Canine allergic dermatitis is a common chronic skin disease of companion animals,1 and effective treatments include orally administered glucocorticoids, cyclosporine, and oclacitinib and subcutaneously administered ASIT and lokivetmab.2–8 Oclacitiniba is a JAK receptor inhibitor that preferentially blocks JAK-1 receptor mediated signal transduction.9 Janus kinase enzymes (JAK-1, JAK-2, JAK-3, and tyrosine kinase 2) are intracellular protein tyrosine kinases that bind the cytoplasmic region of transmembrane cytokine receptors and mediate signaling.10,11 Activation of a pair of JAK receptors results in tyrosine phosphorylation, followed by activation of STATs, and on the basis of receptor binding, this JAK-STAT activation can contribute to cell proliferation, differentiation, migration, apoptosis, or survival.10 Oclacitinib primarily inhibits JAK-1 receptor activation by the proinflammatory and pruritogenic cytokines IL-2, IL-4, IL-6, IL-13, and IL-31 but has minimal effect on JAK-2, JAK-3, or tyrosine kinase 2 receptor activation with hematopoietic cytokines (eg, erythropoietin or granulocyte-macrophage colony-stimulating factor, IL-12, and IL-23).2,9,12,13
Cytokines IL-2 and IL-4, as well as several other cytokines, are involved in immune protection against tumor growth, specifically through JAK-STAT stimulation of NK cells and γδ T cells, which have important contributions as mediators of innate tumor immunosurveillance14–16; however, such JAK-STAT action is inhibited by oclacitinib. Several JAK receptor inhibitors, including tofacitinib and ruxolitinib, have been evaluated in human medicine, and there is clear evidence that ruxolitinib, an inhibitor of JAK-1 and JAK-2 receptors used for the treatment of human myelofibrosis, reduces the potential of cytokine-mediated activation of NK cells.17 In humans, long-term treatment with ruxolitinib has been associated with higher risk of basal cell tumors and squamous cell carcinomas with more malignant behavior.18–21 Another study22 shows that people treated with tofacitinib, an inhibitor of JAK-1 and JAK-3 receptors used for the treatment of RA, had a decrease in NK cells but this decrease was not associated with serious infections or malignancy within the first 6 months of treatment.22 Long-term studies10,22,23 of people with RA show that the risk of cancer was similar for patients treated with tofacitinib versus biological products (eg, vaccines). A study24 of mice used as a model for breast cancer in humans shows that the effect of JAK receptor inhibition on NK cells was pivotal in increasing metastasis formation; however, this primarily involved JAK-2 signaling.
Because of the mechanism of action of oclacitinib and the variability of other JAK receptor inhibitors on the development of malignancies, there is concern regarding the use of oclacitinib in dogs with neoplasia. However, to the best of our knowledge, there have been no studies evaluating the incidence of malignancies in dogs with allergic dermatitis treated long-term with oclacitinib. Therefore, the primary objective of the study reported here was to compare the cumulative incidence of malignancies and benign skin masses in age- and breed-matched dogs with allergic dermatitis treated long-term with versus without oclacitinib. Secondary objectives included comparing the age at death or euthanasia between dogs grouped on the basis of whether they were treated with versus without oclacitinib and evaluating for potential effects of oclacitinib maintenance dosage on the cumulative incidence of malignancies and skin masses.
Materials and Methods
An age- and breed-matched retrospective cohort study design was chosen to reflect clinical practice and evaluate for potential changes to cumulative incidence of malignancy in dogs treated for allergic dermatitis since the introduction of oclacitinib. Further, the use of age and breed matching helped better ensure comparable results for dogs grouped on the basis of whether their long-term treatment for allergic dermatitis was with oclacitinib (exposed group) versus without oclacitinib (nonexposed) because age and breed can be risk factors for malignancies.25–31
Four veterinary dermatology specialty clinics with 29 dermatologists and dermatology residents were included in the study. Dogs (exposed and nonexposed) were excluded from the study if they had been included in previous published studies32,33 of oclacitinib.
Animals
Exposed group—To identify dogs for the exposed group, electronic medical record softwareb was used to identify dogs with allergic dermatitis (ie, atopic dermatitis, cutaneous adverse food reaction, or flea allergic dermatitis) for which prescriptions of oclacitinib were invoiced between January 1 and December 31, 2014. This date range was selected to include dogs with adequate follow-up given that oclacitinib was made widely available to veterinary dermatologists during November 2013. Dogs were included if they received oclacitinib treatment ≥ 6 months and had follow-up examinations that spanned ≥ 24 months after initiation of oclacitinib treatment. Dogs that died or were euthanized within 24 months after initiation of oclacitinib treatment were also included, and reasons for euthanasia and causes of death were recorded when available.
Nonexposed group—To identify dogs for the nonexposed group, electronic medical records from the same 4 clinics were searched for records of dogs with the terms allergic dermatitis, hypersensitivity dermatitis, atopic dermatitis, or atopy listed as the diagnosis and with systemic treatment (eg, glucocorticoids, cyclosporine, ASIT, or antihistamines) for any allergic dermatitis between January 1, 2008, and December 31, 2011. This time frame was chosen to identify a cohort that was treated before wide availability of oclacitinib but that was also temporally close to the time frame of the exposed group so that other treatments (eg, parasite preventions, topical treatments, and antimicrobials) and diagnostic procedures (eg, abdominal ultrasonography and advanced imaging) would have been similar. In addition, use of a similarly affected cohort of client-owned dogs, rather than healthy dogs, was selected to better reflect similar disease and immune system abnormalities of the exposed group. Dogs not treated with oclacitinib were included in the nonexposed group if they had follow-up examinations that spanned ≥ 24 months after initiation of treatment. Dogs that died or were euthanized within 24 months after initiation of treatment were also included, and reasons for euthanasia and causes of death were recorded when available. The follow-up end date for dogs in the nonexposed group was July 1, 2014, to help ensure that these dogs had not received oclacitinib from their primary veterinarian without knowledge of the dermatology specialty practice.
Data collection
Detailed reviews of patient records were performed for dogs in the exposed and nonexposed groups to collect data on dog breed, age at onset of long-term treatment for allergic dermatitis, identification of malignancies or skin masses, and age at death or euthanasia. Records for dogs in the exposed group were additionally reviewed for duration and dosage of treatment with oclacitinib. For malignancies and skin masses diagnosed at outside practices and communicated back to the participating veterinary dermatology specialty clinics, attempts were made to obtain diagnostic methods and results. Each identified mass was categorized as either a malignancy, benign skin mass, or a mass that was unidentified and presumed not to have had clinical impact.
A malignancy was defined as any internal mass or skin mass that had the potential to become metastatic or that displayed aggressive local invasion. Malignant skin masses were diagnosed on the basis of histologic or cytologic findings, when available. If results of histologic examination were unavailable, results of diagnostic imaging (eg, abdominal ultrasonography, CT, MRI, or radiography) were reviewed to identify potential internal masses and invasion into surrounding tissue. In addition, skin masses were considered malignant, regardless of the type of malignancy, if client communication included euthanasia because of cancer. Internal masses identified in dogs were included among malignancies evaluated because, although some benign internal masses do not display typical malignant behavior, they have the potential to create severe complications (eg, hemoabdomen secondary to splenic hemangioma or seizures secondary to pituitary macroadenoma), and we considered these consequences severe enough to have warranted inclusion with the malignancy category.
A benign skin mass was defined as any skin mass that generally did not invade nearby tissue or spread to other parts of the body. Benign skin masses must have been confirmed with results of cytologic (fine-needle aspirate sample) or histologic (biopsy sample) examination. An unidentified mass that was presumed not to have had clinical impact was defined as a mass that the attending veterinarian noticed, suspected of being benign, and only recommended observation.
Age and breed matching
Dogs in the nonexposed group were matched on the basis of age and breed with dogs in the exposed group. For age matching between exposed and nonexposed dogs, the age at onset of long-term treatment for allergic dermatitis needed to have been within 12 months.
Statistical analysis
Data were tabulated, and statistical analyses were performed with available software.c Values of P < 0.05 were considered significant. To verify that matching created balance between the 2 groups, the mean age at onset of treatment was compared between groups with a Student t test, and breed distribution was compared between groups with the Fisher exact test. In addition, the mean age at death was compared between groups with a Student t test. Because of the cohort study design and because dogs with longer follow-up times would have had more time to potentially develop masses, both cumulative incidence (ie, the proportion of affected dogs in each group) and incidence rates (ie, the number of new cases/1,000 patient years) were calculated to quantify likelihood of malignancies or benign skin masses for dogs in the exposed versus nonexposed groups. Multiple malignancies were not considered; each dog was only counted once whether it had 1 or more malignancies. Cumulative incidence was calculated as the proportion of dogs in each group in which a mass (malignancy, benign mass, or a mass that was unidentified and presumed not to have had clinical impact) was diagnosed. For purposes of calculations, masses were considered as events. The 95% CIs were calculated by standard methods (asymptotic confidence limits on proportions). A χ2 test was used to compare cumulative incidence between groups. Incidence rates for each group were calculated by dividing the total number of dogs with masses (malignancies, benign masses, or masses that were unidentified and presumed not to have had clinical impact) by the total number of years of follow-up summed over all dogs. Poisson regression was used to compare incidence rates between groups.
Risk differences, relative risk, and incidence rate ratios, along with respective 95% CIs, were calculated with the following formulas as alternative metrics to quantify comparisons between the 2 groups for likelihoods of malignancy, lymphoma, MCT, histiocytoma, benign skin masses, and any mass (malignancy, benign, and unidentified and presumed not to have had clinical impact).
• Risk difference = (cumulative incidence in the exposed group) - (cumulative incidence in the nonexposed group).
• Relative risk = (cumulative incidence in the exposed group)/(cumulative incidence in the nonexposed group).
• Incidence rate ratio = (incidence rate in the exposed group)/(incidence rate in the nonexposed group).
Univariable logistic regressions for odds of malignancy or other categories of masses, with an independent variable of median daily maintenance dosage of oclacitinib, were used to test for a dose response of oclacitinib. On the basis of known pharmacokinetics of oclacitinib and its FDA-approved label maintenance dosage (0.4 to 0.6 mg/kg [0.18 to 0.27 mg/lb], PO, q 24 h), we considered median daily maintenance dosage as the most relevant measurement and further grouped exposed dogs according to whether their maintenance dosage of oclacitinib was below, within, or above the label dosage.
Results
Animals
Exposed group—A search of medical record databases of the 4 participating veterinary dermatology specialty clinics identified 673 dogs with allergic dermatitis for which prescriptions of oclacitinib were invoiced between January 1 and December 31, 2014, and 339 of these dogs met the inclusion criteria for the exposed group, with ≥ 6 months of oclacitinib treatment combined with ≥ 24 months of active follow-up. There were 159 (46.9%) castrated males, 151 (44.5%) spayed females, 16 (4.7%) sexually intact males, and 13 (3.8%) sexually intact females.
The earliest onset of oclacitinib treatment in the exposed group was November 5, 2013, and the earliest follow-up examination was November 20, 2013. The latest onset of oclacitinib treatment was December 30, 2014, and the latest follow-up examination was September 20, 2018. Mean and median durations of oclacitinib treatment were 35.5 and 36 months (range, 6 to 58 months), respectively, for the exposed group. The sum total follow-up duration included in the study period was 1,105.6 patient years for the exposed group.
Nonexposed group—A search of the medical record databases of the same 4 participating veterinary dermatology specialty clinics identified 11,029 dogs with hypersensitivity disorders managed without oclacitinib. Of these, there were 321 dogs with allergic dermatitis and adequate durations of follow-up that comprised the nonexposed group and were age and breed matched to dogs in the exposed group. Of these 321 dogs, 156 (48.6%) were castrated males, 143 (44.5%) were spayed females, 17 (5.3%) were sexually intact males, and 5 (1.6%) were sexually intact females.
The earliest onset of treatment in the nonexposed group was December 5, 2000, and the earliest follow-up examination was February 19, 2001. The latest onset of treatment was April 10, 2012, and the latest follow-up examination was June 26, 2014. Mean and median durations of treatment were 41 and 37 months (range, 3 to 107 months), respectively, for the nonexposed group. The sum total follow-up duration included in the study period was 1,106.5 patient years for the nonexposed group.
Age and breed matching
Of the 339 dogs in the exposed group, 321 (94.7%) were age and breed matched with dogs in the nonexposed group. Data pertaining to the remaining 18 unmatched dogs in the exposed group were included in statistical analyses. The mean age did not differ significantly (P = 0.658) for dogs in the exposed (6.7 years) versus nonexposed (6.6 years) groups.
There were 104 dog breeds and predominant-breed crosses reported. Labrador Retrievers (n = 52; 26 in each group) and Labrador Retriever crosses (21; 11 exposed and 10 nonexposed) were most commonly reported (73/660 [11.1%]), followed by Golden Retrievers (48; 24 in each group) and Golden Retriever crosses (8; 4 in each group) as the second most common (56/660 [8.5%]), and French Bulldogs (34; 17 in each group) and French Bulldog crosses (2; 1 in each group) as the third most common (36/660 [5.5%]; Supplementary Table S1, available at avmajournals.avma.org/doi/suppl/10.2460/javma.257.5.507). Results of Fisher exact test analysis indicated that breed distribution was balanced between groups.
Masses
Overall, the cumulative incidence of masses (malignancies, benign skin masses, and masses that were unidentified and presumed not to have had clinical impact) did not differ significantly (P = 0.674) between the exposed group (56.6% [192/339]; 95% CI, 51.4% to 62.0%) and the nonexposed group (58.3% [187/321]; 95% CI, 52.9% to 63.7%). In addition, the overall incidence rate for masses did not differ significantly (P = 0.791) between the exposed group (174 new cases/1,000 patient years) and the nonexposed group (169 new cases/1,000 patient years).
Malignancies—There were several dogs in each group with multiple malignancies identified. However, multiple malignancies were not considered for statistical analysis; each dog was only counted once whether it had 1 or more malignancies. All malignancies identified were recorded (Table 1). In the exposed group, there were 67 malignancies in 56 of the 339 (16.5%) dogs, and affected dogs most commonly had MCT (n = 13), noncutaneous lymphoma (6), soft tissue sarcoma (6), intracranial tumor (5), or unspecified malignancy resulting in euthanasia (5; Table 1). In the nonexposed group, there were 50 malignancies in 41 of the 321 (12.8%) dogs, and affected dogs most commonly had MCT (n = 11), hepatic mass (4), pulmonary neoplasia (3), splenic mass (3), squamous cell carcinoma (3), or unspecified malignancy resulting in euthanasia (3). The cumulative incidence of malignancy did not differ significantly (P = 0.174) between the exposed group (16.5% [56/339]; 95% CI, 12.6% to 20.5%) and the nonexposed group (12.8% [41/321]; 95% CI, 9.1% to 16.4%). The relative risk of malignancy was 1.3 (95% CI, 0.9 to 1.9) for dogs in the exposed group versus the nonexposed group.
Types of malignancies or internal masses identified in 97 of the 660 client-owned dogs with allergic dermatitis treated ≥ 6 months with (exposed group; 56/339 [16.5%]) or without (nonexposed group; 41/321 [12.8%]) oclacitinib and with ≥ 24 months of follow-up information available.
| Malignancy or internal mass | ||
|---|---|---|
| MCT | 13 (3.8) | 11 (3.4) |
| Noncutaneous lymphoma | 6 (1.8) | 1 (0.3) |
| Soft tissue sarcoma | 6 (1.8) | 1 (0.3) |
| Unspecified malignancy leading to euthanasia | 5 (1.5) | 3 (0.9) |
| Brain tumor or meningioma | 5 (1.5) | 1 (0.3) |
| Pulmonary neoplasia (unspecified) | 3 (0.9) | 3 (0.9) |
| Spindle cell sarcoma | 3 (0.9) | 2 (0.6) |
| Apocrine gland anal sac adenocarcinoma | 2 (0.6) | 2 (0.6) |
| Liver mass | 2 (0.6) | 4 (1.3) |
| Mammary adenocarcinoma | 2 (0.6) | 1 (0.3) |
| Splenic hematoma | 2 (0.6) | – |
| Splenic mass | 2 (0.6) | 3 (0.9) |
| Squamous cell carcinoma | 2 (0.6) | 3 (0.9) |
| Abdominal mass (unspecified) | 1 (0.3) | 2 (0.6) |
| Bronchioloalveolar adenocarcinoma | 1 (0.3) | – |
| Epitheliotropic lymphoma | 1 (0.3) | 1 (0.3) |
| Gastric carcinoma | 1 (0.3) | 1 (0.3) |
| Iridociliary carcinoma | 1 (0.3) | – |
| Liposarcoma | 1 (0.3) | – |
| Lytic digit mass | 1 (0.3) | – |
| Nasal adenocarcinoma | 1 (0.3) | 1 (0.3) |
| Nerve sheath tumor | 1 (0.3) | – |
| Osteosarcoma | 1 (0.3) | 1 (0.3) |
| Pericardial mass | 1 (0.3) | – |
| Reactive histiocytosis | 1 (0.3) | – |
| Splenic hemangiosarcoma | 1 (0.3) | – |
| Transitional cell carcinoma | 1 (0.3) | 1 (0.3) |
| Testicular tumor | – | 2 (0.6) |
| Pituitary macroadenoma | – | 2 (0.6) |
| Heart base tumor | – | 1 (0.3) |
| Basal cell carcinoma | – | 2 (0.6) |
| Pancreatic tumor | – | 1 (0.3) |
The table lists all malignancies reported, including multiple malignancies identified in dogs; however, multiple malignancies were not included in statistical analysis of cumulative incidence of malignancies.
– = This type of mass was not identified in the group.
Mast cell tumor was the most commonly diagnosed malignancy in both groups. The cumulative incidence of MCT did not differ significantly (P = 0.780) between the exposed group (3.8% [13/339]; 95% CI, 1.8% to 5.9%) and the nonexposed group (3.4% [11/321]; 95% CI, 1.4% to 5.4%; Table 2). The relative risk of MCT was 1.1 (95% CI, 0.5 to 2.5) for dogs in the exposed group versus nonexposed group.
Cumulative incidences, relative risks, and incidence rates for MCT and noncutaneous lymphoma in dogs in the exposed (n = 339) and nonexposed (321) groups described in Table 1.
| Factors | MCT | P value | Noncutaneous lymphoma | P value |
|---|---|---|---|---|
| Cumulative incidence | 0.780 | 0.068 | ||
| Exposed group* | 3.8 (1.8 to 5.9) | 1.8 (0.4 to 3.2) | ||
| Nonexposed group* | 3.4 (1.4 to 5.4) | 0.3 (0.0 to 0.9) | ||
| Risk difference*† | 0.4 (−2.4 to 3.3) | 1.5 (−0.07 to 3.0) | ||
| Relative risk‡ | 1.1 (0.5 to 2.5) | 0.780 | 5.7 (0.7 to 46.9) | 0.068 |
| Incidence rate§ | ||||
| Exposed group | 12/1,000 | 5/1,000 | ||
| Nonexposed group | 10/1,000 | 1/1,000 | ||
| Incidence rate ratio|| | 1.2 (0.5 to 2.6) | 0.682 | 6.0 (0.7 to 49.9) | 0.097 |
Data in parentheses represent 95% CIs for the indicated estimate.
Data reported as percentages.
Risk difference = (cumulative incidence in the exposed group) - (cumulative incidence in the nonexposed group).
Relative risk = (cumulative incidence in the exposed group)/(cumulative incidence in the nonexposed group).
Data reported as new cases/1,000 patient years.
Incidence rate ratio = (incidence rate in the exposed group)/(incidence rate in the nonexposed group).
The histologic grade34,35 of MCT was available for 8 of the 13 affected dogs in the exposed group (2 with low grade, 5 with grade II, and 1 with grade III) and 6 of the 11 affected dogs in the nonexposed group (3 with grade I and 3 with grade II). Diagnosis of MCT was made at 1 of the 4 participating veterinary dermatology specialty clinics for all 13 affected dogs in the exposed group and for 8 of the 11 affected dogs in the nonexposed group. For the remaining 3 dogs with MCT in the nonexposed group, owners conveyed the diagnosis made elsewhere. Diagnosis of MCT was made on the basis of results from cytologic examination of fine-needle aspirate samples alone in 5 of the 13 affected dogs in the exposed group and 2 of the 11 affected dogs in the nonexposed group. Interestingly, MCT was identified in 4 of the 18 pit bull-type dogs in the exposed group and 3 of the 18 pit bull-type dogs in the nonexposed group, whereas no other breed represented had > 2 dogs with MCT diagnosed.
The cumulative incidence of noncutaneous lymphoma did not differ significantly (P = 0.068) between the exposed group (1.8% [6/339]; 95% CI, 0.4% to 3.2%) and the nonexposed group (0.3% [1/321], 95% CI, 0% to 0.9%). The relative risk for noncutaneous lymphoma was 5.7 (95% CI, 0.7 to 46.9) for the dogs in the exposed group versus the nonexposed group.
Benign skin masses—The most commonly diagnosed benign skin masses in dogs of the exposed group were lipoma (n = 20), sebaceous hyperplasia or adenoma (19), histiocytoma (19), acrochordon (10), and papilloma (8; Table 3). The most commonly diagnosed benign skin masses in dogs of the nonexposed group were lipoma (n = 35), follicular cyst (24), sebaceous hyperplasia or adenoma (23), histiocytoma (14), acrochordon (7), and hemangioma (7).
Benign skin masses identified in 180 of the 660 client-owned dogs in the exposed (79/339 [23.3%]) and nonexposed (101/321 [31.5%]) groups described in Table 1.
| Benign skin masses | No. (%) of dogs in the exposed group | No. (%) of dogs in the nonexposed group |
|---|---|---|
| Lipoma | 20 (5.9) | 35 (10.9) |
| Sebaceous hyperplasia or adenoma | 19 (5.6) | 23 (7.2) |
| Histiocytoma | 19 (5.6) | 14 (4.4) |
| Acrochordon | 10 (2.9) | 7 (2.2) |
| Papilloma | 8 (2.4) | 6 (1.9) |
| Follicular cyst | 6 (1.8) | 24 (7.5) |
| Hemangioma | 5 (1.5) | 7 (2.2) |
| Infundibular keratinizing acanthoma | 4 (1.2) | – |
| Meibomian hyperplasia or adenoma | 4 (1.2) | 2 (0.6) |
| Apocrine gland cyst | 3 (0.9) | 2 (0.6) |
| Plasmacytoma | 3 (0.9) | 4 (1.2) |
| Hamartoma | 2 (0.6) | 2 (0.6) |
| Perianal adenoma | 2 (0.6) | 3 (0.9) |
| Collagenous nevus | 1 (0.3) | – |
| Dermal melanocytoma | 1 (0.3) | 3 (0.9) |
| Inflammatory polyp | – | 1 (0.3) |
| Intracutaneous keratinizing acanthoma | 1 (0.3) | – |
| Pigmented viral plaques | 1 (0.3) | – |
| Pilomatricoma | 1 (0.3) | – |
| Polypoid keloidal fibroma | 1 (0.3) | – |
| Sebaceous epithelioma | 1 (0.3) | 3 (0.9) |
| Sebaceous nevus | 1 (0.3) | 1 (0.3) |
| Trichoblastoma | 1 (0.3) | – |
| Tricholemmoma | 1 (0.3) | 2 (0.6) |
| Apocrine gland adenoma | – | 1 (0.3) |
– = This type of skin mass was not identified in the group.
The cumulative incidence of benign skin masses was significantly (P = 0.019) lower for the exposed group (23.3% [79/339]; 95% CI, 18.8% to 27.8%) versus the nonexposed group (31.5% [101/321]; 95% CI, 26.4% to 36.5%). The relative risk of a benign skin mass was 0.7 (95% CI, 0.6 to 0.95) for dogs in the exposed group, compared with those in the nonexposed group. The incidence rate of benign skin masses did not differ significantly (P = 0.103) between the exposed group (71 new cases/1,000 patient years) and the nonexposed group (91 new cases/1,000 patient years). When only histiocytoma was considered, the cumulative incidence of histiocytoma did not differ significantly (P = 0.464) between the exposed group (5.6% [19/339]; 95% CI, 3.2% to 8.1%) and the nonexposed group (4.4% [14/321]; 95% CI, 2.1% to 6.6%), and the relative risk of histiocytoma was 1.3 (95% CI, 0.7 to 2.5) for dogs in the exposed group, compared with dogs in the nonexposed group.
Interestingly, in dogs of the nonexposed group, gingival hyperplasia was identified in 31 of the 105 (29.5%) dogs that received cyclosporine ≥ 4 months. However, oral abnormalities were beyond the scope of the study and not included in statistical analyses.
Age at death or euthanasia
For dogs that died or were euthanized, the mean age at death or euthanasia did not differ significantly (P = 0.208) between the exposed group (11.2 years; n = 81) and the nonexposed group (11.8 years; 71). However, mean age at death was 0.6 years older (95% CI, 0.3 years younger to 1.5 years older) in the nonexposed group than the exposed group.
The mean duration between onset of treatment and euthanasia or death was significantly (P = 0.002) longer for dogs in the nonexposed group (39 months; range, 4 to 110 months), compared with dogs in the exposed group (30 months; range, 6 to 56 months). However, not all dogs in the exposed group received oclacitinib for the entire study period, and the mean duration of treatment with oclacitinib was 26.2 months (range, 6 to 56 months) for dogs in the exposed group that died or were euthanized.
Maintenance dosage of oclacitinib
Overall, the median maintenance dosage of oclacitinib was 0.52 mg/kg (0.24 mg/lb), PO, every 24 hours, or divided evenly for administration every 12 hours, for the 339 dogs in the exposed group. When these dogs were further grouped on the basis of whether their maintenance dosage of oclacitinib was below, within, or above the FDA-approved maintenance dosage (0.4 to 0.6 mg/kg, PO, q 24 h), 231 of the 339 (68.1%) dogs received maintenance dosages within the FDA-approved dosage, 73 (21.5%) received higher dosages (> 0.6 mg/kg/d), and 35 (10.3%) received lower dosages (< 0.4 mg/kg/d; Table 4). Dosage of oclacitinib did not significantly affect odds of malignancy (OR = 1.2; 95% CI, 0.2 to 6.8; P = 0.831) or benign skin masses (OR = 2.1; 95% CI, 0.5 to 7.9; P = 0.288).
Numbers and percentages of dogs in the exposed group described in Table 1 with (56/339 [16.5%]) or without (283 [83.5%]) malignancy stratified by maintenance dosage of oclacitinib.
| Maintenance dosage (mg/kg/d) | No. (%) of dogs | No. (%) of dogs without malignancy | No. (%) of dogs with malignancy |
|---|---|---|---|
| < 0.4 | 35 (10.3) | 29 (82.9) | 6 (17.1) |
| 0.4-0.6 | 231 (68.1) | 195 (84.4) | 36 (15.6) |
| > 0.6 | 73 (21.5) | 59 (80.8) | 14 (l9.2) |
Discussion
We designed the present study as an age- and breed-matched retrospective cohort study to evaluate the cumulative incidence of malignancy and benign skin masses in dogs with allergic dermatitis treated with versus without oclacitinib because there has been speculation regarding the incidence of malignancies in dogs treated with the medication since it became available. We perceive that the driving force behind this speculation stems from the various effects of JAK receptor inhibitors used in human medicine. For instance, tofacitinib is an oral drug that inhibits JAK-1 and JAK-3 receptors, with lesser inhibition of JAK-2 receptors, and is used to treat people with RA, inflammatory bowel disease, transplant rejection, and psoriasis.10,13,36–42 People with RA, regardless of the treatment, have higher risk of certain malignancies (eg, leukemia, myeloma, pulmonary neoplasia, and Hodgkin and non-Hodgkin lymphoma) but lower risk of colorectal and breast cancer, compared with people without RA,10,43,44 and studies10,45 show that the standardized incidence rates of malignancies in tofacitinib-treated patients with RA were within the range expected for patients with moderate-to-severe RA. The most common malignancy reported in those patients was lung cancer. Of the 24 patients with lung cancer, 20 were current or former smokers, and lung cancer was diagnosed in 6 of those patients within 6 months after starting treatment for RA, suggesting a preexisting cancer.45 The role of exposure to secondhand smoke in veterinary patients is less clear,46–49 and in the present study, both the exposed and nonexposed groups each contained 3 dogs that developed pulmonary neoplasia. In addition, certain disease-modifying antirheumatic drugs have been associated with higher incidence of NMSC, such as basal cell carcinoma and squamous cell carcinoma; however, studies10,23,50 show that the incidence rate for NMSC in humans treated with tofacitinib is low and stable over time, with no meaningful effect of tofacitinib dosage on incidence of NMSC.10,23,50 In addition, a study51 of 527 humans with RA shows that 2 patients who received > 12 weeks treatment with high dosages of baricitinib, an inhibitor of JAK-1 and JAK-2 receptors in humans, developed NMSCs. Results for the dogs of the present study identified no association between oclacitinib dosage and odds of malignancy or masses.
In contrast, a study21 shows that the incidence of basal cell and squamous cell carcinomas was higher (17.1%) for people treated with ruxolitinib (an inhibitor of JAK-1 and JAK-2 receptors used to treat people with myelofibrosis, polycythemia vera, and essential thrombocythemia10,52), compared with the incidence (2.7%) in patients who received other best available treatments. In the present study, squamous cell carcinoma was diagnosed in 2 dogs from the exposed group and in 3 dogs from the nonexposed group, and basal cell carcinoma was diagnosed in 2 dogs from the exposed group and none from the nonexposed group. Although studies18–20 show that skin cancers in humans treated with ruxolitinib have more aggressive biological behavior and metastatic potential, biological behavior of skin cancers in dogs of the present study was not evaluated but would make for interesting further research.
On the basis of variation among JAK receptor inhibitors used in human medicine, caution should be taken when making broad conclusions regarding risk of malignancies with use of these drugs. Variations may occur owing to affinity and impact on different JAK receptors. Oclacitinib is a preferential JAK-1 receptor inhibitor, and our findings indicated that there was no meaningful difference in the cumulative incidence of malignancy for exposed versus nonexposed dogs.
Mast cell tumors are common skin tumors in dogs8,29 and were the most commonly diagnosed malignancy in a long-term safety study33 of oclacitinib in 247 client-owned dogs. Similarly, MCT was the most frequently identified malignancy for both the exposed and nonexposed groups of the present study. Several breeds and breed crosses (eg, Labrador Retriever, Golden Retriever, Boston Terriers, and pit bull-type dogs) were overrepresented in our study and have been reported to have higher incidence of MCT.27,29–31,53,54 Our findings indicated no substantial difference in MCT cumulative incidence or risk ratio for dogs in the exposed group versus the nonexposed group.
Similarly, the cumulative incidence of noncutaneous lymphoma did not meaningfully differ between the exposed group and the nonexposed group, and interestingly, no Labrador Retriever or Golden Retriever in either group had lymphoma. However, there was 1 dog in each group with cutaneous lymphoma (more often T cell in origin and worse prognosis than B-cell lymphoma55,56), which is considered a separate disease from multicentric lymphoma (more often a B-cell lymphoma).57 A previous study had suggested a relationship between atopic dermatitis and epitheliotropic lymphoma58; however, there were only 2 dogs in the present study with epitheliotropic lymphoma.
The mean duration of treatment with oclacitinib before detection of malignancy in dogs of the present study was 24 months (range, 6.0 to 53.0 months) but was 7.9 months (range, 0.6 to 21.5 months) in a previous long-term study.33 This difference could have been attributed to our inclusion criteria of dogs treated with oclacitinib ≥ 6 months, thereby excluding dogs that may have developed masses and discontinued oclacitinib before our 6-month benchmark. In both the present study and a previous study,33 large numbers of dogs had skin masses that, based on veterinarians’ visual assessment, did not necessitate further diagnostic procedures or surgical removal. However, considering the aggressive behavior of skin cancers in human patients treated with ruxolitinib, we believe it is important for veterinarians to perform routine dermatologic examinations on patients receiving long-term oclacitinib and to identify and remove any new skin masses.
Alternative treatments to oclacitinib for managing pruritus in dogs with allergic dermatitis are medications such as cyclosporine, glucocorticoids, ASIT, and lokivetmab. Cyclosporine, a calcineurin inhibitor, causes a downregulation of synthesis of numerous cytokines, including IL-2 and interferon-γ.59 However, a recent study60 shows little effect on the inhibition of IL-2 when cyclosporine was used at a low dosage (5 mg/kg [2.3 mg/lb], PO, q 24 h) indicated for atopic dermatitis. Therefore, theoretically, dogs with allergic dermatitis treated long-term with cyclosporine may have lower risk of developing neoplasia than would dogs treated with oclacitinib. Cyclosporine has been associated with cutaneous papillomatosis and gingival hyperplasia.4,59,61 Gingival hyperplasia was reported in 2.6% (3/117)62 and 2.3% (6/266)63 of dogs treated with cyclosporine for 4 months. In contrast, gingival hyperplasia was identified in 31 of the 105 (29.5%) nonexposed dogs treated with cyclosporine ≥ 4 months in the present study. The degree of severity of gingival hyperplasia in the dogs of the present study was not always indicated in the records and was not severe enough to warrant discontinuing treatment. We suspected that the higher proportion of dogs with gingival hyperplasia in the present study was because the clinicians actively looked for such changes, as suggested by notations in the medical records that included whether gingival hyperplasia was or was not present on most physical examinations.
The incidence of histiocytoma has been reportedd to be higher in older dogs with longer duration of oclacitinib treatment, compared with younger dogs with shorter duration of cyclosporine treatment. A study32 of 283 dogs shows that histiocytoma was identified in 11 of 283 (3.9%) dogs treated with oclacitinib. Similarly, in the present study, histiocytoma was identified in 19 of the 339 (5.6%) dogs in the exposed group and 14 of the 321 (4.4%) dogs in the nonexposed group, with no meaningful difference detected between the groups.
A major limitation to the present study was its retrospective nature. Necropsies were not routinely performed, and most euthanasias were done at primary care or other specialty hospitals, with the event reported back to the dermatology clinics that participated in the present study, and for several dogs in each group, clients had reported that their pets had been euthanized because of cancer, with no further details. Additionally, some malignancies, such as abdominal, thoracic, or intracranial masses, were not fully diagnosed, limiting our ability to draw full conclusions. Attempts were made to obtain records regarding diagnostic procedures performed and reasons for euthanasia from the involved veterinary hospitals; however, many attempts were unsuccessful because of the duration since their pet was euthanized or because of clients wishing to not revisit their loss. Further, many skin masses were observed, but not definitively diagnosed through cytologic or histologic evaluation. Veterinary dermatologists are trained in the evaluation of skin masses, and with their skills combined with prolonged follow-up of patients, misdiagnosis of malignant skin tumors as benign skin masses was unlikely but possible.
There were malignancies (eg, noncutaneous lymphoma, soft tissue sarcoma, and intracranial tumors) that had numerically higher counts, but were not statistically overrepresented, in the exposed group, compared with the nonexposed group. Prospective research should be aimed at further defining the patient population at risk for developing these malignancies and defining other risk factors for malignancy in dogs with allergic dermatitis treated with versus without oclacitinib. The present study did not evaluate the impact of oclacitinib on tumor behavior or patient outcome after malignancy diagnosis. Given the more aggressive behavior of squamous cell carcinoma and basal cell tumors in human patients taking ruxolitinib,18–20 future studies could evaluate this subset of tumors or other malignancies (eg, MCT and multicentric lymphoma) for behavior variation in dogs treated with oclacitinib. Although cumulative incidence of MCT did not differ between groups in the present study, further research could examine potential differences in grade, metastasis, and patient outcome between dogs receiving long-term treatment with oclacitinib, compared with other dogs.
The cumulative incidence of malignancies and the mean age at death or euthanasia in dogs with allergic dermatitis did not differ between dogs treated long-term with versus without oclacitinib. Veterinarians should continue to observe FDA-approved label warning and precaution statements for oclacitinib regarding exacerbation of existing neoplasia in dogs treated with the drug and monitor such patients for the development of neoplasia. Regular physical examinations to screen for malignancies are recommended, whether oclacitinib or any other systemic treatment is used in the management of pruritus associated with allergic skin disease in dogs.
Acknowledgments
No third-party funding or support was received in connection with the present study or the writing or publication of the manuscript.
Dr. Lancellotti has no financial or personal relationships with individuals or organizations that could inappropriately influence or bias the content of the paper.
Dr. Angus, specific to Zoetis Animal Health, has received either personal or business financial support for participation in continuing education lectures and seminars, and personally owns Zoetis Animal Health stock. In addition, he has lectured and performed research or advisory board duties for Elanco Animal Health, Boehringer Ingelheim, Vet Biotech, Ceva Animal Health, Dechra Animal Health, Bayer Animal Health, and Royal Canin Animal Nutrition.
Dr. Edginton, specific to Zoetis Animal Health, has received either personal or business financial support for participation in continuing education lectures and seminars. In addition, she has lectured for Ceva Animal Health.
Dr. Rosenkrantz, specific to Zoetis Animal Health, has previously lectured and received either personal or business financial support for participation in clinical research studies and personally owns Zoetis Animal Health and Pfizer stock. In addition, he has lectured and performed research or advisory board duties for Elanco Animal Health, Merck Animal Health, Boehringer Ingelheim, Vet Biotech, Ceva Animal Health, Dechra Animal Health, Purina Animal Nutrition, and Veterinary Allergy Reference Lab.
Presented in abstract form at the North American Veterinary Dermatology Forum, Austin, Tex, 2019.
The authors thank Deborah Keyes for statistical analysis and interpretation and Emily Estrada, Dr. Trenton Ewing, Claudia Lau, and Emily Shaw for their assistance in data collection.
ABBREVIATIONS
| ASIT | Allergy specific immunotherapy |
| IL | Interleukin |
| JAK | Janus kinase |
| MCT | Mast cell tumor |
| NK | Natural killer |
| NMSC | Nonmelanoma skin cancer |
| RA | Rheumatoid arthritis |
| STAT | Signal transducers and activators of transcription |
Footnotes
Apoquel, Zoetis Services LLC, Parsippany, NJ.
DVMax, Idexx Laboratories Inc, Westbrook, Me.
SAS, version 9.3, SAS Institute Inc, Cary, NC.
High EJ, Lam A, Ferrer L. A retrospective study comparing the incidence of cutaneous histiocytoma development in atopic dogs treated with oclacitinib and ciclosporin (abstr). Vet Dermatol 2017;28:4355.
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