome (Table 3). Adverse events reported included anemia, vomiting, and an increase in ALT, creatinine, BUN, and soft stool in Giardia-positive individuals. The pharmacokinetics of orally administered oclacitinib in cats is described in 6 cats,38 and plasma levels of 28 cats have been reported.37 Compared to dogs, oclacitinib was absorbed and eliminated more rapidly with greater individual variability in plasma levels39,40 and appears to have a greater dose and/or frequency requirement. Improvements in dermatitis and pruritus are not correlated to plasma levels.37
Summary of studies published that evaluated oclacitinib in cats.
| Authors | Study type | Diagnosis | Oclacitinib dose, duration | n | Efficacy | Adverse events |
|---|---|---|---|---|---|---|
| Noli et al34 | Double-blinded, randomized, methylprednisolone-controlled | Feline atopic skin syndrome | 0.7–1.2 mg/kg, PO, q 12 h for 28 days | 20 | ≥ 50% reduction in owner-assessed VAS in 12/20 | Increase in ALT, creatinine, and BUN (n = 4) |
| ≥ 50% reduction in owner-assessed VAS in 14/20 | ||||||
| Lopes et al35 | Blinded, randomized, placebo-controlled | Healthy, nonallergic cats | Group 1: 1 mg/kg, PO, q 12 h for 28 days; n = 10 | 20 | Not evaluated: safety study of healthy cats | Group 2: vomiting n = 2; soft stool n = 2 (Giardia positive) |
| Group 2: 2 mg/kg, PO, q 12 h for 28 days; n = 10 | Group 1: transient lymph node enlargement n = 1 | |||||
| Group 2: transient lymph node enlargement n = 1 | ||||||
| Group 1: increased renal ultrasound echogenicity n = 1 | ||||||
| Ortalda et al36 | Open, multicenter | Feline atopic skin syndrome | 0.4–0.6 mg/kg, PO, q 12 h for 14 days and then q 24 h for 14 days | 12 | ≥ 50% reduction in SCORFAD in 5/12 | None reported |
| ≥ 50% reduction in owner-assessed VAS in 3/12 | ||||||
| Owner assessed efficacy good/excellent in 4/12 | ||||||
| Carrasco et al37 | Prospective, multicenter, noncontrolled | Feline atopic skin syndrome | 1 mg/kg, PO, q 12 h for 14 days and then 1 mg/kg, PO, q 24 h for 14 days | 28 | ≥ 50% reduction in SCORFAD in 16/18 | Vomiting: n = 2 |
| ≥ 50% reduction in SCORFAD in 16/18 | Reduced hematocrit, n = 1 | |||||
| ≥ 50% reduction in owner-assessed VAS in 11/18 | Transient reduction in leukocyte count, n = 1 | |||||
| Ferrer et al38 | Prospective, 2-treatment, 2-period design with washout | Healthy, nonallergic research cats | 0.5 mg/kg, IV, single dose, followed by 1 week washout and then 1 mg/kg, PO, single dose | 6 | Not evaluated: pharmacokinetic study of healthy cats | None reported |
SCORFAD = SCORing Feline Allergic Dermatitis. VAS = Visual analog scale.
Doses ranged from 0.25 mg/kg, PO, every 24 hours to 2 mg/kg, PO, every 12 hours (Table 3). The safety of oclacitinib was investigated in a prospective, placebo-controlled study.37 In this study, 20 cats receiving oclacitinib at 1 or 2 mg/kg, PO, every 24 hours for 28 days demonstrated no significant differences in mean complete blood count, nor urinalysis parameters compared to the placebo group at 7, 14, and 28 days of treatment. Mean serum chemistry values were not significantly different than placebo on these treatment days, except fructosamine elevation to high normal in treatment groups on day 7.
Fatal toxoplasmosis has been reported in a feline immunodeficiency virus-positive cat receiving oclacitinib.41 Toxoplasmosis has been reported also in cats receiving cyclosporine.39,42–44 For the efficacy and doses of oclacitinib used in feline studies, see Table 3.
Given safety and efficacy data are limited to fewer than 100 cats and 28 days of dosing, it is prudent to limit oclacitinib to cats failing approved or conventional therapies for feline atopic skin syndrome or those receiving medications that contraindicate their use. Chronic oclacitinib monotherapy has been anecdotally reported as safe within the aforementioned dosing ranges, without significant serologic, hematologic, or urinary abnormalities. Given that long-term safety data are not presently available, it is prudent to perform serologic and hematologic evaluation, urinalysis, and physical examination prior to therapy and routinely.
Use in equine allergic skin diseases
Anecdotally, oclacitinib maleate has been used off-label by equine veterinarians and several specialists to relieve pruritus in horses for both insect bite hypersensitivity (IBH) and AD. Pharmacokinetics of oclacitinib in horses following a single intravenous (n = 4; 0.25 mg/kg, IV) and oral dose (6; 0.2 mg/kg) showed that the half-life (t1/2) was similar for both routes (9 to 10 hours) and longer than dogs suggesting that once a day dosing should maintain plasma concentrations.40 Oclacitinib was evaluated in 6 horses at a dose comparable to the approved dosage in dogs as a single dose (0.5 mg/kg). The estimated t1/2 was 7.5 to 8 hours further supporting a longer half-life than what is reported in dogs supporting the once a day dosing.45
The efficacy and safety of 2 oral doses (0.1 and 0.25 mg/kg, q 24 h, was evaluated compared to a placebo control group. Fifty-eight horses were randomized into the treatment groups (placebo, n = 19; 0.1 mg/kg, 19; and 0.25 mg/kg, 21) Horses were evaluated based on PVAS and clinical lesional scoring and all had clinical signs consistent with allergic dermatitis. No significant difference (P ≤ .0938) was found for 0.25-mg/kg dosing compared to placebo at all time points. Lesional scoring was also not significantly different (P ≤ .136). Adverse events and clinical pathology revealed no effects that appeared clinically significant or biologically important.46 Although many practitioners and specialists have used oclacitinib off label at 0.25 mg/kg, every 24 hours, further controlled clinical studies are needed to fully evaluate the efficacy and safety of oclacitinib in horses with atopic dermatitis or other allergic condition.
Use for Nonallergic/Atopic Disease
Autoimmune/immune-mediated diseases
Oclacitinib’s immune modulatory effects on numerous cytokines have prompted investigation of its use in nonallergic, cytokine-mediated inflammatory, and autoimmune- or immune-mediated diseases in dogs either as monotherapy or an adjunctive treatment. Oclacitinib was used at 0.4 to 0.7 mg/kg twice daily, along with a tapering regimen of oral prednisolone to manage ischemic dermatopathy in 4 dogs.47 Other case reports48,49 for use in ischemic dermatopathy showed a positive response when oclacitinib was used at 0.6 mg/kg twice daily for 60 days and then once daily.
Oclacitinib was used as monotherapy for the control of a presumed autoimmune subepidermal blistering dermatosis,50 and complete resolution was obtained at 0.5 mg/kg twice daily after 2 weeks. Relapse was observed when the regimen was reduced to once daily. Oclacitinib was also useful in a case of drug-induced-pemphigus vulgaris at 0.5 mg/kg twice daily.51
In a retrospective study,52 cases diagnosed with ulcerative ear tip dermatosis nonresponsive to conventional therapy responded to oclacitinib at 0.4 to 0.6 mg/kg within 1 to 3 months (22/25 dogs). Several of the dogs required prolonged use of twice-daily dosing.
Oclacitinib was used to treat hyperkeratotic erythema multiforme in 2 cases with rapid improvement when used at 0.6 to 0.9 mg/kg twice daily.53 Oclacitinib also provided temporary relief in a case of inherited sensory and autonomic neuropathy, heritable neuropathy,54 and idiopathic rhinitis.55 These reports are few in number and the information is limited by the format of abstracts presented at meetings. Collectively, in these case reports, dogs were treated with 0.4 to 1 mg/kg twice daily for at least 2 weeks followed by either long-term twice-daily administration or a reduction to once-daily administration. Topical 0.1% oclacitinib has been used to treat canine keratoconjunctivitis sicca (KCS), and its efficacy has been compared to that of 0.1% topical tacrolimus.56 Topical 0.1% oclacitinib twice daily was not effective in controlling the ocular signs of KCS in dogs, and its use is not justified.
In cats, effective control of nonallergic cutaneous inflammatory conditions with oclacitinib is limited to a publication57 of a 13-year-old cat with pemphigus foliaceus (1 mg/kg, PO, q 12 h). A 50% clinical improvement was observed after 7 days and was maintained at a dose of 0.5 mg/kg, PO, every 12 hours. Oclacitinib (1 mg/kg, PO, q 12 to 24 h) failed to control urticaria-pigmentosa-like mastocytic dermatitis in a 14-month-old cat.58
Oclacitinib for Neoplastic Conditions
The use of oclacitinib in dogs diagnosed with neoplastic conditions is highly debated. Oclacitinib primarily inhibits JAK1-dependent cytokine receptor complexes involved in allergic inflammation; however, it has less effect on JAK2, JAK3, and TYK2.1 Indeed, retrospective analysis of the long-term use of oclacitinib in atopic dogs reveals no increased risk for neoplasia development.21 More recently, treatment of a single case of canine cutaneous epitheliotropic T-cell lymphoma with oclacitinib (0.7 mg/kg, q 12 h) resulted in partial remission for 3 months with marked histological cytoreduction of neoplastic cells.59 The authors reported that the dose was well-tolerated and posed fewer potential adverse effects than traditional chemotherapy protocols, although the dog did not achieve complete remission.
Aberrant JAK/signal transducer and activator of transcription (STAT) signaling within hematologic and solid tumors has been implicated as a driver of tumor growth. One study60 evaluated oclacitinib coadministration with other chemotherapeutics (4 dogs received carboplatin and 5 received doxorubicin). Tumors treated included recurrent anal sac adenocarcinoma, oral malignant melanoma with pulmonary metastasis, distal radial osteosarcoma without metastasis, and oral malignant melanoma for the carboplatin group and pulmonary metastasis from appendicular osteosarcoma and 1 dog with recurrent abdominal myxosarcoma for the doxorubicin group. No unexpected toxicities occurred, and the incidence of adverse events with combination therapy was not increased. The authors concluded that oclacitinib was well tolerated when given in combination with carboplatin or doxorubicin but had no observable effect on tumor inhibition.
Additional investigation into oclacitinib’s antitumor effects is warranted since constitution activation of JAK/STAT pathway leads to increased tumor proliferation, survival, invasion, and metastasis.61 JAK1/2 inhibitors that have been used in clinical trials for treating various hematologic cancers in humans and in vitro experiments have shown that JAK1/2 inhibitors can successfully inhibit canine lymphoma cell growth in vitro in a dose-dependent manner.62 The antitumor properties of oclacitinib are not known at this time and are worth investigating.
Use in Nondomestic Animals
Oclacitinib has been administered to treat pruritus to 3 captive Andean bears (Tremarctos ornatus) diagnosed with alopecia syndrome with a rapid response at 0.5 mg/kg twice daily initially and then tapered to 0.2 to 0.4 mg/kg once daily as maintenance.63
Where Do We Go From Here?
The last 10 years have allowed us to accumulate a lot of experience with oclacitinib, and we continuously explore new uses and discover its usefulness for a variety of diseases ranging from inflammatory to immune mediated. We have learned about the safety, efficacy, and speed of action of oclacitinib compared to glucocorticoids. Instinctively we had assumed that injectable glucocorticoids would be faster than an oral medication, but the current evidence proves the opposite.
A topic of debate is whether oclacitinib has clinically appreciable anti-inflammatory properties and how they would compare to glucocorticoids. While initially oclacitinib was considered a quick drug to stop itch, we now realize how blocking the signaling of so many cytokines involved in allergic inflammation affects a cascade of events that affect inflammation and not just pruritus. Yet, no study has specifically addressed this topic in a controlled fashion. Another question is whether oclacitinib could be of help for stenotic ear canals in allergic patients, a presentation for which the majority of dermatologists rely on glucocorticoids to decrease the swelling and inflammation. Proper studies are needed to address both of these questions. Topical formulations could also be of interest in the future, not only for ocular diseases but possibly also for ear disease and localized conditions like pododermatitis.
We have learned how to best educate owners and fellow clinicians to increase their comfort level with the use of this medication. Education on the different types of JAK inhibitors is particularly important to avoid lumping oclacitinib in the same group as JAK2 inhibitors. Prompting owners to use the medication as prescribed is equally important since, with higher doses, possible unwanted effects on JAK2 may occur. As the effect of oclacitinib on the various JAKs is concentration dependent and an issue of threshold, frequency of administration besides dose is important. Most case reports on the use of oclacitinib for autoimmune cases required twice-daily administration for extended periods of time to keep the diseases into remission highlighting the ability to immunosuppress by giving the medication more frequently and selecting the high end of the approved dose. As clinicians, we need to continue to be observant to provide the best care for our patients to maximize benefits and minimize unwanted adverse effects. Oclacitinib has proven to be a great tool in our armamentarium and has opened countless opportunities for an alternative option to the use of glucocorticoids.
Acknowledgments
No external funding was used in the preparation of this manuscript.
Dr. Marsella has received honoraria for lectures from Zoetis. Dr. Gonzales is an employee of Zoetis. Dr. Doerr states no conflict. Dr. Schissler was providing diagnostic consultations for Zoetis Diagnostics at the time of writing of the manuscript and will be a full-time employee of Zoetis at the time of publication of this review. Dr. Marsella served as Guest Editor for this Journal of the American Veterinary Medical Association (JAVMA) supplemental issue. She declares that she had no role in the editorial direction of this manuscript.
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