History

A 3-year-old neutered male hound-mix dog was presented for treatment of ongoing pruritic ears. The patient had a history of allergies and was on oclacitinib (Apoquel), 0.5 mg/kg once daily PO, and a hydrolyzed protein diet (z/d; Hill’s Pet Nutrition Inc). Oral preventatives included milbemycin oxime (Interceptor) and fluralaner (Bravecto).

Otic cytology revealed budding yeast (AS, yeast 4+, and AD, yeast 2+), which was treated with orbifloxacin/mometasone/posaconazole suspension (Posatex) in both ears for 14 days. Since the patient was not amicable toward examinations, no recheck was recommended as long as the patient was doing well. However, the patient presented again 2 months later for the same issue. Otic cytology revealed yeast 2+ in the left ear, and the patient was sent home with miconazole/polymyxin B/prednisolone (Surolan) for the left ear for 14 days following an ear cleaning with a commercially available ear flush in the clinic. The patient presented again 3 months after the initial presentation for otitis, and otic cytology revealed yeast 4+ in the left ear, which was treated with orbifloxacin/mometasone/posaconazole suspension. Otic cytology a week later revealed yeast 2+ in the left ear, and the recommendation was to continue orbifloxacin/mometasone/posaconazole suspension for another week and recheck otic cytology. The patient presented 2 weeks later with yeast 4+ in the left ear on otic cytology. The patient had not been given oclacitinib for an unspecified time before this visit (4 months since initial presentation). The recommendation was to clean the left ear with ketoconazole/TrizEDTA (TrizUltra + Keto) flush every other day for 2 weeks and repeat ear cytology. Otitis resolved per otic cytology at the end of the 2-week period. Cleaning ears with the flush and oclacitinib was recommended to be continued for 2 more weeks, and regular ear cleaning with an over-the-counter ear cleanser was recommended. The patient was again presented a month later for recurrent otitis in the left ear (yeast 1+ to 2+). Ketoconazole/TrizEDTA ear flushes were recommended every other day until recheck in 2 to 4 weeks. Treatment with oclacitinib was recommended to be continued. At recheck, the patient had yeast 1+ in the left ear, and treatment was initiated with gentamicin/mometasone/clotrimazole (Mometamax) and oclacitinib was recommended to be continued indefinitely. Upon recheck 2 weeks later, the patient was found to have yeast 2+ in the left ear, and a decision was made to start the patient on antifungal therapy PO.

Diagnostic Findings and Interpretation

Baseline blood work (CBC, serum biochemistry, and total T4) revealed mildly elevated alkaline phosphatase levels at 172 U/L (5 to 160 U/L) and low normal albumin levels at 2.7 g/dL (2.7 to 3.9 g/dL), and glucose was 26 mg/dL (63 to 114 mg/dL) due to lack of separation of cells from serum prior to transport to the reference laboratory. Fluconazole therapy was initiated at 3.14 mg/kg once daily for 28 days, along with orbifloxacin/mometasone/posaconazole suspension in the left ear. Blood work was repeated 2 weeks later, and while alkaline phosphatase had normalized at 97 U/L (5 to 160 U/L), serum albumin levels had further declined to 2.6 g/dL (2.7 to 3.9 g/dL). Blood work at the conclusion of fluconazole treatment revealed similar serum albumin levels. Otic cytology revealed 1 budding yeast in the right ear, and orbifloxacin/mometasone/posaconazole suspension was continued in the right ear for 1 more week before concluding therapy for otitis. Oclacitinib was continued for ongoing generalized pruritus. Given the concern for progressively decreasing serum albumin levels, a urinalysis was done and revealed no protein being lost through urine. It was recommended that serum albumin levels be rechecked 3 months later.

The patient was presented 8 months and 3 weeks after initial presentation for loose stools. Fecal testing for intestinal parasites was negative for hookworm, whipworm, and roundworm antigens, and no eggs or parasites were observed on microscopic examination of the sample. The sample was, however, positive for giardia antigens, and the patient was dewormed with fenbendazole.

Serum albumin levels were rechecked in 3 months from the last blood work, and the levels had decreased to 2.3 g/dL (2.7 to 3.9 g/dL). Pre- and postprandial bile acids were normal at < 1 μmol/L (0.0 to 14.9 μmol/L) and 4.3 μmol/L (0.0 to 29.9 μmol/L), respectively. A gastrointestinal panel was submitted to Texas A&M Gastrointestinal Laboratory. Serum trypsin-like immunoreactivity was elevated at > 50 μg/L (5.7 to 45.2 μg/L); however, pancreatic lipase immunoreactivity and fasting serum folate and fasting serum cobalamin levels were within normal limits at 70 μg/L (< 200 μg/L), 10.5 μg/L (7.7 to 24.4 μg/L), and 556 ng/L (251 to 908 ng/L), respectively.

Abdominal ultrasound was unremarkable except for a few enlarged lymph nodes that were presumed to be evidence of reactive rather than infiltrative disease. Deworming was repeated with fenbendazole at 50 mg/kg once daily for 5 days. ACTH stimulation test was performed using cosyntropin, 5 µg/kg. The results were inconsistent with hypoadrenocorticism with pre-ACTH cortisol at 1.9 μg/L (2 to 6 μg/L) and post-ACTH cortisol at 7.9 μg/L (6 to 18 μg/L).

Thirteen months after initial presentation, α-1 proteinase inhibitor test was conducted with 3 stool samples, and results were within normal limits: 7.8 μg/g, 6.8 μg/g, and 6 μg/g (2.2 to 18.7 μg/g).

Given anecdotal evidence of oclacitinib causing hypoalbuminemia, it was discontinued in favor of lokivetmab (Cytopoint).

Treatment and Outcome

Oclacitinib was discontinued, and the patient was started on lokivetmab injections. Albumin levels were rechecked 1 month after discontinuation of oclacitinib, and albumin levels were increased at 2.6 g/dL (2.7 to 3.9 g/dL). Serum albumin level rechecked 4 months later was within normal limits at 2.9 g/dL (2.7 to 3.9 g/dL).

Comments

Oclacitinib was approved for use in the US in 2013 and is still the only Janus kinase inhibitor approved for use in veterinary medicine. While it is labeled for use by the FDA for management of pruritus associated with allergic and atopic dermatitis in canine patients over 12 months of age, it has a variety of off-label uses, including treatment of ischemic dermatopathy, tentatively diagnosed autoimmune subepidermal blistering dermatosis, drug-induced pemphigus vulgaris, and hyperkeratotic erythema multiforme.¹

The drug is considered to be a game changer in the management of atopic and allergic dermatitis, with the most common side effects being gastrointestinal (diarrhea and vomiting). There are reports of mild leukopenia^2,3 and occasional serum biochemistry changes with long-term administration of oclacitinib.⁴ There is a case report⁵ that acknowledges a chronological association between oclacitinib administration and hypoalbuminemia and subsequent discontinuation of oclacitinib and resolution of the hypoalbuminemia. However, to the author’s knowledge, there is no formal report of hypoalbuminemia that could be correlated with oclacitinib administration.

Hypoalbuminemia can be caused by decreased production, increased loss, or redistribution of albumin. Several infectious, inflammatory, and metabolic diseases and also toxicoses can give rise to hypoalbuminemia. To the author’s knowledge, while there is anecdotal evidence of hypoalbuminemia being caused by oclacitinib, no formal report to this effect exists to date. This case report is meant to be a step in this direction. This particular report is useful in that there was exhaustive testing performed on the patient to rule out all other possible causes of hypoalbuminemia, bringing us to the only possible conclusion that this patient’s hypoalbuminemia was caused by oclacitinib, the discontinuation of which was followed by normalization of albumin levels, which continued to be normal months after discontinuation of the drug.

Disclosures

The author has nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The author has nothing to disclose.